**Acknowledgement**

We would like to thank Dr. Michael Hendry and Dr. Janet McNicholl for valuable input. Work performed at the Centers for Disease Control and Prevention was supported in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Interagency Agreement no. Y1-AI-0681-01.

### **7. References**

[10] Juompan, L.Y., et al., Analysis of the immune responses in chimpanzees infected with HIV type 1 isolates. AIDS Res Hum Retroviruses, 2008. 24: p. 573-586.

Simian-Human Immunodeficiency Viruses and Their Impact on Non-Human Primate Models for AIDS 343

[25] Kwa, S., et al., Plasmacytoid dendritic cells are recruited to the colorectum and contribute to immune activation during pathogenic SIV infection in rhesus macaques.

[26] Mandi, J.N., et al., Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nat Med, 2008. 14: p.

[27] Nigam, P., et al., Loss of IL-17–producing CD8 T Cells during late chronic stage of pathogenic simian immunodeficiency virus infection. J Immunol, 2011. 186: p. 745-753. [28] Paiardini, M., Th17 cells in natural SIV hosts. Curr Opin HIV AIDS, 2010. 5: p. 166-172. [29] Paiardini, M., et al., Low levels of SIV infection in sooty mangabey central memory CD4+ T cells are associated with limited CCR5 expression. Nat Med, 2011. 17: p. 830-

[30] Pereira, L.E., P.R. Johnson, and A.A. Ansari, Sooty mangabeys and rhesus macaques exhibit significant divergent natural killer cell responses during both acute and chronic

[31] Riddick, N.E., et al., A novel CCR5 mutation common in sooty mangabeys reveals SIVsmm infection of CCR5-null natural hosts and efficient alternative coreceptor use in

[32] Rout, N., et al., Paucity of CD4+ natural killer T (NKT) lymphocytes in sooty mangabeys is associated with lack of NKT cell depletion after SIV infection. PLos ONE, 2010. 5: p.

[33] Estes, J.D., et al., Damaged intestinal epithelial integrity linked to microbial translocation in pathogenic simian immunodeficiency virus infections. PLoS Pathog,

[34] Klatt, N.R., et al., Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation, and IL-17 production in the absence of SIV infection. Mucosal Immunol, 2010. 3(4): p. 387-98. [35] Chan, M.L., et al., Limited CD4+ T cell proliferation leads to preservation of CD4+ T cell counts in SIV-infected sooty mangabeys. Proc Biol Sci, 2010. 277: p. 3773-3781. [36] Gordon, S.N., et al., Short-lived infected cells support virus replication in sooty mangabeys naturally infected with simian immunodeficiency virus: implications for

[37] Milush, J.M., et al., Lack of clinical AIDS in SIV-infected sooty mangabeys with significant CD4+ T cell loss is associated with double-negative T cells. J Clin Invest,

[38] Keele, B.F., et al., Increased mortality and AIDS-like immunopathology in wild

[39] Ling, B., et al., Classic AIDS in a sooty mangabey after an 18-year natural infection. J

[40] Barry, A.P., et al., Depletion of CD8+ cells in sooty mangabey monkeys naturally infected with simian immunodeficiency virus reveals limited role for immune control of

virus replication in a natural host species. J Immunol, 2007. 178: p. 8002-8012.

chimpanzees infected with SIVcpz. Nature, 2009. 460: p. 515-519.

phases of SIV infection. Cell Immunol, 2008. 254: p. 10-19.

vivo. PLos Pathog, 2010. 6: p. e1001064.

AIDS pathogenesis. J Virol, 2008. 82: p. 3725-3735.

Blood, 2011. 118: p. 2763-2773.

1077-1087.

836.

e9787.

2010. 6(8): p. e1001052.

2011. 121(3): p. 1102-10.

Virol, 2004. 78: p. 8902-8908.

[25] Kwa, S., et al., Plasmacytoid dendritic cells are recruited to the colorectum and contribute to immune activation during pathogenic SIV infection in rhesus macaques. Blood, 2011. 118: p. 2763-2773.

342 Immunodeficiency

85(24): p. 13077-87.

J Virol, 2006. 80(10): p. 4858-67.

macaques. J Virol, 1998. 72: p. 9597-9611.

outcome. J Virol, 2008. 82: p. 5145-5152.

Virol, 2010. 84(12): p. 6248-53.

Virol, 2007. 81: p. 8838-8842.

879-885.

2007. 250: p. 91-104.

[10] Juompan, L.Y., et al., Analysis of the immune responses in chimpanzees infected with

[11] Apetrei, C., et al., Immunovirological analyses of chronically simian immunodeficiency virus SIVmnd-1- and SIVmnd-2-infected mandrills (*Mandrillus sphinx*). J Virol, 2011.

[12] Pandrea, I., et al., Simian immunodeficiency virus SIVagm.sab infection of Caribbean African green monkeys: a new model for the study of SIV pathogenesis in natural hosts.

[13] Estes, J.D., et al., Early resolution of acute immune activation and induction of PD-1 in SIV-Infected sooty mangabeys distinguishes nonpathogenic from pathogenic infection

[14] Jacquelin, B., et al., Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response. J Clin Invest, 2009. 119: p. 3544-3555. [15] Kaur, A., et al., Diverse host responses and outcomes following simian immunodeficiency virus SIVmac239 infection in sooty mangabeys and rhesus

[16] Li, B., et al., Nonpathogenic simian immunodeficiency virus infection of sooty mangabeys is not associated with high levels of autologous neutralizing antibodies. J

[17] Choudhary, S.K., et al., Low immune activation despite high levels of pathogenic human immunodeciency virus Type 1 results in long-term asymptomatic disease. J

[18] Diop, O.M., et al., High levels of viral replication during primary simian immunodeficiency virus SIVagm infection are rapidly and strongly controlled in

[19] Rey-Cuille, M.-A., et al., Simian immunodeficiency virus replicates to high levels in

[20] Beaumier, C.M., et al., CD4 downregulation by memory CD4+ T cells in vivo renders African green monkeys resistant to progressive SIVagm infection. Nat Med, 2009. 15: p.

[21] Diop, O.M., et al., Plasmacytoid dendritic cell dynamics and alpha interferon production during Simian immunodeficiency virus infection with a nonpathogenic

[22] Favre, D., et al., Critical loss of the balance between Th17 and T regulatory cell

[23] Jaroenpool, J., et al., Differences in the constitutive and SIV infection induced expression of Siglecs by hematopoietic cells from non-human primates. Cell Immunol,

[24] Kuhmann, S.E., et al., Frequent substitution polymorphisms in African green monkey CCR5 cluster at critical sites for infections by simian immunodeficiency virus SIVagm,

populations in pathogenic SIV infection. PLos Pathog, 2009. 5: p. e1000295.

implying ancient virus-host coevolution. J Virol, 2001. 75: p. 8449-8460.

sooty mangabeys without inducing disease. J Virol, 1998. 72: p. 3872-3886.

HIV type 1 isolates. AIDS Res Hum Retroviruses, 2008. 24: p. 573-586.

in rhesus macaques. J Immunol, 2008. 180: p. 6798-6807.

African green monkeys. J Virol, 2000. 74(16): p. 7538-47.

[41] Gaufin, T., et al., Effect of B-cell depletion on viral replication and clinical outcome of simian immunodeciency virus infection in a natural host. J Virol, 2009. 83: p. 10347- 10357.

Simian-Human Immunodeficiency Viruses and Their Impact on Non-Human Primate Models for AIDS 345

[59] Smith, M.W., et al., Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression.  Science, 1997.

[60] Ling, B., et al., SIV(mac) pathogenesis in rhesus macaques of Chinese and Indian origin compared with primary HIV infections in humans. AIDS, 2002. 16(11): p. 1489-96. [61] Maness, N.J., et al., Chinese origin rhesus macaque major histocompatibility complex class I molecules promiscuously present epitopes from SIV associated with molecules of Indian origin; implications for immunodominance and viral escape. Immunogenetics,

[62] Southwood, S., et al., Functional analysis of frequently expressed Chinese rhesus macaque MHC class I molecules Mamu-A1\*02601 and Mamu-B\*08301 reveals HLA-A2

[64] Otting, N., et al., Unparalleled complexity of the MHC class I region in rhesus

[65] Sauermann, U., Making the animal model for AIDS research more precise: the impact of major histocompatibility complex (MHC) genes on pathogenesis and disease

[66] Wambua, D., et al., SIV-infected Chinese-origin rhesus macaques express specific MHC class I alleles in either elite controllers or normal progressors. J Med Primatol, 2011.

[67] Knapp, L.A., et al., A high frequency of Mamu-A\*01 in the rhesus macaque detected by polymerase chain reaction with sequence-specific primers and direct sequencing. Tissue

[68] Pal, R., et al., ALVAC-SIV-gag-pol-env-based vaccination and macaque major histocompatibility complex class I (A\*01) delay simian immunodeficiency virus

[69] Lim, S.Y., et al., Contributions of Mamu-A\*01 status and TRIM5 allele expression, but not CCL3L copy number variation, to the control of SIVmac251 replication in Indian-

[70] Yant, L.J., et al., The high-frequency major histocompatibility complex class I allele Mamu-B\*17 is associated with control of simian immunodeficiency virus SIVmac239

[71] Du, Y., et al., Seasonal changes in the reproductive physiology of female rhesus

[72] Batten, C.J., et al., Comparative evaluation of simian, simian-human, and human immunodeficiency virus infections in the pigtail macaque (*Macaca nemestrina*) model.

macaques (*Macaca mulatta*). J Am Assoc Lab Anim Sci, 2010. 49(3): p. 289-93.

progression in SIV-infected monkeys. Curr Mol Med, 2001. 1(4): p. 515-22.

SIVmac-induced immunodeficiency. J Virol, 2002. 76(1): p. 292-302.

origin rhesus monkeys. PLoS Genet, 2010. 6(6): p. e1000997.

replication. J Virol, 2006. 80(10): p. 5074-7.

AIDS Res Hum Retroviruses, 2006. 22(6): p. 580-8.

and HLA-A3 supertypic specificities. Immunogenetics, 2011. 63(5): p. 275-90. [63] Muhl, T., et al., MHC class I alleles influence set-point viral load and survival time in simian immunodeficiency virus-infected rhesus monkeys. J Immunol, 2002. 169(6): p.

macaques. Proc Natl Acad Sci U S A, 2005. 102(5): p. 1626-31.

277(5328): p. 959-65.

2011. 63(9): p. 587-97.

3438-46.

40(4): p. 244-7.

Antigens, 1997. 50(6): p. 657-61.

[59] Smith, M.W., et al., Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression.  Science, 1997. 277(5328): p. 959-65.

344 Immunodeficiency

10357.

8991-9005.

p. 13456-68.

2005. 79: p. 14044-14056.

viruses. Virus Res, 1994. 32: p. 183-203.

virus load. Nat Med, 1996. 2: p. 1084-1089.

Microbiol Immunol, 1994. 188: p. 107-22.

Hum Retroviruses, 2011. 27: p. 1259-1269.

Infect Immun, 2002. 70: p. 869-877.

Lancet, 2004. 363: p. 619-622.

Similar HIV-1 Vaccine. J Virol, 2012. 86(4): p. 2239-50.

disadvantage. Science, 1999. 283(5408): p. 1748-52.

control of HIV-1. Science, 2007. 317(5840): p. 944-7.

[41] Gaufin, T., et al., Effect of B-cell depletion on viral replication and clinical outcome of simian immunodeciency virus infection in a natural host. J Virol, 2009. 83: p. 10347-

[42] Klatt, N.R., et al., Availability of activated CD4+ T cells dictates the level of viremia in naturally SIV-infected sooty mangabeys. J Clin Invest, 2008. 118: p. 2039-2049. [43] Locher, C.P., et al., Baboons as an animal model for human immunodeficiency virus

[44] Apetrei, C., et al., Molecular epidemiology of simian immunodeficiency virus SIVsm in U.S. primate centers unravels the origin of SIVmac and SIVstm. J. Virol., 2005. 79: p.

[45] Johnson, P.R., et al., Molecular clones of SIVsm and SIVagm: Experimental infection of

[46] Beer, B.E., et al., Immunodeficiency in the absence of high viral load in pig-tailed macaques infected with simian immunodeficiency virus SIVsun or SIVl'hoest. J Virol,

[47] Hirsch, V.M. and P.R. Johnson, Pathogenic diversity of simian immunodeficiency

[48] Karlsson, I., et al., Dynamics of T-cell responses and memory T cells during primary simian immunodeficiency virus infection in cynomolgus macaques. J Virol, 2007. 81(24):

[49] Cohen, J., Did Merck's failed HIV vaccine cause harm? Science, 2007. 318: p. 1048-1049. [50] Bolton, D.L., et al., Comparison of systemic and mucosal vaccination: impact on

[51] Marx, P.A., et al., Progesterone implants enhance SIV vaginal transmission and early

[52] Miller, C.J., Mucosal transmission of simian immunodeficiency virus. Curr Top

[53] Ma, Z.M., et al., SIVmac251 is inefficiently transmitted to rhesus macaques by penile inoculation with a single SIVenv variant found in ramp-up phase plasma. AIDS Res

[54] Qureshi, H., et al., Low-Dose Penile SIVmac251 Exposure of Rhesus Macaques Infected with Adenovirus Type 5 (Ad5) and Then Immunized with a Replication-Defective Ad5- Based SIV gag/pol/nef Vaccine Recapitulates the Results of the Phase IIb Step Trial of a

[55] Shen, Y., et al., Induction of an AIDS virus-related tuberculosis-like disease in macaques: a model of simian immunodeficiency virus- mycobacterium coinfection.

[56] Gottleib, G.S., et al., Dual HIV-1 infection associated with rapid disease progression.

[57] Carrington, M., et al., HLA and HIV-1: heterozygote advantage and B\*35-Cw\*04

[58] Fellay, J., et al., A whole-genome association study of major determinants for host

intravenous and rectal SIV challenge. Mucosal Immunol, 2012. 5: p. 41-52.

pathogenesis and vaccine development. Immunol Rev, 2001. 183: p. 127-140.

macaques and African green monkeys. J Med Primatol, 1990. 19: p. 279-286.

[73] Klatt, N.R., et al., Dynamics of simian immunodeficiency virus SIVmac239 infection in pigtail macaques. J Virol, 2012. 86(2): p. 1203-13.

Simian-Human Immunodeficiency Viruses and Their Impact on Non-Human Primate Models for AIDS 347

[90] Beer, B.E., et al., Characterization of novel simian immunodeficiency viruses from redcapped mangabeys from Nigeria (SIVrcmNG409 and -NG411). J Virol, 2001. 75(24): p.

[91] Courgnaud, V., et al., Characterization of a novel simian immunodeficiency virus from guereza colobus monkeys (*Colobus guereza*) in Cameroon: a new lineage in the

[92] Courgnaud, V., et al., Characterization of a novel simian immunodeficiency virus with a vpu gene from greater spot-nosed monkeys (*Cercopithecus nictitans*) provides new insights into simian/human immunodeficiency virus phylogeny. J Virol, 2002. 76(16): p.

[93] Hu, J., et al., Characterization and comparison of recombinant simian immunodeficiency virus from drill (*Mandrillus leucophaeus*) and mandrill (*Mandrillus*

[94] Keele, B.F., et al., Chimpanzee reservoirs of pandemic and nonpandemic HIV-1.

[95] Daniel, M.D., et al., Isolation of T-cell tropic HTLV-III-like retrovirus from macaques.

 AIDS Res

[99] Mori, K., et al., Complex determinants of macrophage tropism in env of simian

[100] Koff, W.C., et al., HIV vaccine design: insights from live attenuated SIV vaccines. Nat

[101] Haaland, R.E., et al., Inflammatory genital infections mitigate a severe genetic bottleneck in heterosexual transmission of subtype A and C HIV-1. PLoS Pathog, 2009.

[102] Salazar-Gonzalez, J.F., et al., Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection. J Exp Med,

[103] Long, E.M., et al., Gender differences in HIV-1 diversity at time of infection. Nat Med,

[104] Ritola, K., et al., Multiple V1/V2 env variants are frequently present during primary infection with human immunodeficiency virus type 1. J Virol, 2004. 78(20): p. 11208-18. [105] Sagar, M., et al., Human immunodeficiency virus type 1 (HIV-1) diversity at time of infection is not restricted to certain risk groups or specific HIV-1 subtypes. J Virol, 2004.

nonhuman primate lentivirus family. J Virol, 2001. 75(2): p. 857-66.

immunodeficiency virus. Science, 1990. 248(4959): p. 1109-12.

tropic retrovirus STLV-III. Science, 1985. 230(4721): p. 71-3.

immunodeficiency virus. J Virol, 1992. 66(4): p. 2067-75.

*sphinx*) isolates. J Virol, 2003. 77(8): p. 4867-80.

Science, 2006. 313(5786): p. 523-6.

Science, 1985. 228(4704): p. 1201-4.

Hum Retroviruses, 1992. 8(3): p. 395-402.

Immunol, 2006. 7(1): p. 19-23.

5(1): p. e1000274.

2000. 6(1): p. 71-5.

78(13): p. 7279-83.

2009. 206(6): p. 1273-89.

12014-27.

8298-309.

[90] Beer, B.E., et al., Characterization of novel simian immunodeficiency viruses from redcapped mangabeys from Nigeria (SIVrcmNG409 and -NG411). J Virol, 2001. 75(24): p. 12014-27.

346 Immunodeficiency

351-3.

[73] Klatt, N.R., et al., Dynamics of simian immunodeficiency virus SIVmac239 infection in

[74] Fernandez, C.S., et al., Screening and confirmatory testing of MHC class I alleles in pig-

[75] Moore, C., et al., Identification of the peptide-binding motif recognized by the pigtail macaque class I MHC molecule Mane-A1\*082:01 (Mane A\*0301). Immunogenetics, 2012. [76] Blakley, G.B., T.W. Beamer, and W.R. Dukelow, Characteristics of the menstrual cycle in nonhuman primates. IV. Timed mating in *Macaca nemestrina*. Lab Anim, 1981. 15(4): p.

[77] Heffron, R., et al., Use of hormonal contraceptives and risk of HIV-1 transmission: a

[78] Vishwanathan, S.A., et al., High susceptibility to repeated, low-dose, vaginal SHIV exposure late in the luteal phase of the menstrual cycle of pigtail macaques. J Acquir

[79] Kim, C.N., et al., Repetitive exposures with simian/human immunodeficiency viruses: strategy to study HIV pre-clinical interventions in non-human primates. J Med

[80] Henning, T., et al., Development of a pigtail macaque model of sexually transmitted infection/HIV coinfection using *Chlamydia trachomatis, Trichomonas vaginalis*, and

[81] Kuang, Y.Q., et al., Genotyping of TRIM5 locus in northern pig-tailed macaques (*Macaca leonina*), a primate species susceptible to Human Immunodeficiency Virus type 1

[82] Liao, C.H., et al., A novel fusion gene, TRIM5-Cyclophilin A in the pig-tailed macaque determines its susceptibility to HIV-1 infection. AIDS, 2007. 21 Suppl 8: p. S19-26. [83] Virgen, C.A., et al., Independent genesis of chimeric TRIM5-cyclophilin proteins in two

[84] Reimann, K.A., et al., Pathogenicity of simian-human immunodeficiency virus SHIV-89.6P and SIVmac is attenuated in cynomolgus macaques and associated with early T-

[85] Burwitz, B.J., et al., Mauritian cynomolgus macaques share two exceptionally common major histocompatibility complex class I alleles that restrict simian immunodeficiency

[86] Krebs, K.C., et al., Unusually high frequency MHC class I alleles in Mauritian origin

[87] Lin, P.L., et al., Quantitative comparison of active and latent tuberculosis in the

[88] Allan, J.S., et al., Species-specific diversity among simian immunodeficiency viruses

[89] Beer, B.E., et al., Patterns of genomic sequence diversity among their simian immunodeficiency viruses suggest that L'Hoest monkeys (*Cercopithecus lhoesti*) are a

pigtail macaques. J Virol, 2012. 86(2): p. 1203-13.

Immune Defic Syndr, 2011. 57(4): p. 261-4.

SHIV(SF162P3). J Med Primatol, 2011. 40(4): p. 214-23.

lymphocyte responses. J Virol, 2005. 79(14): p. 8878-85.

virus-specific CD8+ T cells. J Virol, 2009. 83(12): p. 6011-9.

cynomolgus macaques. J Immunol, 2005. 175(8): p. 5230-9.

from African green monkeys. J Virol, 1991. 65(6): p. 2816-28.

natural lentivirus reservoir. J Virol, 2000. 74(8): p. 3892-8.

cynomolgus macaque model. Infect Immun, 2009. 77(10): p. 4631-42.

primate species. Proc Natl Acad Sci U S A, 2008. 105(9): p. 3563-8.

Primatol, 2006. 35(4-5): p. 210-6.

infection. Retrovirology, 2009. 6: p. 58.

tailed macaques. Immunogenetics, 2011. 63(8): p. 511-21.

prospective cohort study. Lancet Infect Dis, 2012. 12(1): p. 19-26.

[106] Liu, J., et al., Low-dose mucosal simian immunodeficiency virus infection restricts early replication kinetics and transmitted virus variants in rhesus monkeys. J Virol, 2010. 84(19): p. 10406-12.

Simian-Human Immunodeficiency Viruses and Their Impact on Non-Human Primate Models for AIDS 349

[122] Reimann, K.A., et al., A chimeric simian/human immunodeficiency virus expressing a primary patient human immunodeficiency virus type 1 isolate env causes an AIDS-like

[124] Luciw, P.A., et al., Persistent infection of rhesus macaques with T-cell-line-tropic and macrophage-tropic clones of simian/human immunodeficiency viruses (SHIV). Proc

[125] Narayan, S.V., et al., Characterization of a neutralization-escape variant of SHIVKU-1, a virus that causes acquired immune deficiency syndrome in pig-tailed macaques.

[126] Buch, S.J., et al., Innate differences between simian-human immunodeficiency virus (SHIV)(KU-2)-infected rhesus and pig-tailed macaques in development of neurological

[127] Stephens, E.B., et al., Simian-human immunodeficiency virus-associated nephropathy

[128] Harouse, J.M., et al., Mucosal transmission of pathogenic CXCR4-utilizing SHIVSF33A

[129] Joag, S.V., et al., Animal model of mucosally transmitted human immunodeficiency virus type 1 disease: intravaginal and oral deposition of simian/human immunodeficiency virus in macaques results in systemic infection, elimination of CD4+

[130] Lu, Y., et al., Rhesus macaques that become systemically infected with pathogenic SHIV 89.6-PD after intravenous, rectal, or vaginal inoculation and fail to make an antiviral antibody response rapidly develop AIDS. J Acquir Immune Defic Syndr Hum

[131] Harouse, J.M., et al., Mucosal transmission and induction of simian AIDS by CCR5 specific simian/human immunodeficiency virus SHIVSF162P3.  Proc Natl Acad Sci U S A, 1999. 96(24): p. 14049-54.

clade C env cause AIDS in rhesus monkeys. Retrovirology, 2008. 5: p. 94.

encoding HIV clade C Env. J Virol, 2006. 80(17): p. 8729-38.

models. PLoS One, 2010. 5(7): p. e11689.

disease after in vivo passage in rhesus monkeys. J Virol, 1996. 70(10): p. 6922-8. [123] Harouse, J.M., et al., Distinct pathogenic sequela in rhesus macaques infected with

CCR5 or CXCR4 utilizing SHIVs. Science, 1999. 284(5415): p. 816-819.

in macaques. AIDS Res Hum Retroviruses, 2000. 16(13): p. 1295-306.

variants in rhesus macaques. Virology, 1998. 248(1): p. 95-107.

T cells, and AIDS. J Virol, 1997. 71(5): p. 4016-23.

Natl Acad Sci U S A, 1995. 92(16): p. 7490-4.

disease. Virology, 2002. 295(1): p. 54-62.

Virology, 1999. 256(1): p. 54-63.

Retrovirol, 1998. 19(1): p. 6-18.

1990-1995.

2003. 33(3): p. 300-7.

[122] Reimann, K.A., et al., A chimeric simian/human immunodeficiency virus expressing a primary patient human immunodeficiency virus type 1 isolate env causes an AIDS-like disease after in vivo passage in rhesus monkeys. J Virol, 1996. 70(10): p. 6922-8.

348 Immunodeficiency

2010. 84(19): p. 10406-12.

Virol, 2010. 84(14): p. 7083-95.

Pathog, 2011. 7(2): p. e1001293.

28(3): p. 97-104.

2010. 5(7): p. e11678.

2007. 12(9): p. 397-402.

10.

AIDS Res Hum Retroviruses, 2010. 26(10): p. 1115-31.

immunodeficiency virus. J Virol, 2000. 74(15): p. 7158-63.

[106] Liu, J., et al., Low-dose mucosal simian immunodeficiency virus infection restricts early replication kinetics and transmitted virus variants in rhesus monkeys. J Virol,

[107] Stone, M., et al., A limited number of simian immunodeficiency virus (SIV) env variants are transmitted to rhesus macaques vaginally inoculated with SIVmac251. J

[108] Whitney, J.B., et al., Genital tract sequestration of SIV following acute infection. PLoS

[109] Bixby, J.G., et al., Diversity of envelope genes from an uncloned stock of SIVmac251.

[110] Gicheru, M.M., et al., Neutralizing antibody responses in Africa green monkeys naturally infected with simian immunodeficiency virus (SIVagm). J Med Primatol, 1999.

[111] Glamann, J. and V.M. Hirsch, Characterization of a macaque recombinant monoclonal antibody that binds to a CD4-induced epitope and neutralizes simian

[112] Hirsch, V., et al., A molecularly cloned, pathogenic, neutralization-resistant simian

[113] Kimata, J.T., et al., Emerging cytopathic and antigenic simian immunodeficiency virus

[114] Sugimoto, C., et al., Protection of macaques with diverse MHC genotypes against a heterologous SIV by vaccination with a deglycosylated live-attenuated SIV. PLoS One,

[115] Seaman, M.S., et al., Tiered categorization of a diverse panel of HIV-1 Env pseudoviruses for assessment of neutralizing antibodies. J Virol, 2010. 84(3): p. 1439-52. [116] Siddappa, N.B., et al., Development of a tier 1 R5 clade C simian-human immunodeficiency virus as a tool to test neutralizing antibody-based

[117] Edinger, A.L., et al., Differential utilization of CCR5 by macrophage and T cell tropic simian immunodeficiency virus strains. Proc Natl Acad Sci U S A, 1997. 94(8): p. 4005-

[118] Edinger, A.L., et al., Use of GPR1, GPR15, and STRL33 as coreceptors by diverse human immunodeficiency virus type 1 and simian immunodeficiency virus envelope

[119] Arasteh, K. and H. Stocker, Tropism switch in patients infected with HIV-1 and its clinical implications for the treatment with CCR5-receptor inhibitors. Eur J Med Res,

[120] Chu, C. and P.A. Selwyn, Complications of HIV infection: a systems-based approach.

[121] Stephens, E.B., et al., Significance of macrophage tropism of SIV in the macaque model

immunodeficiency virus, SIVsmE543-3. J Virol, 1997. 71(2): p. 1608-20.

variants influence AIDS progression. Nat Med, 1999. 5(5): p. 535-41.

immunoprophylaxis. J Med Primatol, 2011. 40(2): p. 120-128.

proteins. Virology, 1998. 249(2): p. 367-78.

Am Fam Physician, 2011. 83(4): p. 395-406.

of HIV disease. J Leukoc Biol, 1997. 62(1): p. 12-9.

[137] Chen, Z., et al., Enhanced infectivity of an R5-tropic simian/human immunodeficiency virus carrying human immunodeficiency virus type 1 subtype C envelope after serial passages in pig-tailed macaques (*Macaca nemestrina*). J Virol, 2000. 74(14): p. 6501-10.

Simian-Human Immunodeficiency Viruses and Their Impact on Non-Human Primate Models for AIDS 351

[152] Otten, R.A., et al., Multiple vaginal exposures to low doses of R5 simian-human immunodeficiency virus: strategy to study HIV preclinical interventions in nonhuman

[153] Subbarao, S., et al., Direct stringency comparison of two macaque models (single-high vs. repeat-low) for mucosal HIV transmission using an identical anti-HIV

[154] Chakrabarti, L., et al., Variable course of primary simian immundeficiency virus infection in lymph nodes: relation to disease progression. J Virol, 1994. 68: p. 6634-6643. [155] Reimann, K.A., et al., Viral burden and disease progression in rhesus monkeys infected with chimeric simian-human immunodeficiency viruses. Virology, 1999. 256(1):

[156] Daniel, M.D., et al., Long-term persistent infection of macaque monkeys with the

[157] Boily, M.C., et al., Heterosexual risk of HIV-1 infection per sexual act: systematic review and meta-analysis of observational studies.    AIDS, 2000. 14(12): p. 1761-

[162] Willer, D.O., et al., Multi-low-dose mucosal simian immunodeficiency virus SIVmac239 challenge of cynomolgus macaques immunized with "hyperattenuated" SIV

[163] ten Haaft, P., et al., Comparison of early plasma RNA loads in different macaque species and the impact of different routes of exposure on SIV/SHIV infection. J Med

[164] Bimber, B.N., et al., Ultradeep pyrosequencing detects complex patterns of CD8+ Tlymphocyte escape in simian immunodeficiency virus-infected macaques. J Virol, 2009.

[165] Wiseman, R.W., et al., Simian immunodeficiency virus SIVmac239 infection of major histocompatibility complex-identical cynomolgus macaques from Mauritius. J Virol,

[166] Tsai, C.C., et al., Cyanovirin-N gel as a topical microbicide prevents rectal transmission of SHIV89.6P in macaques. AIDS Res Hum Retroviruses, 2003. 19(7): p.

chemoprophylaxis intervention. J Med Primatol, 2007. 36(4-5): p. 238-43.

simian immunodeficiency virus. J Gen Virol, 1987. 68 ( Pt 12): p. 3183-9.

Sydney in the era of HAART. AIDS, 2010. 24(6): p. 907-13.

Transm Dis, 2008. 35(11): p. 910-1.

constructs. J Virol, 2010. 84(5): p. 2304-17.

Primatol, 2001. 30(4): p. 207-14.

83(16): p. 8247-53.

2007. 81(1): p. 349-61.

535-41.

Dis, 2002. 29(1): p. 38-43.

primates. J Infect Dis, 2005. 191(2): p. 164-73.

p. 15-21.

29.

5.

[152] Otten, R.A., et al., Multiple vaginal exposures to low doses of R5 simian-human immunodeficiency virus: strategy to study HIV preclinical interventions in nonhuman primates. J Infect Dis, 2005. 191(2): p. 164-73.

350 Immunodeficiency

Hum Retrovirol, 1997. 15(1): p. 1-4.

HIV therapy. Retrovirology, 2009. 6: p. 101.

from HIV-1. Virology, 2012. 432: p. 173-183.

evasion. Science, 2006. 314(5796): p. 95.

A, 2009. 106(11): p. 4425-9.

433-43.

macaques. J Med Primatol, 2010. 39(4): p. 213-23.

protease inhibitors. Microbes Infect, 2007. 9(4): p. 475-82.

76(11): p. 5803-6.

85(2): p. 1067-76.

13553-61.

[137] Chen, Z., et al., Enhanced infectivity of an R5-tropic simian/human immunodeficiency virus carrying human immunodeficiency virus type 1 subtype C envelope after serial passages in pig-tailed macaques (*Macaca nemestrina*). J Virol, 2000. 74(14): p. 6501-10. [138] Balzarini, J., E. De Clercq, and K. Uberla, SIV/HIV-1 hybrid virus expressing the reverse transcriptase gene of HIV-1 remains sensitive to HIV-1-specific reverse transcriptase inhibitors after passage in rhesus macaques. J Acquir Immune Defic Syndr

[139] Soderberg, K., et al.,  J Virol, 2002.

[140] Ambrose, Z., et al., In vitro characterization of a simian immunodeficiency virushuman immunodeficiency virus (HIV) chimera expressing HIV type 1 reverse transcriptase to study antiviral resistance in pigtail macaques. J Virol, 2004. 78(24): p.

[141] Hofman, M.J., et al., Efavirenz therapy in rhesus macaques infected with a chimera of simian immunodeficiency virus containing reverse transcriptase from human immunodeficiency virus type 1. Antimicrob Agents Chemother, 2004. 48(9): p. 3483-90. [142] Kearney, M., et al., Genetic diversity of simian immunodeficiency virus encoding HIV-1 reverse transcriptase persists in macaques despite antiretroviral therapy. J Virol, 2011.

[143] Shao, W., et al., RT-SHIV subpopulation dynamics in infected macaques during anti-

[144] Smith, J.M., et al., Generation of a dual RT Env SHIV that is infectious in rhesus

[145] Pal, R., et al., Virological and molecular characterization of a simian human immunodeficiency virus (SHIV) encoding the envelope and reverse transcriptase genes

[146] Ishimatsu, M., et al., Construction of a novel SHIV having an HIV-1-derived protease gene and its infection to rhesus macaques: a useful tool for in vivo efficacy tests of

[147] Hatziioannou, T., et al., A macaque model of HIV-1 infection. Proc Natl Acad Sci U S

[148] Hatziioannou, T., et al., Generation of simian-tropic HIV-1 by restriction factor

[149] Humes, D. and J. Overbaugh, Adaptation of subtype a human immunodeficiency virus type 1 envelope to pig-tailed macaque cells. J Virol, 2011. 85(9): p. 4409-20. [150] Sanders-Beer, B., et al., Depo-Provera does not alter disease progression in SIVmacinfected female Chinese rhesus macaques. AIDS Res Hum Retroviruses, 2010. 26(4): p.

[151] Kersh, E.N., et al., Repeated rectal SHIVSF162P3 exposures do not consistently induce sustained T cell responses prior to systemic infection in the repeat-low dose preclinical

macaque model. AIDS Res Hum Retroviruses, 2009. 25(9): p. 905-17.

[167] Patton, D.L., et al., Preclinical safety assessments of UC781 anti-human immunodeficiency virus topical microbicide formulations. Antimicrob Agents Chemother, 2007. 51(5): p. 1608-15.

Simian-Human Immunodeficiency Viruses and Their Impact on Non-Human Primate Models for AIDS 353

[183] S, S., et al., Replication-defective adenovirus serotype 5 vectors elicit durable cellular and humoral immune responses in nonhuman primates. J Virol, 2005. 79: p. 6516-6522. [184] Casimiro, D.R., et al., Attenuation of simian immunodeficiency virus SIVmac239 infection by prophylactic immunization with dna and recombinant adenoviral vaccine

[185] Letvin, N.L., et al., Immune and Genetic Correlates of Vaccine Protection Against

[188] Boily, M.C., et al., The future role of rectal and vaginal microbicides to prevent HIV infection in heterosexual populations: implications for product development and

[189] Dias, A.S., et al., Animal models used for the evaluation of antiretroviral therapies.

[190] Hendrix, C.W., Y.J. Cao, and E.J. Fuchs, Topical microbicides to prevent HIV: clinical drug development challenges. Annu Rev Pharmacol Toxicol, 2009. 49: p. 349-375. [191] Van Rompay, K.K., Evaluation of antiretrovirals in animal models of HIV infection.

[192] Van Rompay, K.K., The use of nonhuman primate models of HIV infection for the evaluation of antiviral strategies. AIDS Res Hum Retroviruses, 2012. 28: p. 16-35. [193] Feldblum, P., et al., SAVVY vaginal gel (C31G) for prevention of HIV infection: a

[194] Peterson, L., et al., SAVVY (C31G) gel for prevention of HIV infection in women: a Phase 3, double-blind, randomized, placebo-controlled trial in Ghana.  Lancet, 2002.

[196] Patton, D.L., et al., Effects of multiple applications of benzalkonium chloride and nonoxynol 9 on the vaginal epithelium in the pigtailed macaque (Macaca nemestrina).

[197] Celum, C. and J.M. Baeten, Tenofovir-based pre-exposure prophylaxis for HIV

[198] Karim, Q.A., et al., Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women. Science, 2010. 329(5996): p.

[199] Karim, S.S. and Q.A. Karim, Antiretroviral prophylaxis: a defining moment in HIV

[200] Van Damme, L., Corneli, A., Ahmed, K., Agot, K., Lombaard, J., Kapiga, S., Grant, R., Kashuba, A., Crucitti, T., Taylor, D., and FEM-PrEP Study group. The FEM-PrEP Trial of Emtricitabine/Tenofovir Disoproxil Fumarate (Truvada) among African Women. in 19th Conference on Retroviruses and Opportunistic Infections. 2012. Seattle, WA, USA.

American Journal of Obstetrics and Gynecology, 1999. 180(5): p. 1080-1087.

prevention: evolving evidence. Curr Opin Infect Dis, 2012. 25(1): p. 51-7.

Mucosal Infection by SIV in Monkeys. Sci Transl Med, 2011. 3(81): p. 81ra36. [186] Plotkin, S.A., The RV144 Thai HIV vaccine trial. Hum Vaccin, 2010. 6(2): p. Epub. [187] Quinn, T.C. and J. Overbaugh, HIV/AIDS in women: an expanding epidemic. Science,

prevention. Sexually Transmitted Infections, 2011. 87(7): p. 646-653.

randomized controlled trial in Nigeria. PLos ONE, 2008. 3: p. e1474.

vectors expressing Gag. J Virol, 2005. 79(24): p. 15547-55.

2005. 308(5728): p. 1582-3.

Curr Hiv Res, 2006. 4: p. 431-436.

Antiviral Res, 2010. 85: p. 159-175.

control. Lancet, 2011. 378(9809): p. e23-5.

2: p. e1312.

1168-1174.

360(9338): p. 971-977.

[183] S, S., et al., Replication-defective adenovirus serotype 5 vectors elicit durable cellular and humoral immune responses in nonhuman primates. J Virol, 2005. 79: p. 6516-6522.

352 Immunodeficiency

Chemother, 2007. 51(5): p. 1608-15.

1989. 63(10): p. 4277-84.

Dis, 2011. 11: p. 253.

AIDS, 2006. 20(11): p. 1491-5.

6391-6400.

[167] Patton, D.L., et al., Preclinical safety assessments of UC781 anti-human immunodeficiency virus topical microbicide formulations. Antimicrob Agents

[168] Ho, O., et al., Pathogenic infection of *Macaca nemestrina* with a CCR5-tropic subtype-C

[169] Miller, C.J., et al., Genital mucosal transmission of simian immunodeficiency virus: animal model for heterosexual transmission of human immunodeficiency virus. J Virol,

[170] Miller, C.J., et al., Intravaginal inoculation of rhesus macaques with cell-free simian immunodeficiency virus results in persistent or transient viremia. J Virol, 1994. 68: p.

[171] Marthas, M.L., et al., Titration of an SIVmac251 stock by vaginal inoculation of Indian and Chinese origin rhesus macaques: transmission efficiency, viral loads, and antibody

[172] Lu, Y., et al., Vaginal transmission of chimeric simian/human immunodeficiency

[173] Auvert, B., et al., Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med, 2005. 2(11): p. e298. [174] Lissouba, P., et al., Adult male circumcision as an intervention against HIV: an operational study of uptake in a South African community (ANRS 12126). BMC Infect

[175] Mahiane, S.G., et al., Transmission probabilities of HIV and herpes simplex virus type 2, effect of male circumcision and interaction: a longitudinal study in a township of

[176] Hirbod, T., et al., Abundant expression of HIV target cells and C-type lectin receptors in the foreskin tissue of young Kenyan men. Am J Pathol, 2010. 176(6): p. 2798-805. [177]  The TRIM5 gene modulates penile mucosal acquisition of simian immunodeficiency virus in rhesus monkeys. J Virol, 2011. 85(19): p. 10389-98. [179] Qureshi, H., et al., Low-dose penile SIVmac251 exposure of rhesus macaques infected with adenovirus type 5 (Ad5) and then immunized with a replication-defective Ad5 based SIV gag/pol/nef vaccine recapitulates the results of the phase IIb step trial of a

[180] Polacino, P., et al., Protection of macaques against intrarectal infection by a combination immunization regimen with recombinant simian immunodeficiency virus

[181] Ahmad, S., et al., Reduced virus load in rhesus macaques immunized with recombinant gp160 and challenged with simian immunodeficiency virus. AIDS Res

[182] Buchbinder, S.P., et al., Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-

simian-human immunodeficiency virus. Retrovirology, 2009. 6: p. 65.

responses. AIDS Res Hum Retroviruses, 2001. 17(15): p. 1455-66.

viruses in rhesus macaques. J Virol, 1996. 70(5): p. 3045-50.

South Africa. AIDS, 2009. 23(3): p. 377-383.

similar HIV-1 vaccine. J Virol, 2012. 86: p. 2239-2250.

SIVmne gp160 vaccines. J Virol, 1999. 73(4): p. 3134-46.

Hum Retroviruses, 1994. 10(2): p. 195-204.

concept trial. Lancet, 2008. 372(9653): p. 1881-93.

[201] Veazey, R.S., et al., Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion. Nature, 2005. 438(7064): p. 99-102.

Simian-Human Immunodeficiency Viruses and Their Impact on Non-Human Primate Models for AIDS 355

SHIV Exposures in Macaques by a Topical Gel with an Integrase Inhibitor. in

[217] Bunge, K., et al., The Safety, Persistence, and Acceptability of an Antiretroviral Microbicide Candidate UC781. J Acquir Immune Defic Syndr, 2012. 60(4): p. 337-43. [218] Karim, S.S., et al., Drug concentrations after topical and oral antiretroviral preexposure prophylaxis: implications for HIV prevention in women. Lancet, 2011.

[219] Clark, M.R., et al., A hot-melt extruded intravaginal ring for the sustained delivery of the antiretroviral microbicide UC781. Journal of Pharmaceutical Sciences, 2012. 101(2):

[220] Gupta, K.M., et al., Polyurethane intravaginal ring for controlled delivery of dapivirine, a nonnucleoside reverse transcriptase inhibitor of HIV-1 (vol 97, pg 4228,

[221] Johnson, T.J., et al., Segmented polyurethane intravaginal rings for the sustained combined delivery of antiretroviral agents dapivirine and tenofovir. European Journal

[222] Malcolm, R.K., et al., Long-term, controlled release of the HIV microbicide TMC120 from silicone elastomer vaginal rings. Journal of Antimicrobial Chemotherapy, 2005.

[223] Woolfson, A.D., et al., Intravaginal ring delivery of the reverse transcriptase inhibitor TMC 120 as an HIV microbicide. International Journal of Pharmaceutics, 2006. 325(1-2):

[224] Promadej-Lanier, N., et al., Development and evaluation of a vaginal ring device for sustained delivery of HIV microbicides to non-human primates. J Med Primatol, 2009.

[225] Gunawardana, M., et al., Microbial biofilms on the surface of intravaginal rings worn in non-human primates. Journal of Medical Microbiology, 2011. 60(6): p. 828-837. [226] Srinivasan, P., Rabe, L., Ellenberger, D., Mitchell, J., Hendry, M., McNicholl, J., Malcolm, K., Kiser, P., Otten, R., Smith, J. Multi-Study Assessment of Vaginal Cytokines and Microflora in the Safety Evaluation of Intravaginal Rings in Pig-Tailed Macaques.

[227] Grant, R.M., et al., Preexposure chemoprophylaxis for HIV prevention in men who

[228] Himathongkham, S., et al., Simian-human immunodeficiency virus containing a human immunodeficiency virus type 1 subtype-E envelope gene: persistent infection, CD4(+) T-cell depletion, and mucosal membrane transmission in macaques. J Virol,

[229] Li, J., et al., Infection of cynomolgus monkeys with a chimeric HIV-1/SIVmac virus that expresses the HIV-1 envelope glycoproteins. J Acquir Immune Defic Syndr, 1992. 5(7):

[230] Morton, W.R., et al., Transmission of the simian immunodeficiency virus SIVmne in

2008). Journal of Pharmaceutical Sciences, 2009. 98(3): p. 1199-1199.

of Pharmaceutical Sciences, 2010. 39(4): p. 203-212.

in Microbicides 2010. 2010.  N Engl J Med, 2010. 363(27): p. 2587-99.

macaques and baboons. J Med Primatol, 1989. 18(3-4): p. 237-45.

Microbicides 2010. 2010. Pittsburgh, PA, USA.

378(9787): p. 279-81.

p. 576-587.

56(5): p. 954-956.

38(4): p. 263-271.

2000. 74(17): p. 7851-60.

p. 639-46.

p. 82-89.

SHIV Exposures in Macaques by a Topical Gel with an Integrase Inhibitor. in Microbicides 2010. 2010. Pittsburgh, PA, USA.

[217] Bunge, K., et al., The Safety, Persistence, and Acceptability of an Antiretroviral Microbicide Candidate UC781. J Acquir Immune Defic Syndr, 2012. 60(4): p. 337-43.

354 Immunodeficiency

2012.

e28.

S A, 2008. 105(30): p. 10531-10536.

Med Rev Ther, 2010. 2: p. a2004.

J Virol, 2012. 86(2): p. 718-25.

Retroviruses, 2011. 27(9): p. 933-943.

[201] Veazey, R.S., et al., Protection of macaques from vaginal SHIV challenge by vaginally

[202] Veazey, R.S., et al., Tropism-independent protection of macaques against vaginal transmission of three SHIVs by the HIV-1 fusion inhibitor T-1249. Proc Natl Acad Sci U

[203] Tsai, C.C., et al., Cyanovirin-N inhibits AIDS virus infections in vaginal transmission

[204] Lederman, M.M., et al., Prevention of vaginal SHIV transmission in rhesus macaques

[205] Veazey, R.S., et al., Protection of Rhesus Macaques from Vaginal Infection by Vaginally Delivered Maraviroc, an Inhibitor of HIV-1 Entry via the CCR5 Co-Receptor.

[206] Anderson, P.L. and J.E. Rower, Zidovudine and Lamivudine for HIV Infection. Clin

[207] Robbins, B.L., et al., Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2 phosphonomethoxypropyl)adenine (PMPA), bis(isopropyloxymethylcarbonyl)PMPA.

[208] Rower, J.E., et al., The effect of HIV-1 infection and sex on the cellular pharmacology of the antiretroviral drugs zidovudine and lamivudine. Antimicrob Agents Chemother,

[209] Garcia-Lerma, J.G., et al., Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Med, 2008. 5(2): p.

[210] Subbarao, S., et al., Chemoprophylaxis with tenofovir disoproxil fumarate provided partial protection against infection with simian human immunodeficiency virus in

[212] Parikh, U.M., et al., Complete protection from repeated vaginal simian-human immunodeficiency virus exposures in macaques by a topical gel containing tenofovir

[213] Dobard, C., et al., Durable protection from vaginal simian-human immunodeficiency virus infection in macaques by tenofovir gel and its relationship to drug levels in tissue.

[214] Kenney, J., et al., An Antiretroviral/Zinc Combination Gel Provides 24 Hours of Complete Protection against Vaginal SHIV Infection in Macaques. PLoS One, 2011. 6(1). [215] Stolte-Leeb, N., et al., Topical Nonnucleoside Reverse Transcriptase Inhibitor MC 1220 Partially Prevents Vaginal RT-SHIV Infection of Macaques. AIDS Res Hum

[216] Dobard, C., Sharma,S., Martin, A., Hazuda, D., Hanson, D., Smith, J., Otten, R.A., Novembre, F., Garcia-Lerma, G., Heneine, W. Protection Against Repeated Vaginal

macaques given multiple virus challenges. J Infect Dis, 2006. 194(7): p. 904-11. [211] Garcia-Lerma, J.G., et al., Intermittent prophylaxis with oral truvada protects

macaques from rectal SHIV infection. Sci Transl Med, 2010. 2(14): p. 14ra4.

alone or with emtricitabine. J Virol, 2009. 83(20): p. 10358-65.

delivered inhibitors of virus-cell fusion. Nature, 2005. 438(7064): p. 99-102.

models. AIDS Res Hum Retroviruses, 2004. 20(1): p. 11-18.

Journal of Infectious Diseases, 2010. 202(5): p. 739-744.

Antimicrob Agents Chemother, 1998. 42(3): p. 612-617.

through inhibition of CCR5. Science, 2004. 306(5695): p. 485-487.

[231] Overbaugh, J., et al., Variation in simian immunodeficiency virus env is confined to V1 and V4 during progression to simian AIDS. J Virol, 1991. 65(12): p. 7025-31.

**Chapter 16**

© 2012 Alves and Pimenta dos Reis, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is

© 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

properly cited.

females, at a rate slightly elevate in male cats.

**Feline Immunodeficiency**

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/51631

**1. Introduction**

population.

human beings.

Fabiana Alves and Jenner Karlisson Pimenta dos Reis

normal host barriers or deregulation of cellular immunity.

infections, neurologic diseases, and tumors.

Classic infectious causes of immunodeficiency in felines are the immunodeficiency by retroviruses, including feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV). Immunodeficiency caused by these infectious agents may result from disruption of

The feline immunodeficiency virus and the feline leukemia virus are detected worldwide and are among the most common infectious diseases of domestic cats, others small felids and wild cats, and causes immunodeficiency, with increased risk for opportunistic

Feline immunodeficiency virus and feline leukemia virus are retrovirus, but they differ in their potential to cause disease. FIV is classified as a *Lentivirus* and, FeLV as a *Gamaretrovirus*. The high incidence of FIV and FeLV is associated with density of cat

FIV causes immune dysfunctions in cats similar to those observed in people infected with human immunodeficiency virus (HIV). Diseases associated with FeLV and FIV may affect some organ, and may cause among other disorders, lymphoma, blood dyscrasias, alterations in the function of central nervous system, and secondary and opportunistic infections, with a significant number of opportunistic pathogens of viral, bacterial, protozoal, and fungal origin. Therefore, infected animals may play a role in transmission of various pathogens to

Risk groups for infection with FIV and FeLV are different: FIV is mainly associated with males, free access to streets and bites inflicted during fights for territory, therefore, the risk of FIV transmission is low in socially well-adapted cats, while FeLV infection is associated with social contacts and thus the FeLV infection is found almost equally between males and

and reproduction in any medium, provided the original work is properly cited.


*3.4.1. HCV induces oxidative stress that damages mitochondria*

HCV infection typically leads to generation of ROS, which interferes with the calcium signaling pathways of the cell [9]. This disruption of calcium homeostasis alters the structure of the endoplasmic reticulum, and increased calcium is taken up by the mitochondria, leading to disruption of the MMP. Recent molecular studies have shown that many other HCV proteins, such as E2 [59], and NS4B [60], are important in generating oxidative stress. In addition, the nonstructural HCV protein NS5A is an integral membrane protein that is important for viral replication, apoptosis, immune responses (such as interferon resistance), and changes in cellular calcium [61]. The proteins NS5Aand NS3 have roles in increasing calcium uptake and in the oxidation of glutathione (GSH) to glutathione disulfide (GSSG) in mitochondria, which ultimately leads to oxidative stress [61–63]. The imbalance of ROS created in the mitochondria leads to activation and translocation of NF-B and STAT3 to the nucleus, as part of disease progression. Antioxidants block the NS5A-mediated activation of NF-B and STAT3 [64]. NS4B also promotes translocation of NF-B to the nucleus in a PTK-mediated pathway. The resulting production of ROS and nitric oxide (NO) causes oxidative damage and inhibits DNA repair [60] and leads to apoptosis. ROS-mediated disruption of mitochondria is believed to be the sole cause of liver inflammation in HCV infections [9].

of the host and virus at the molecular level is needed to develop new antiviral drugs and vaccines. There is an urgent need to find more effective therapeutic agents for the treatment of viral infections. Researchers have recently started testing treatments based on RNA interference (RNAi), using either microRNA (miRNA) or small interfering RNA (siRNA). Although this approach is still in its infancy, there has been some success in silencing the viral genes

Modulation of Mitochondria During Viral Infections http://dx.doi.org/10.5772/intechopen.73036 451

RNAi is an endogenous defense that cells use as a defense against harmful nucleic acids, either generated by the cell itself or from external environment (such as a viral invasions) [75]. RNAi is successful against many virus infections, but the delivery and stability of RNAi molecules within the cell are major concerns. The stability of RNAi is affected by its charge and biochemical activity within a cell, so these two parameters must be considered when designing RNAi-based therapies. In addition, the effectiveness of RNAi-based therapies depends on the delivery route [76], target gene [77, 78], target pathogen [75, 78], and target tissue [75]. The adverse effects of using RNAi-based treatment on the environment and treatment costs must also be considered, and we must have a deeper understanding of RNAi at the molecular level. The growing interest of molecular virologists in the use of RNAi suggests that this is one of

the most exciting new therapeutic approaches for treatment of viral diseases [75].

The increased generation of ROS and reactive nitrogen species (RNS) is a key part of the pathogenesis of many virus infections. OS induces loss of the MMP, so mitochondria are become more susceptible to ROS damage. However, cells also have defenses against ROS, such as reduced glutathione (GSH),which acts as an antioxidant during the oxidative production of ATP in healthy cells [9, 79–81]. An imbalance between the generation of ROS and ROS quenching by the cell's endogenous antioxidant defense system usually leads to a disease and is common during viral invasion. In recent years, due to the unavailability of antiviral drugs, researchers have proposed a number of new strategies to protect against free radical-induced OS. These strategies may be characterized as repair and protection. Protection is achieved by enzymes and by nonenzymatic compounds, such as carotenoids, vitamin C, vitamin E, GSH, and flavonoids [82]. Recent studies have shown the importance of both classes of these mol-

Identifying the main cause of a new epidemic is the most important factor in controlling disease outbreak. Many host responses appear to contribute to the pathogenesis of viral infections, and recent cellular and molecular studies have shown that many viruses specifically target mitochondria. Several different host responses and viral proteins directly or indirectly act on the mitochondria and lead to loss of the MMP. Mitochondria play important roles in cell survival and cell death, so a better understanding how different viruses use mitochondrial responses to control cells may provide a foundation for the development of new treatments for different viral diseases. More specifically, clarification of the roles of viruses

**4.2. Host antioxidant defense system fights viral invasion**

ecules in defense against oxidative stress [9, 83–86].

**5. Concluding remarks**

responsible for virulence [73, 74].

#### *3.4.2. HCV-encoded proteins target mitochondria*

HCV remains persistent in its host because it lowers the host cell immune response. The HCV protein NS3/4A is a serine protease that inhibits interferon beta production by the retinoic acid-inducible gene I (RIG-I) pathway. Studies of the NS3/4A protein show that this protease cleaves MAVS at Cys-508, a few residues before its mitochondrial targeting domain. Cleavage of MAVS inactivates this protein because its soluble form is not functional. NS3/4A has a mitochondrial localizing signal, so it can directly cleave MAVS in the mitochondria [65, 66]. Substitution of Cys-508 with arginine prevents cleavage of MAVS. Cleavage of MAVS is thus an important mechanism by which HCV reduces host cell defenses [66].


**7. 3D printing of magnetic polymer nanocomposites for medical applications**

Magnetic nanoparticles in their pure form are rarely used for therapeutic purposes. Usually, they are encapsulated and/or placed in biologically inert matrixes (oligomers or polymers, including those of natural origin) with the view of reducing a possible toxic influence of the magnetic phase, raising its physicochemical stability and creating of the immobilization conditions on the surface of drugs capsules or matrixes. This problem is successfully solved by the AT methods [51]. The capsulation is usually conducted in ultrafine ferri-, ferro- and superparamagnetic particles, containing stabilizing reagents called "magnetic liquids" [52, 53]. Magnetic nanodots are essentially the same class of nanoparticles, that are respondent to the magnetic field influence. Such particles usually consist of magnetics, such as iron, nickel, and cobalt, and of their chemical mixtures. The increased interest to these objects is explained by their possible application in the catalysis, biomedicine, magnetic-resonance (MR) spectro‐ scopy, and data storage.

Physicochemical characteristics of the magnetic nanoparticles are strongly dependent on the method of their preparation and chemical structure. In most cases, these are particles of the size ranging from 1 up to 100 nm with the apparent superparamagnetism.

During their motion by the blood flow, the nanoparticles could become coated with the blood plasma protein, or absorbed by the immune protectors (macrophages). In order to extent the nanoparticles lifetime in the organism, the polymeric chains are fastened to the nanoparticles. Another method consists in the attachment to nanoparticles of antibodies for malignant tumorous cells since they "know" the pathway to the target (the cancer tumor). The magnetic nanoparticles behavior inside the organism is caused by the surface phenomena, size of nanoparticles and their magnetic characteristics (magnetic moment, remanent magnetism) [54]. The surface phenomena chemistry is particularly important for the elimination of the influence of reticular-endothelial system (RES) being the part of the immune system, and for the elongation of the nanoparticles lifetime within the bloodstream. The nanoparticle coating by a neutral and hydrophilic compound (i.e., polyethylene glycol (PEG), polysaccharides, etc.) enlarges the circulating time of the particle existence from minutes to hours and even days [55].

One more possible way is the reduction of the particles size. However in spite of all the efforts, the RES effect has not been completely avoided, and toxicological problems due to the undesirable displacement into other organism areas are still remaining.

Magnetic nanoparticles have found a lot of efficient applications in biomedicine that open new possibilities for therapy and diagnostics of a number of heavy diseases. Alive organisms are built of cells with a typical size of about 10 μm. And in turn, the cell components are much smaller and have the size less than 1 μm. For medical applications, it is important that nanoparticles have controllable sizes within the range of several nanometers to hundreds nanometers, which are comparable with the sizes of intracellular biological objects—(10–100 nm), viruses (20–450 nm), proteins (5–50 nm), and genes (about 2 nm in the transverse direction and 10–100 nm lengthwise). By their size (from 4 to 1000 nm) and their mass, nanoparticles are intermediate between molecules and alive cells.

This size range opens great freedom for promissory medical application of nanoparticles at the AT.

## **7.1. Magnetic hyperthermia**

**7. 3D printing of magnetic polymer nanocomposites for medical**

Magnetic nanoparticles in their pure form are rarely used for therapeutic purposes. Usually, they are encapsulated and/or placed in biologically inert matrixes (oligomers or polymers, including those of natural origin) with the view of reducing a possible toxic influence of the magnetic phase, raising its physicochemical stability and creating of the immobilization conditions on the surface of drugs capsules or matrixes. This problem is successfully solved by the AT methods [51]. The capsulation is usually conducted in ultrafine ferri-, ferro- and superparamagnetic particles, containing stabilizing reagents called "magnetic liquids" [52, 53]. Magnetic nanodots are essentially the same class of nanoparticles, that are respondent to the magnetic field influence. Such particles usually consist of magnetics, such as iron, nickel, and cobalt, and of their chemical mixtures. The increased interest to these objects is explained by their possible application in the catalysis, biomedicine, magnetic-resonance (MR) spectro‐

Physicochemical characteristics of the magnetic nanoparticles are strongly dependent on the method of their preparation and chemical structure. In most cases, these are particles of the

During their motion by the blood flow, the nanoparticles could become coated with the blood plasma protein, or absorbed by the immune protectors (macrophages). In order to extent the nanoparticles lifetime in the organism, the polymeric chains are fastened to the nanoparticles. Another method consists in the attachment to nanoparticles of antibodies for malignant tumorous cells since they "know" the pathway to the target (the cancer tumor). The magnetic nanoparticles behavior inside the organism is caused by the surface phenomena, size of nanoparticles and their magnetic characteristics (magnetic moment, remanent magnetism) [54]. The surface phenomena chemistry is particularly important for the elimination of the influence of reticular-endothelial system (RES) being the part of the immune system, and for the elongation of the nanoparticles lifetime within the bloodstream. The nanoparticle coating by a neutral and hydrophilic compound (i.e., polyethylene glycol (PEG), polysaccharides, etc.) enlarges the circulating time of the particle existence from minutes to hours and even days [55].

One more possible way is the reduction of the particles size. However in spite of all the efforts, the RES effect has not been completely avoided, and toxicological problems due to the

Magnetic nanoparticles have found a lot of efficient applications in biomedicine that open new possibilities for therapy and diagnostics of a number of heavy diseases. Alive organisms are built of cells with a typical size of about 10 μm. And in turn, the cell components are much smaller and have the size less than 1 μm. For medical applications, it is important that nanoparticles have controllable sizes within the range of several nanometers to hundreds nanometers, which are comparable with the sizes of intracellular biological objects—(10–100 nm), viruses (20–450 nm), proteins (5–50 nm), and genes (about 2 nm in the transverse direction

size ranging from 1 up to 100 nm with the apparent superparamagnetism.

undesirable displacement into other organism areas are still remaining.

**applications**

248 New Trends in 3D Printing

scopy, and data storage.

Magnetic nanoparticles can be incorporated into a bioresorbable polymer matrix so that they could reverberatory respond on the alternating external magnetic field (EMF) of a certain frequency and amplitude, and concurrently effectively absorb the EM energy and transfer it as a heating to the surrounding biological tissues. For instance, a magnetic nanoparticle can be used as hyperthermia agent heated in the applied EMF and delivering mortal doses of thermal energy to the tumors cells [56]; or as facility capable of increasing the efficiency of chemotherapy, beam and laser therapy, where magnetic nanoparticles lead to a moderate degree of heating resulting in a more efficient destruction of the malignant tissue. For the magnetic hyperthermia the particles are to possess high SAR (specific absorption rate) allowing their fast heating in the alternating magnetic field. The cancerous cells are known to be ruined under 42–43°C.

Study on the absorption rate of the EME by the magnetic liquid SAR with nanoparticles is important for the certification of fluid-magnetic hyperthermia (FMH) drugs. Along with the parameters, such as Curie point, value of saturation-specific magnetization, and toxicity, the SAR as an attribute of the magnetic liquid determines the possibility and efficiency of medical applications. For the FMH, it is necessary to develop in polymers the magnetic nanoparticle compositions, capable of releasing a dosated portion of magnetic particles. At present, superparamagnetic particles on the magnetite base have been developed, with the substitution of Fe2− by manganese and zinc, and Fe3−—by the gadolinium. At a slight decrease in the specific magnetic receptivity and specific magnetization saturation, the Curie temperature reduction from 575°C (magnetite) to 70°C was achieved. A similar problem was also solved for man‐ ganites.

The tendency to reducing the size resulted in a dominating use of superparamagnetic systems (for instance, superparamagnetic iron nano-oxides (SPIO)) without a hysteresis loop. The magnetic nanoparticles used for therapeutic purposes, can consist of ferromagnetic, ferrimag‐ netic, or superparamagnetic materials. Their main advantage is the possibility of contactless control of their displacement in the organism under the EMF. In our researches, it was shown that promissory materials are iron oxide nanoparticles with spinel structure (magnetite, maghemite) and even high-temperature superconducting ceramics (SrFe12O19) [31].

## **7.2. Radio-absorbing coatings from polymers with nano inclusions**

To protect against the EMF, radioabsorbed materials (RAM) are widely used, in particular polymer composites with ferrimagnetic or ferromagnetic nanoadditives are used as RAM. Efficient RAM should satisfy a number of requirements: maximum absorption of electromag‐ netic waves within a wide frequency range, minimum reflection and lack of harmful fumes, fire safety, small dimensions, and light weight.

Two types of RAM are distinguished: interference type, wherein the electromagnetic waves are weakened due to the destructive interference, and absorbing type in which the electro‐ magnetic energy is converted into thermal one due to scattered currents, dielectric or magnetic relaxation. Depending on the main source of relaxation, the RAM can be of dielectric or magnetodielectric types, and depending on the operating range of the absorption frequencies, there exist narrow band or wide band RAM.

As the alternative, the transparent in visual light materials (glass, polymer) can be used with embedded magnetic nanoparticles (particularly, magnetite Fe3O4 nanoparticles and hexagonal strontium ferrite SrFe12O19 nanoparticles) [11, 31]. It is known that spinel ferrites and their composites effectively absorb EMR within the frequency band of 0.8–2.0 GHz. Hexagonal ferrites intensively absorb in the range of tens of GHz. So, by combining the nanoparticles of magnetite and hexaferrites (e.g., strontium hexaferrite), it is possible to improve the RAM performance at the edges of the frequency band, i.e., at few GHz and at tens GHz, thus significantly increasing the operating range of RAM.

Earlier, we have obtained the 3D parts from polymers with nano inclusions of Fe3O4 and SrFe12O19 by the SLS/M. By the proposed method, it is possible to fulfill easy polymer coatings with nanoparticles of the above-mentioned ferrites on the surface of medical equipment thus providing its protective covering [57, 58].

#### **7.3. Magnetic nanoparticles for targeted drug delivery systems**

The targeted drug delivering (TDD) is one more promissory sphere for the medical application of magnetic nanoparticles [49]. Its main advantages are significant reducing of the drug toxic effect on other organs and systems, possibility to direct and retain the drug-containing nanoparticles in a certain place with the help of magnetic field, and to visualize them by the magnetic resonance imaging (MRI) methods. An important property of magnetic nanoparti‐ cles is a possibility of their local heating by the high-frequency magnetic field for the initiating of the drug desorption/decapsulation mechanism or for magnetic hyperthermia. Usually for the TDD, the superparamagnetic particles are used as the magnetic carrier since after the magnetic field influence they are not aggregating. However, there exists the problem of the reduction of magnetic influence power after the drug delivery, resulting in complicating of the particles retaining in close proximity from the target object, particularly under the powerful blood flow effect.

For a long time, already various one- and multicomponent liposomes generating in lipid solutions have been well known. For the practical purposes, liposomes with sizes of 20–50 nm are of interest since they are used as drug delivering systems to a biological target [59]. There is also a whole set of natural nanocarriers, for instance, viruses. Especially, processed adeno‐ viruses can effectively be used for vaccination through the skin. Other examples of biogenic nanoparticles capable of the targeted delivering are lipid nanotubes, nanoparticles and nanoemulsion of natural origin, some cyclical peptides, chitozans, and nucleic acids [60].

"Magnetic" bacteria can deliver drugs, for instance they can be used as a system for the point delivery of drugs to the diseased tissues also. The MC-1 bacteria are capable of a fast moving owing to the rotating of their own flagellums. Besides, they contain magnetic nanoparticles and are therefore sensitive to the magnetic field and are enforced to move along the lines of force. As a generator of these lines of force the MRT device, for instance, can serve.

netic waves within a wide frequency range, minimum reflection and lack of harmful fumes,

Two types of RAM are distinguished: interference type, wherein the electromagnetic waves are weakened due to the destructive interference, and absorbing type in which the electro‐ magnetic energy is converted into thermal one due to scattered currents, dielectric or magnetic relaxation. Depending on the main source of relaxation, the RAM can be of dielectric or magnetodielectric types, and depending on the operating range of the absorption frequencies,

As the alternative, the transparent in visual light materials (glass, polymer) can be used with embedded magnetic nanoparticles (particularly, magnetite Fe3O4 nanoparticles and hexagonal strontium ferrite SrFe12O19 nanoparticles) [11, 31]. It is known that spinel ferrites and their composites effectively absorb EMR within the frequency band of 0.8–2.0 GHz. Hexagonal ferrites intensively absorb in the range of tens of GHz. So, by combining the nanoparticles of magnetite and hexaferrites (e.g., strontium hexaferrite), it is possible to improve the RAM performance at the edges of the frequency band, i.e., at few GHz and at tens GHz, thus

Earlier, we have obtained the 3D parts from polymers with nano inclusions of Fe3O4 and SrFe12O19 by the SLS/M. By the proposed method, it is possible to fulfill easy polymer coatings with nanoparticles of the above-mentioned ferrites on the surface of medical equipment thus

The targeted drug delivering (TDD) is one more promissory sphere for the medical application of magnetic nanoparticles [49]. Its main advantages are significant reducing of the drug toxic effect on other organs and systems, possibility to direct and retain the drug-containing nanoparticles in a certain place with the help of magnetic field, and to visualize them by the magnetic resonance imaging (MRI) methods. An important property of magnetic nanoparti‐ cles is a possibility of their local heating by the high-frequency magnetic field for the initiating of the drug desorption/decapsulation mechanism or for magnetic hyperthermia. Usually for the TDD, the superparamagnetic particles are used as the magnetic carrier since after the magnetic field influence they are not aggregating. However, there exists the problem of the reduction of magnetic influence power after the drug delivery, resulting in complicating of the particles retaining in close proximity from the target object, particularly under the powerful

For a long time, already various one- and multicomponent liposomes generating in lipid solutions have been well known. For the practical purposes, liposomes with sizes of 20–50 nm are of interest since they are used as drug delivering systems to a biological target [59]. There is also a whole set of natural nanocarriers, for instance, viruses. Especially, processed adeno‐ viruses can effectively be used for vaccination through the skin. Other examples of biogenic nanoparticles capable of the targeted delivering are lipid nanotubes, nanoparticles and nanoemulsion of natural origin, some cyclical peptides, chitozans, and nucleic acids [60].

fire safety, small dimensions, and light weight.

250 New Trends in 3D Printing

there exist narrow band or wide band RAM.

significantly increasing the operating range of RAM.

**7.3. Magnetic nanoparticles for targeted drug delivery systems**

providing its protective covering [57, 58].

blood flow effect.

Nanospheres and nanocapsules are referred to the polymer nano objects. The nanospheres are solid matrixes with an active material spread over their polymer surfaces, while in nanocap‐ sules the polymer coatings form the cavity filled with liquid. Hence, the active material is released into the organism by different mechanisms—the release from the nanospheres is of an exponential nature, whereas from the nanocapsules it happens with a constant velocity and for a long time. Polymer nanoparticles could be received via the SLS/M process as core/shell composites. They are polysaccharides, polyglycolic acids, polylactides, polyacrylates, acrylic polymers, polyethyleneglycol (PEG), etc. Polymer materials are characterized by a whole number of useful properties for the medical transportations, such as biocompatibility, ability to be biologically decomposed, and multifunctionality.

Dendrimers are becoming of a high interest. This is a new type of polymers, having a branch‐ ing, dendrite-like structure instead of the usual linear one. Dendrimers are often mentioned in the context of their nanotechnological and medical applications. Dendrimers are a unique type of polymers since their size and shape can be superaccurately specified under the chemical synthesis that is extremely important for the TDD. Dendrimers are obtained from monomers by conducting their consequent convergent and divergent polymerization (including the use of the peptide synthesis methods), thus determining the pattern of branching.

Typical monomers used in the synthesis are polyamide-amine and amino acid—lysine. The "target" molecules are linked with dendrimers either by means of forming complexes with their surface, or by means of embedding deep between their separate chains. It is also possible to place in a stereo-specific way the necessary functional groups on the dendrimers surface so that they could interact with viruses and cells.

Carbon nanoparticles (fullerenes and nanotubes) are well known material for the TDD. Nanotubes can be used as microscopic containers introduced by the SLS/M process for the transporting of many chemical or biologically active materials: proteins, poisonous gases, fuel components, and even melted metals. For medical applications, the nanotubes possess an important increased affinity to lipid structures, they are able to form stable complexes with peptides and DNA-oligonucleotides and even encapsulate these molecules. Taken together, all these characteristics and properties provide their application as efficient drug delivering systems for vaccines and genetic material.

Promissory platform technologies are microcapsulation, technology for manufacturing of matrix, multilayered, and coated tablets and capsules. Designed and described in the literature are the platform technologies for making the nanosize complexes of active materials with biocompatible and biodegradable synthetic and natural polymers [6, 18]. The nanosize may result in the increase in a drug activity by several times and also in the reinforcement of therapeutic characteristics. Preclinical studies of known drugs in new nanopacking are already carried out (e.g., taksol or nurophene of a prolongation effect). Platform technologies for a controllable drugs release are very important for the targeted delivery of high toxic antineo‐ plastic drugs.

Traditional cancer drugs are evenly distributed by the whole organism, thus reaching both the diseased and healthy organs. This problem can be solved with the help of directed DDS (drug delivery system) when the drug is delivered along with a biodegradable polymer used as transport. In this case, the drug is released not immediately, but gradually, in the process of the polymer degradation.

There exist the target drugs delivering by nanoparticles of a genetic material, DNA or RNA. For the magnetic target influence, the drug or therapeutic radionuclide is attached to magnetic compound, which is entered into the organism, and then concentrated in the area of the target influence by means of a magnetic field (here the implanted constant magnet or the EMF could be used).

The magnetic DDS in its current state is mostly applicable to well-studied tumors, whereas the medical treatment of metastatic and/or small tumors at their early stage of development still remains an unsolved problem. The therapy of emerging tumors implies the development of a new generation of nanoparticles of teradiagnostics type, capable of recognizing small clusters of cancerous cells and delivering the elements (drugs or hyperthermia materials) required for their destruction. Teradiagnostics will ensure a permanent control of the course of treatment with a concurrent checkup of the drug delivery results and influences.

#### **7.4. Magnetic resonance imaging**

Lately, a number of directions in the molecular visualization sphere have got a wide devel‐ opment via the 3D printing. MRI is one of the most powerful noninvasive methods of visual‐ izations intensively used in clinical medicine [61]. Contrast agents based on the magnetic nanoparticles are one of the most perspective medical applications and are considered as the following MRI-agents generation. Magnetic SPIO are also actively researched as contrast agents for the MRI.  In contrast to paramagnetic ions, the SPIO nanoparticles have a higher molecular relaxation. Therefore, in case of their use under low concentration for the bloodstream checkup, they can have some advantages. The MRI yields to positron spectroscopy in its resolution but it gains in its cost. An inexpensive MRI procedure with the SPIO nanoparticles use, distinguishes tumor metastasis of approximately 1 mm size.


*Supporting open minds since 2005*

Veterinary Anatomy and Physiology http://dx.doi.org/10.5772/intechopen.73942 Edited by Catrin Sian Rutland and Valentina Kubale

Part of IntechOpen Book Series: Veterinary Medicine and Science, Volume 2 Book Series Editor: Rita Payan-Carreira

#### Contributors

Dmitrii Oleinikov, Carlos Eduardo Fonseca-Alves, Antonio Fernando Leis Filho, Ramzi Al-Agele, Catrin Rutland, Emily Paul, Valentina Kubale, Cyril Rauch, Craig Sturrock, Samir El-Gendy, Emma Cousins, Clara Bailey, James Nguhiu-Mwangi, Peter Mbithi, Meskerem Adamu, Maria De Lurdes Pinto, Diana Fernandes

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**1. Introduction**

Ferroelectric liquid crystals (FLCs) have attracted significant interest from both fundamental and practical perspectives [1, 2]. Even though liquid crystals (LCs) are liquid, some of them exhibit ferroelectricity. The response of FLCs to an applied electric field is very fast, in the range of a few tens of microseconds to a few milliseconds. The fast response of FLCs is advantageous for display applications; however, the treatment of FLCs requires sophisticated techniques because FLCs are very viscous. Displays that employ FLCs are not commercially available nowadays, due to the difficulty of fabrication into wide area displays. Recently, the photorefractive effect in FLCs was investigated, and FLCs were found to exhibit very high performance. The photorefractive effect is a phenomenon in which a dynamic hologram is

© 2015 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

formed in a material. When two laser beams interfere in a photorefractive material, a refractive index grating is formed. This phenomenon is applicable to devices related to diffraction optics, including 3D displays, optical amplification, optical tomography, novelty filters, and phaseconjugate wave generators [3]. The unique feature of the photorefractive effect is the asym‐ metric energy exchange in two-beam coupling; when two laser beams interfere in a photorefractive material, the energy of one of the interfering beams is transferred to the other beam. The asymmetric energy exchange can be used to coherently amplify signal beams [4]; therefore, it has the potential to be used as a transistor for electrical circuits in a wide range of optical technologies (Figure 1). Optically transparent materials that possess both photovoltaic and electro-optic properties also exhibit the photorefractive effect. There have been a lot of studies to develop photorefractive materials, such as inorganic photoconductive ferroelectric crystals, organic photoconductive ferroelectric crystals, organic photoconductive polymers, amorphous organic photoconductive materials, photoconductive amphiphilic compounds, and photoconductive LCs [5-8]. Since 1991, organic materials have attracted significant interest because they exhibit large photorefractivity and a shorter response time compared with that of inorganic crystals [3, 7, 8]. The photorefractive effect induces a change in the refractive index by a mechanism that involves both photovoltaic and electro-optic effects (Figure 2). An organic photorefractive material is composed of a photoconductive compound, an electro-optic compound, and an electron-trap reagent. Thus, the active wavelength can be determined by the selection of the photoconductive compound. With interfering two laser beams in an organic photorefractive material, charge generation occurs at the bright positions of the interference fringe and the generated charges diffuse within the material. The distances of the diffusions of positive and negative charges are different in an organic material because the mobilities of the positive and negative charges are different. That leads to a formation of charge-separated state. The higher mobility charge diffuses over a longer distance than the lower mobility charge. While the charges with low mobility stay in the bright areas, the charges with high mobility diffuse to the dark areas. Thus, the bright area and dark area are charged with opposite polarities, and an internal electric field (space charge field) is formed in the area between the brightest and the darkest positions. The refractive indices of the areas are changed by the electro-optic effect. In such a way, a refractive index grating is produced. A high electric field of 10–50 V/μm is typically applied to a polymer film, aside from the internal electric field, to obtain photorefractivity. The polymer material is typically 100 μm thick, so that a voltage of 1–5 kV is required to apply on the film to achieve photorefractivity, which is almost comparable to the breakdown voltage of the polymer film. This electric field is necessary for increasing the charge generation efficiency.

It is expected that a multiplex hologram display devices can be developed using photorefrac‐ tive polymers [9, 10]. It was shown that clear 3D images were recorded in the photorefractive polymer film. However, if polymer photorefractive materials are put into practical uses, a high voltage (3–5 kV) required to activate the photorefractive effect in polymer materials must be improved. There have been reports on the photorefractive effect of LCs [11]. LCs can easily be driven by a low electric field because LCs are liquid in nature. The most well-known LC phases are nematic and smectic phases (Figure 3). LCs that show nematic phase are used in liquid crystal displays (LCDs). However, LCs that show smectic phases are very viscous so that they are seldom utilized in practical applications. The LCs of which the photorefractivity was firstly investigated were nematic LCs [11]. It was found that a large photorefractivity was obtained with the application of low activation voltage (a few volts). The photorefractivity of ferroelec‐ tric liquid crystals doped with photoconductive compounds has been reported [12-14]. FLCs are considered to be candidates for practical photorefractive materials. A sub-millisecond refractive index grating formation time and a large gain coefficient are easily obtained in photorefractive FLCs.

**Figure 1.** Transistor in electric circuit and photorefractive amplifier.

formed in a material. When two laser beams interfere in a photorefractive material, a refractive index grating is formed. This phenomenon is applicable to devices related to diffraction optics, including 3D displays, optical amplification, optical tomography, novelty filters, and phaseconjugate wave generators [3]. The unique feature of the photorefractive effect is the asym‐ metric energy exchange in two-beam coupling; when two laser beams interfere in a photorefractive material, the energy of one of the interfering beams is transferred to the other beam. The asymmetric energy exchange can be used to coherently amplify signal beams [4]; therefore, it has the potential to be used as a transistor for electrical circuits in a wide range of optical technologies (Figure 1). Optically transparent materials that possess both photovoltaic and electro-optic properties also exhibit the photorefractive effect. There have been a lot of studies to develop photorefractive materials, such as inorganic photoconductive ferroelectric crystals, organic photoconductive ferroelectric crystals, organic photoconductive polymers, amorphous organic photoconductive materials, photoconductive amphiphilic compounds, and photoconductive LCs [5-8]. Since 1991, organic materials have attracted significant interest because they exhibit large photorefractivity and a shorter response time compared with that of inorganic crystals [3, 7, 8]. The photorefractive effect induces a change in the refractive index by a mechanism that involves both photovoltaic and electro-optic effects (Figure 2). An organic photorefractive material is composed of a photoconductive compound, an electro-optic compound, and an electron-trap reagent. Thus, the active wavelength can be determined by the selection of the photoconductive compound. With interfering two laser beams in an organic photorefractive material, charge generation occurs at the bright positions of the interference fringe and the generated charges diffuse within the material. The distances of the diffusions of positive and negative charges are different in an organic material because the mobilities of the positive and negative charges are different. That leads to a formation of charge-separated state. The higher mobility charge diffuses over a longer distance than the lower mobility charge. While the charges with low mobility stay in the bright areas, the charges with high mobility diffuse to the dark areas. Thus, the bright area and dark area are charged with opposite polarities, and an internal electric field (space charge field) is formed in the area between the brightest and the darkest positions. The refractive indices of the areas are changed by the electro-optic effect. In such a way, a refractive index grating is produced. A high electric field of 10–50 V/μm is typically applied to a polymer film, aside from the internal electric field, to obtain photorefractivity. The polymer material is typically 100 μm thick, so that a voltage of 1–5 kV is required to apply on the film to achieve photorefractivity, which is almost comparable to the breakdown voltage of the polymer film. This electric field is necessary for increasing the

It is expected that a multiplex hologram display devices can be developed using photorefrac‐ tive polymers [9, 10]. It was shown that clear 3D images were recorded in the photorefractive polymer film. However, if polymer photorefractive materials are put into practical uses, a high voltage (3–5 kV) required to activate the photorefractive effect in polymer materials must be improved. There have been reports on the photorefractive effect of LCs [11]. LCs can easily be driven by a low electric field because LCs are liquid in nature. The most well-known LC phases are nematic and smectic phases (Figure 3). LCs that show nematic phase are used in liquid crystal displays (LCDs). However, LCs that show smectic phases are very viscous so that they are seldom utilized in practical applications. The LCs of which the photorefractivity was firstly investigated were nematic LCs [11]. It was found that a large photorefractivity was obtained

charge generation efficiency.

126 Ferroelectric Materials – Synthesis and Characterization

**Figure 3.** Structures of the nematic and smectic phases.


**3. The AnnAGNPS model**

AnnAGNPS is a distributed parameter, physically based, continuous simulation, daily time step model, developed initially in 1998 through a partnering project between the USDA Ag‐ ricultural Research Service (ARS) and the Natural Resources Conservation Service (NRCS). The model simulates runoff, sediment, nutrients and pesticides leaving the land surface and shallow subsurface and transported through the channel system to the watershed outlet, with output available on an event, monthly and annual scale. Required inputs for model im‐ plementation include climate data, watershed physical information, as well as crop and oth‐ er land uses as well as irrigation management data.

Because of the continuous nature of AnnAGNPS, climate information, which includes daily precipitation, maximum and minimum temperatures, dew point temperatures, sky cover and wind speed, is necessary to take into account temporal weather variations. The spatial variability of soils, land use, topography and climatic conditions can be accounted for by di‐ viding the watershed into user-specified homogeneous drainage areas. The basic compo‐ nents of the model include hydrology, sedimentation and chemical transport.

The SCS curve number technique (USDA-SCS, 1972) is used within the AnnAGNPS hydro‐ logic submodel to determine the surface runoff on the basis of a continuous soil moisture balance. AnnAGNPS only requires initial values of curve number (CN) for antecedent mois‐ ture condition AMC-II, because the model updates the hydrologic soil conditions on the ba‐ sis of the daily soil moisture balance and according to the crop cycle.

**4.1. Cannata watershed**

*4.1.1. Geomorphological information*

The watershed covers about 1.3 km2

**Figure 1.** View of the Cannata watershed in proximity of its outlet.

ment were reported previously (Licciardello and Zimbone, 2002).

0.2 to 17.6 mm h-1.

The Cannata watershed, located in eastern Sicily, southern Italy (outlet coordinates 37 53'N, 14 46'E), is a mountainous tributary, ephemeral in flow, of the Flascio River (Figure 1).

Prediction of Surface Runoff and Soil Erosion at Watershed Scale: Analysis of the AnnAGNPS Model

an average land slope of 21%. The longest channel pathway is about 2.4 km, with an average

In a survey conducted at the start of experimental campaign, five different soil textures (clay, loam, loam-clay, loam-sand and loam-sand-clay) were recognized on 57 topsoil samples; clay-loam (USDA classification) resulted as the dominant texture. The soil satu‐ rated hydraulic conductivity, measured by a Guelph permeameter, resulted in the range

Continuous monitoring of land use has highlighted the prevalence of pasture areas (ranging between 87% and 92% of the watershed area) with different vegetation complexes (up to 15 species) and ground covers. Four soil cover situations can be distinguished: a high-density herbaceous vegetation (eventually subjected to tillage operations), a medium-density herba‐ ceous vegetation, sparse shrubs and cultivated winter wheat with a wheat-fallow rotation. More detailed information about the watershed characteristics and the monitoring equip‐

slope of about 12% (Figure 2). The Kirpich concentration time is 0.29 h.

between 903 m and 1270 m above mean sea level with

http://dx.doi.org/10.5772/50427

7

The peak flow is determined using the extended TR-55 method (Cronshey and Theurer, 1998). This method is a modification of the original NCRS-TR-55 technology (USDA-NRCS, 1986), which is considered as a robust empirical approach suitable for wide varie‐ ty of conditions including those where input data might be limited as in the experimental watershed (Polyakov et al., 2007).

The AnnAGNPS erosion component simulates storm events on a daily basis for sheet and rill erosion based on the RUSLE method (Revised Universal Soil Loss Equation, version 1.5, Renard et al., 1997). The HUSLE (Hydrogeomorphic Universal Soil Loss Equation, Theurer and Clarke, 1991) is used to simulate the total sediment volume delivered from the field to the channel after sediment deposition.

The sediment routing component simulates sheet and rill sediment deposition in five parti‐ cle size classes (clay, silt, sand and small and large aggregates) on the basis of density and fall velocity of the particles and then routes sediment separately through the channel net‐ work to the watershed outlet as a function of sediment transport capacity (calculated by the Bagnold equation; Bagnold, 1966). A key assumption is that the aggregates break up into their primary particles once they enter the stream channel.

For the chemical component of the model, dissolved and adsorbed sediment predictions are assessed for each cell by a mass balance approach. Algorithms for nutrient (nitrogen, phos‐ phorous and organic carbon) and pesticide dynamics are largely similar to the EPIC (Wil‐ liams et al., 1984) and GLEAMS (Leonard et al., 1987) models.

More details on the theoretical background of AnnAGNPS are reported by Bingner and Theurer (2005).