heterotrimer complex served as the viral ligand for cd46. soon thereafter, another glycoprotein named gq2 was identified and found to be part of the gh/gl/gq1 ligand complex, forming a heterotetramer that was positively identified as the viral cd46 ligand. the exact process of entry is not yet well understood. salivary glands the salivary glands have been described as an in vivo reservoir for hhv-6 infection. leukocytes researchers conducted a study to show that t cells are highly infectable by hhv-6. nervous system during the year 2011, researchers at the national institutes of health attempted to elucidate the then unknown method whereby hhv-6a gains entry into the nervous system. as such, they autopsied the brains of around 150 subjects. when various anatomical regions were assayed for their viral load, olfactory tissues were found to have the highest hhv-6 content. they concluded that these tissues are the entry point for hhv-6a. the results above are consistent with those of previous studies that involved hsv-1 (and a number of other viruses), which also disseminates into the cns through olfactory tissue. researchers also hypothesized that olfactory ensheathing cells (oecs), a group of specialized glial cells found in the nasal cavity, may have a role in hhv-6 infectivity. they suspected this association as a result of oecs having properties similar to those of astrocytes, another type of glial cell that was previously identified as being susceptible to hhv-6 infection. research continued by infecting oecs in vitro with both types of hhv-6. ultimately, only oecs in which hhv-6a was used tested positive for signs of de novo viral synthesis, as is also characteristic of astrocytes. cellular activity once inside, two outcomes have been described: active and inactive infections. active infection active infections involve the linear dsdna genome circularizing by end to end covalent linkages. this process was first reported for the herpes simplex virus. once circularized, hhv-6 begins to express what are known as "immediate early" genes. these gene products are believed to be transcription activators and may be regulated by the expression of viral micro rnas. subsequent expression of "early genes" then occurs and activates, for instance, viral dna polymerases. early genes are also involved in the rolling circle replication that follows. hhv-6's replication results in the formation of concatemers, which are long molecules that contain several repeats of a dna sequence. these long concatemers are then cleaved between the pac-1 and pac-2 regions for packaging of the genome into individual virions. inactive infection not all newly infected cells begin rolling circle replication. herpesviruses may enter a latent stage, inactively infecting their human host. since its discovery in 1993, this phenomenon has been found among all of the betaherpesviruses. other betaherpesviruses establish latency as a nuclear episome, which is a circular dna molecule (analogous to plasmids). for hhv-6, latency is believed to occur exclusively through the integration of viral telomeric repeats into human subtelomeric regions. only one other virus, marek's disease virus, is known to achieve latency in this fashion. this phenomenon is possible as a result of the telomeric repeats found within the direct repeat termini of hhv-6's genome. the right direct repeat terminus integrates within 5 to 41 human telomere repeats, and preferentially does so into the proximal end of chromosomes 9, 17, 18, 19, and 22, but has also occasionally been found in chromosomes 10 and 11. nearly 70 million individuals are suspected to carry chromosomally integrated hhv-6. a number of genes expressed by hhv-6 are unique to its inactive latency stage. these genes involve maintaining the genome and avoiding destruction of the host cell. for instance, the u94 protein is believed to repress genes that are involved in cellular lysis (apoptosis) and also may aid in telomeric integration. once stored in human telomeres, the virus is reactivated intermittently. reactivation the specific triggers for reactivation are not well understood. some researchers have suggested that injury, physical or emotional stress, and hormonal imbalances could be involved. researchers during 2011 discovered that reactivation can positively be triggered in vitro by histone deacetylase inhibitors. once reactivation begins, the rolling circle process is initiated and concatemers are formed as described above. interactions human herpesvirus 6 lives primarily on humans and, while variants of the virus can cause mild to fatal illnesses, can live commensally on its host. it has been demonstrated that hhv-6 fosters the progression of hiv-1 upon coinfection in t cells. hhv-6 upregulates the expression of the primary hiv receptor cd4, thus expanding the range of hiv susceptible cells. several studies also have shown that hhv-6 infection increases production of inflammatory cytokines that enhance in vitro expression of hiv-1, such as tnf-alpha, il-1 beta, and il-8. a more recent in vivo study shows hhv-6a coinfection to dramatically accelerate the progression from hiv to aids in pigtailed macaques. hhv-6 has also been demonstrated to transactivate epstein–barr virus. epidemiology age humans acquire the virus at an early age, some as early as less than one month of age. hhv-6 primary infections account for up to 20% of infant emergency room visits for fever in the united states and are associated with several more severe complications, such as encephalitis, lymphadenopathy, myocarditis and myelosuppression. the prevalence of the virus in the body increases with age (rates of infection are highest among infant between 6 and 12 months old) and it is hypothesized that this is due to the loss of maternal antibodies in a child that protect him or her from infections. there are inconsistencies with the correlations between age and seropositivity: according to some reports there is a decrease of seropositivity with the increase of age, while some indicate no significant decline, and others report an increased rate of seropositivity for individuals age 62 and older. after primary infection, latency is established in salivary glands, hematopoietic stem cells, and other cells, and exists for the lifetime of the host. geographical distribution the virus is known to be widespread around the world. an hhv-6 infection rate of 64–83% by age 13 months has been reported for countries including the united states, united kingdom, japan and taiwan. studies have found seroprevalence varying "from approximately 39 to 80% among ethnically diverse adult populations from tanzania, malaysia, thailand, and brazil." there are no significant differences among ethnic groups living in the same geographical location or between sexes. while hhv-6b is present in almost all of the world's populations, hhv-6a appears to be less frequent in japan, north america, and europe. transmission transmission is believed to occur most frequently through the shedding of viral particles into saliva. both hhv-6b and hhv-7 are found in human saliva, the former being at a lower frequency. studies report varying rates of prevalence of hhv-6 in saliva (between 3–90%), and have also described the salivary glands as an in vivo reservoir for hhv-6. the virus infects the salivary glands, establishes latency, and periodically reactivates to spread infection to other hosts. vertical transmission has also been described, and occurs in approximately 1% of births in the united states. this form is easily identifiable as the viral genome is contained within every cell of an infected individual. diagnosis the diagnosis of hhv-6 infection is performed by both serologic and direct methods. the most prominent technique is the quantification of viral dna in blood, other body fluids, and organs by means of real-time pcr. clinical significance the classical presentation of primary hhv-6b infection is as exanthema subitum (es) or "roseola", featuring a high temperature followed by a rash. however, one study (1997) indicated that a rash is not a distinguishing feature of hhv-6 infection, with rates similar to non-hhv-6 infections (10–20% of febrile children in both groups). hhv-6 infections more frequently present with high temperatures (over 40c), at a rate of around two thirds compared to less than half in the non-hhv-6 patients. similarly significant differences were seen in malaise, irritability, and tympanic membrane inflammation. primary infection in adults tend to be more severe. diagnosis for the virus, particularly hhv-6b, is vital for the patient because of the infection's adverse effects. symptoms that point to this infection, such as rashes, go unnoticed in patients that receive antibiotics because they can be misinterpreted as a side-effect of the medicine. hhv-6b is known to be associated with the childhood disease roseola infantum, as well as other illnesses caused by the infection. these include hepatitis, febrile convulsions, and encephalitis. children who have exanthema subitum, caused by an hhv-6b infection, experience fevers lasting 3 to 5 days; rashes on the torso, neck, and face; and sometimes febrile convulsions, however, the symptoms are not always present together. primary infections in adults are rare since most occurrences are in children. when the infection does occur for the first time in an adult the symptoms can be severe. the virus periodically re-activates from its latent state, with hhv-6 dna being detectable in 20–25% of healthy adults in the united states. in the immunocompetent setting, these re-activations are often asymptomatic, but in immunosuppressed individuals there can be serious complications. hhv-6 re-activation causes severe disease in transplant recipients and can lead to graft rejection, often in consort with other betaherpesviridae. likewise in hiv/aids, hhv-6 re-activations cause disseminated infections leading to end organ disease and death. although up to 100% of the population are exposed (seropositive) to hhv-6, most by 3 years of age, there are rare cases of primary infections in adults. in the united states, these have been linked more with hhv-6a, which is thought to be more pathogenic and more neurotropic and has been linked to several central nervous system-related disorders. hhv-6 has been reported in multiple sclerosis patients and has been implicated as a co-factor in several other diseases, including chronic fatigue syndrome, aids, and temporal lobe epilepsy. multiple sclerosis main article: multiple sclerosis multiple sclerosis (ms) is an autoimmune and inflammatory disorder of the nervous system that results in demyelination of axons in the brain and spinal cord. the first study to specifically investigate hhv-6-related demyelination appeared in the literature during 1996, when a previously healthy 19-month-old child developed acute encephalopathy. levels of myelin basic protein were elevated in his cerebrospinal fluid, suggesting that demyelination was occurring. this link was almost forgotten, until four years later when an ms-related study was published showing an hhv-6 prevalence of 90% among demyelinated brain tissues. in comparison, a mere 13% of disease-free brain tissues possessed the virus. the molecular mimicry hypothesis, in which t cells are essentially confusing an hhv-6 viral protein with myelin basic protein, first appeared around this time. early on in the development of this hypothesis (2002), italian researchers used the hhv-6a variant along with bovine myelin basic protein to generate cross-reactive t cell lines. these were compared to the t cells of individuals with ms as well as those of controls, and no significant difference was found between the two. their early research suggested that molecular mimicry may not be a mechanism that is involved in ms. several similar studies followed. a study from october 2014 supported the role of long-term hhv-6 infection with demyelination in progressive neurological diseases. chronic fatigue syndrome chronic fatigue syndrome (cfs) is a debilitating illness, cause of which is unknown. patients with cfs have abnormal neurological, immunological, and metabolic findings. for many, but not all, patients who meet criteria for cfs, the illness begins with an acute, infectious-like syndrome. cases of cfs can follow well-documented infections with several infectious agents. a study of 259 patients with a "cfs-like" illness published shortly after hhv-6 was discovered used primary lymphocyte cultures to identify people with active replication of hhv-6. such active replication was found in 70% of the patients vs. 20% of the control subjects ( p < 10 − 8 ). the question raised but not answered by this study was whether the illness caused subtle immune deficiency that led to reactivation of hhv-6, or whether reactivation of hhv-6 led to the symptoms of the illness. subsequent studies employing only serological techniques that do not distinguish active from latent infection have produced mixed results: most, but not all, have found an association between cfs and hhv-6 infection. other studies have employed assays that can detect active infection: primary cell culture, pcr of serum or plasma, or igm early antigen antibody assays. the majority of these studies have shown an association between cfs and active hhv-6 infection, although