According to the rheostat model of NK education, the strength of the inhibitory input received by NK cells determines the threshold of activation that is set in each NK cell. The higher the inhibitory input, the more likely the NK cell will pass the threshold required to respond to stimuli with an increased frequency of effector cells and an increased number of effector functions (Brodin, Karre, and Hoglund 2009). During development, NK cells must acquire sufficient inhibitory signals to prevent autoreactivity through recognition of ligands for inhibitory NK receptors (Valiante et al. 1997; Hoglund et al. 1997). The larger the contribution of given receptor-ligand pairing to NK cell inhibition under homeostatic conditions the more potent a missing self response will be when the ligand is lost. This situation would be encountered in a setting of HIV infection where HIV encoded Nef downmodulates HLA-A and B molecules from the cells surface abrogating inhibitory

In this report we have focused on comparisons of the tri-functional subset of NK cells. This was done because the percent contribution of this subset to the entire K562 stimulated response was the only functional subset that differed between carriers *3DL1+B\*27* and a KIR/HLA receptor-ligand combination unable to signal through 3DL1 NK receptors. NK cells able elicit 3 functions are more potent in terms of the intensity of each of their functions than corresponding mono-functional NK cells (Kamya et al. 2011). This is similar to what has been reported for poly- versus mono-functional CD8+ T cells (Darrah et al. 2007; Betts et al. 2006) Poly-functional HIV-specific CD8+ T cells in SPs may play a role in superior anti-HIV activity (Betts et al. 2006; Makedonas and Betts 2011)*.* This is still a controversial area as the low VL seen in SPs may preserve multi-functional HIV-specific immune response. Although the biological relevance of poly-functional antigen specific CD8+ T cells in HIV infection is not yet clear, they do serve as an indicator of an effective response to HIV. Our experiments did not directly test the anti-viral activity of NK cells since we did not use HIV infected cells as stimuli. The role of tri-functional NK cells in inhibition of viral replication

If stimulation with HIV infected cells produces higher functionality in NK cells from *3DL1+B\*27* versus *3DL1+Bw6* carriers and tri-functional NK cells are endowed with a superior capacity to suppress viral replication it would be interesting to study the ability

signals mediated by 3DL1 receptors (Collins et al. 1998; Cohen et al. 1999).

responses to missing self. The rationale for investigating the role of B\*27 in educating NK cells for NK functional potential in HIV infected SP is that this allele is over represented among SP compared to the uninfected or HIV susceptible subjects. Among 101 SPs enrolled in the Canadian Cohort of HIV Infected SP typed to date 18 (17.8%) were B\*27 positive whereas in HIV susceptible subject enrolled in a Primary HIV Infection cohort 26 of 434 (6%) expressed this allele (p<0.001; Fisher's Exact test), an allele frequency similar to that seen in uninfected Caucasian (www.allelefrequencies.net). The frequency of individuals expressing both a *B\*27* allele and a homozygous *3DL1* genotype would be expected to be even lower. This provided the rationale for investigating this phenomenon in SPs in whom the frequency of the *KIR/HLA* genotype under investigation was higher than in uninfected subjects. We also reasoned that SPs with either controlled viremia or long term non progression would constitute a population with limited NK dysfunction due to HIV infection.

Others have reported that HIV infection dysregulates NK cell subset distribution such that there is a reduction in the frequency of the CD56+CD16+ NK subset with cytolytic activity with an associated increase the frequency of an anergic CD56-/CD16+ subset (Mavilio et al. 2005; Tarazona et al. 2002). VL seems to play a key role in this redistribution of NK cell subsets. Even though a decrease of cytotoxic NK cells is observed in SPs compared to healthy controls it is not as pronounced as that observed in viremic HIV infected progressor subjects (O'Connor et al. 2007; Barker et al. 2007). NK function may be altered by direct contact with HIV. The gp120 Envelope glycoprotein has been shown to suppress the activity, proliferation and survival of NK cells (Kottilil et al. 2006). Perturbations in the NK cell receptor repertoire have been reported in HIV infection, affecting both inhibitory and activating receptors (Kottilil et al. 2004; Mavilio et al. 2003; De Maria et al. 2003; O'Connor et al. 2007). Furthermore, HIV can escape NK cell recognition by restricting upregulation of activating NK cell receptor ligands such as NKp44L (Fausther-Bovendo et al. 2009), MICA and ULBP1 and 2 (Cerboni et al. 2007) and by preventing downregulation of HLA-C/E (Bonaparte and Barker 2004). Results reported by Kamya et al. demonstrated a negative correlation between NK cell tri-functional potential and VL suggesting VL and HIV infection negatively impact NK function (Kamya et al. 2011). In summary, although NK function in SPs may be affected by HIV infection the effect would be expected to be limited in this population. Our results demonstrate that NK cells from *3DL1+B\*27* SPs can produce IFN-γ and TNF-α and express CD107a following K562 stimulation to a greater extent than those from *3DL1+Bw6*. This finding is unlikely to be due to difference of VL as these 2 groups had a similar VL (Table 2).

We have previously shown that NK cells from SP who carry \**h/\*y+B\*57* have a level of trifunctional potential that is significantly higher than those from individuals carrying either *3DL1\*h/\*y* or *3DL1\*l/\*x* genotypes with *Bw4* alleles other than *B\*27* or *B\*57*. The elevated tri-functional potential of NK cells from *\*h/\*y+B\*57* carriers depends on the presence of both the *3DL1\*h/\*y* receptor genotype and *HLA-B\*57* since carriers of *3DL1\*l/\*x* with *HLA-B\*57* also have significantly lower NK tri-functional potential (Kamya et al. 2011). In contrast, we observed no differences in tri-functional potential in NK cells from *HLA-B\*27* positive SPs carrying either the *3DL1\*h/\*y* or *\*l/\*x* receptor genotypes. It should be noted that a limitation in making this assertion is the small number of subject who were *\*h/\*y+B\*27* versus *\*l/\*x+B\*27* available to make this comparison. Epidemiological studies found that compared to *Bw6 hmz* the *B\*57* effect on time to AIDS and VL control was HIV Infection in the Era of Highly Active 204 Antiretroviral Treatment and Some of Its Associated Complications

responses to missing self. The rationale for investigating the role of B\*27 in educating NK cells for NK functional potential in HIV infected SP is that this allele is over represented among SP compared to the uninfected or HIV susceptible subjects. Among 101 SPs enrolled in the Canadian Cohort of HIV Infected SP typed to date 18 (17.8%) were B\*27 positive whereas in HIV susceptible subject enrolled in a Primary HIV Infection cohort 26 of 434 (6%) expressed this allele (p<0.001; Fisher's Exact test), an allele frequency similar to that seen in uninfected Caucasian (www.allelefrequencies.net). The frequency of individuals expressing both a *B\*27* allele and a homozygous *3DL1* genotype would be expected to be even lower. This provided the rationale for investigating this phenomenon in SPs in whom the frequency of the *KIR/HLA* genotype under investigation was higher than in uninfected subjects. We also reasoned that SPs with either controlled viremia or long term non progression would constitute a population with limited NK dysfunction

Others have reported that HIV infection dysregulates NK cell subset distribution such that there is a reduction in the frequency of the CD56+CD16+ NK subset with cytolytic activity

2005; Tarazona et al. 2002). VL seems to play a key role in this redistribution of NK cell subsets. Even though a decrease of cytotoxic NK cells is observed in SPs compared to healthy controls it is not as pronounced as that observed in viremic HIV infected progressor subjects (O'Connor et al. 2007; Barker et al. 2007). NK function may be altered by direct contact with HIV. The gp120 Envelope glycoprotein has been shown to suppress the activity, proliferation and survival of NK cells (Kottilil et al. 2006). Perturbations in the NK cell receptor repertoire have been reported in HIV infection, affecting both inhibitory and activating receptors (Kottilil et al. 2004; Mavilio et al. 2003; De Maria et al. 2003; O'Connor et al. 2007). Furthermore, HIV can escape NK cell recognition by restricting upregulation of activating NK cell receptor ligands such as NKp44L (Fausther-Bovendo et al. 2009), MICA and ULBP1 and 2 (Cerboni et al. 2007) and by preventing downregulation of HLA-C/E (Bonaparte and Barker 2004). Results reported by Kamya et al. demonstrated a negative correlation between NK cell tri-functional potential and VL suggesting VL and HIV infection negatively impact NK function (Kamya et al. 2011). In summary, although NK function in SPs may be affected by HIV infection the effect would be expected to be limited in this population. Our results demonstrate that NK cells from *3DL1+B\*27* SPs can produce IFN-γ and TNF-α and express CD107a following K562 stimulation to a greater extent than those from *3DL1+Bw6*. This finding is unlikely to be due to difference of VL as these 2

We have previously shown that NK cells from SP who carry \**h/\*y+B\*57* have a level of trifunctional potential that is significantly higher than those from individuals carrying either *3DL1\*h/\*y* or *3DL1\*l/\*x* genotypes with *Bw4* alleles other than *B\*27* or *B\*57*. The elevated tri-functional potential of NK cells from *\*h/\*y+B\*57* carriers depends on the presence of both the *3DL1\*h/\*y* receptor genotype and *HLA-B\*57* since carriers of *3DL1\*l/\*x* with *HLA-B\*57* also have significantly lower NK tri-functional potential (Kamya et al. 2011). In contrast, we observed no differences in tri-functional potential in NK cells from *HLA-B\*27* positive SPs carrying either the *3DL1\*h/\*y* or *\*l/\*x* receptor genotypes. It should be noted that a limitation in making this assertion is the small number of subject who were *\*h/\*y+B\*27* versus *\*l/\*x+B\*27* available to make this comparison. Epidemiological studies found that compared to *Bw6 hmz* the *B\*57* effect on time to AIDS and VL control was

/CD16+ subset (Mavilio et al.

with an associated increase the frequency of an anergic CD56-

due to HIV infection.

groups had a similar VL (Table 2).

enhanced in the presence of *3DL1\*h/\*y* compared to *3DL1\*l/\*x*. Overall, the effect of *B\*27* on these outcomes was more moderate than that of *B\*57* in the presence of *3DL1 \*h/\*y*. Compared to *Bw6 hmz* the *B\*27-80T* allele *B\*2705* was more protective in the presence of *3DL1\*l/\*x* than in the presence of *3DL1\*h/\*y* (Martin et al. 2007). All but one of the *3DL1+B\*27* group of subjects in our study population expressed *B\*27-80T* alleles (Carrington, Martin, and van Bergen 2008). Furthermore, there is also evidence that B\*2705 has a greater affinity for one or more of the KIR3DL1\*l allotypes (Luque et al. 1996). Our findings that NK cells from *\*h/\*y+B\*27* and *\*l/\*x+B\*27* carriers have similar levels of trifunctional potential that may be more modest than of *\*h/\*y+B\*57 carriers* is in line with B\*27 being able to interact with receptors encoded by *3DL1\*h/\*y* and *\*l/\*x* genotypes in *3DL1+B\*27* carriers and this more effectively that B\*57 interacting with receptors encoded by *3DL1\*l/\*x* genotypes (Kamya et al. 2011)*.* There is also a trend towards NK cells from *3DL1+B\*27* carriers having higher function that those from *3DL1+Bw4* individuals. These results argue in favour of HLA-B\*27 and B\*57 being unique among HLA-Bw4 antigens in their impact on educating NK cells for subsequent activity, although the effect of B\*27 is more modest than that of B\*57.

According to the rheostat model of NK education, the strength of the inhibitory input received by NK cells determines the threshold of activation that is set in each NK cell. The higher the inhibitory input, the more likely the NK cell will pass the threshold required to respond to stimuli with an increased frequency of effector cells and an increased number of effector functions (Brodin, Karre, and Hoglund 2009). During development, NK cells must acquire sufficient inhibitory signals to prevent autoreactivity through recognition of ligands for inhibitory NK receptors (Valiante et al. 1997; Hoglund et al. 1997). The larger the contribution of given receptor-ligand pairing to NK cell inhibition under homeostatic conditions the more potent a missing self response will be when the ligand is lost. This situation would be encountered in a setting of HIV infection where HIV encoded Nef downmodulates HLA-A and B molecules from the cells surface abrogating inhibitory signals mediated by 3DL1 receptors (Collins et al. 1998; Cohen et al. 1999).

In this report we have focused on comparisons of the tri-functional subset of NK cells. This was done because the percent contribution of this subset to the entire K562 stimulated response was the only functional subset that differed between carriers *3DL1+B\*27* and a KIR/HLA receptor-ligand combination unable to signal through 3DL1 NK receptors. NK cells able elicit 3 functions are more potent in terms of the intensity of each of their functions than corresponding mono-functional NK cells (Kamya et al. 2011). This is similar to what has been reported for poly- versus mono-functional CD8+ T cells (Darrah et al. 2007; Betts et al. 2006) Poly-functional HIV-specific CD8+ T cells in SPs may play a role in superior anti-HIV activity (Betts et al. 2006; Makedonas and Betts 2011)*.* This is still a controversial area as the low VL seen in SPs may preserve multi-functional HIV-specific immune response. Although the biological relevance of poly-functional antigen specific CD8+ T cells in HIV infection is not yet clear, they do serve as an indicator of an effective response to HIV. Our experiments did not directly test the anti-viral activity of NK cells since we did not use HIV infected cells as stimuli. The role of tri-functional NK cells in inhibition of viral replication warrants further investigation.

If stimulation with HIV infected cells produces higher functionality in NK cells from *3DL1+B\*27* versus *3DL1+Bw6* carriers and tri-functional NK cells are endowed with a superior capacity to suppress viral replication it would be interesting to study the ability

Natural Killer Cells from HIV Infected Slow Progressors Who Carry

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of NK cells from *3DL1+Bw6* for other NK cells functions. Our results demonstrate that these individuals have a limited NK cell tri-functional potential upon missing self stimulation. Since these SPs are able to control viral replication and/or maintain CD4 counts above 400 for 7 or more years it is not unreasonable to assume that NK cells from these subjects possess other NK function. NK cells are known to mediated antibodydependent cell-mediated cytotoxicity which has been shown to play a role in controlling viral replication (Forthal, Landucci, and Daar 2001) and may play a role in preventing infection (Rerks-Ngarm et al. 2009). In addition, NK cells are also able to regulate antiviral immunity by modulating DC function (Gerosa et al. 2002; O'Leary et al. 2006). In the presence of HIV replication the cross talk between NK cells and DC is impaired (Mavilio et al. 2006; Melki et al. 2010; Alter et al. 2010). It would be interesting to assess whether the interaction between NK cells and DC is maintained in SPs, particularly in *3DL1+Bw6* carriers*.*

### **5. Conclusion**

We have demonstrated that NK cells from *3DL1+B\*27* SPs have a higher tri-functional potential following K562 stimulation than those from *3DL1+Bw6*. A test of trend found that NK tri-functional potential declines significantly in NK isolated from carriers of the following genotypes: *\*h/\*y+B\*57* > *3DL1+B\*27 > 3DL1+Bw4.* Our results suggest that although the protective effect on HIV infection conferred by HLA-B\*27 is mediated in part by CD8+ T cells recognizing HIV epitopes restricted by this allele, the protective effect of this alleles may also be mediated by its interaction with inhibitory 3DL1 receptors. HLA-B\*27, like HLA-B\*57, appears to have an impact on NK education that is superior to that of other Bw4 alleles. Although this remains to be demonstrated experimentally we hypothesize that in carriers of certain *3DL1* and *HLA-B\*27* or *HLA-B\*57* genotypes, virusinfected cells that have down modulated the HLA ligand for their inhibitory 3DL1 NK receptors may be able to recruit a larger number NK cells with multiple functions, which can play a role in viral control. Such information is relevant to vaccine design by providing a rationale for modulating NK activity at the time of vaccination to favor developing protective immunity.

#### **6. Acknowledgements**

The authors wish to thank the study participants of the Canadian Cohort of HIV Infected SPs and the NIAID Cohort. We are grateful to the following physicians, who recruited and followed study subjects enrolled in the Canadian Cohort for HIV Infected SPs: Drs. Bernard Lessard, Danielle Legault, Benoit Trottier, Michel Boissonault, Serge Dufresne, Jean-Guy Baril, Danièle Longpré, Benoit Trottier, Danielle Rouleau, Howard Turner, Julian Falutz, Joseph Cox, James Allan, John MacLoed, Marina B Klein and Roger LeBlanc. We are also grateful to Ms. Stephanie Matte for Cohort coordination. We thank Mr. Benjamin Tallon, Ms. Marie-Pierre Boisvert, Ms. Tsoarello Mabanga and Mr. Saied Sharafi for the expert technical assistance with HLA and KIR allotyping. This work was supported by grants #HOP-86862 and MOP-111155 from the Canadian Institutes for Health Research (CIHR), and a grant from the Fonds de Recherche en Santé du Québec (FRSQ) AIDS and Infectious Disease Network. CMP was supported by a Ph.D. scholarship from CIHR.

#### **7. References**

HIV Infection in the Era of Highly Active 206 Antiretroviral Treatment and Some of Its Associated Complications

of NK cells from *3DL1+Bw6* for other NK cells functions. Our results demonstrate that these individuals have a limited NK cell tri-functional potential upon missing self stimulation. Since these SPs are able to control viral replication and/or maintain CD4 counts above 400 for 7 or more years it is not unreasonable to assume that NK cells from these subjects possess other NK function. NK cells are known to mediated antibodydependent cell-mediated cytotoxicity which has been shown to play a role in controlling viral replication (Forthal, Landucci, and Daar 2001) and may play a role in preventing infection (Rerks-Ngarm et al. 2009). In addition, NK cells are also able to regulate antiviral immunity by modulating DC function (Gerosa et al. 2002; O'Leary et al. 2006). In the presence of HIV replication the cross talk between NK cells and DC is impaired (Mavilio et al. 2006; Melki et al. 2010; Alter et al. 2010). It would be interesting to assess whether the interaction between NK cells and DC is maintained in SPs, particularly in *3DL1+Bw6*

We have demonstrated that NK cells from *3DL1+B\*27* SPs have a higher tri-functional potential following K562 stimulation than those from *3DL1+Bw6*. A test of trend found that NK tri-functional potential declines significantly in NK isolated from carriers of the following genotypes: *\*h/\*y+B\*57* > *3DL1+B\*27 > 3DL1+Bw4.* Our results suggest that although the protective effect on HIV infection conferred by HLA-B\*27 is mediated in part by CD8+ T cells recognizing HIV epitopes restricted by this allele, the protective effect of this alleles may also be mediated by its interaction with inhibitory 3DL1 receptors. HLA-B\*27, like HLA-B\*57, appears to have an impact on NK education that is superior to that of other Bw4 alleles. Although this remains to be demonstrated experimentally we hypothesize that in carriers of certain *3DL1* and *HLA-B\*27* or *HLA-B\*57* genotypes, virusinfected cells that have down modulated the HLA ligand for their inhibitory 3DL1 NK receptors may be able to recruit a larger number NK cells with multiple functions, which can play a role in viral control. Such information is relevant to vaccine design by providing a rationale for modulating NK activity at the time of vaccination to favor developing

The authors wish to thank the study participants of the Canadian Cohort of HIV Infected SPs and the NIAID Cohort. We are grateful to the following physicians, who recruited and followed study subjects enrolled in the Canadian Cohort for HIV Infected SPs: Drs. Bernard Lessard, Danielle Legault, Benoit Trottier, Michel Boissonault, Serge Dufresne, Jean-Guy Baril, Danièle Longpré, Benoit Trottier, Danielle Rouleau, Howard Turner, Julian Falutz, Joseph Cox, James Allan, John MacLoed, Marina B Klein and Roger LeBlanc. We are also grateful to Ms. Stephanie Matte for Cohort coordination. We thank Mr. Benjamin Tallon, Ms. Marie-Pierre Boisvert, Ms. Tsoarello Mabanga and Mr. Saied Sharafi for the expert technical assistance with HLA and KIR allotyping. This work was supported by grants #HOP-86862 and MOP-111155 from the Canadian Institutes for Health Research (CIHR), and a grant from the Fonds de Recherche en Santé du Québec (FRSQ) AIDS and Infectious Disease

Network. CMP was supported by a Ph.D. scholarship from CIHR.

carriers*.*

**5. Conclusion**

protective immunity.

**6. Acknowledgements**

Natural Killer Cells from HIV Infected Slow Progressors Who Carry

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### *Edited by Elaheh Aghdassi*

Human immunodeficiency virus (HIV) infection is a complex illness affecting the immune system. Acquired immunodeficiency syndrome (AIDS) is an advanced form of HIV infection in which the patient has developed opportunistic infections or certain types of cancer and/or the CD4+ T cell count has dropped below 200/μL.  The disease causes 3 million deaths worldwide each year, 95% of them in developing countries. Optimal management of human immunodeficiency virus requires strict adherence to highly active antiretroviral treatment (HAART) regimens, but the complexity of these regimens (e.g., pill burden, food requirements, drug interactions, and severe adverse effects) limits effective treatment. However, more patients with HIV are surviving longer today because of these drugs. This allows further study of commonly associated adverse effects. These may affect all body systems and range from serious toxicities to uncomfortable but manageable events. This book reviews some of HAART-related metabolic and neurological complications.

HIV Infection in the Era of Highly Active Antiretroviral Treatment

and Some of Its Associated Complications

HIV Infection in the Era of

Highly Active Antiretroviral

Treatment and Some of Its

Associated Complications

*Edited by Elaheh Aghdassi*

Photo by Aunt\_Spray / iStock