Human herpesvirus 6

When an extracellular HHV-6 virion comes across human cells, it encounters the human receptor protein cluster of differentiation 46 (CD46), which plays a role in regulating the complement system. The CD46 protein possesses a single variable region, as a result of alternative splicing. As such, at least fourteen isoforms of CD46 exist, all of which bind HHV-6a.[28]

The extracellular region of CD46 contains four short consensus repeats of about 60 amino acids that fold into a compact beta-barrel domain surrounded by flexible loops.[23] As has been demonstrated for CD46 with other ligands, the CD46 protein structure linearizes upon binding HHV-6. While their precise interaction has not yet been determined, the second and third SCR domains have been demonstrated as required for HHV-6 receptor binding and cellular entry.

Mori et al. first identified the gene product gQ1, a glycoprotein unique to HHV-6, and found that it forms a complex with gH and gL glycoproteins.[12][29] They believed that this heterotrimer complex served as the viral ligand for CD46.[22] 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.[29] The exact process of entry is not yet well understood.

The salivary glands have been described as an in vivo reservoir for HHV-6 infection.[23]

Researchers[30] conducted a study to show that T cells are highly infectable by HHV-6.

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.[16]

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.[31]

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.[16] 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.[32] 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.[32]

Active infections involve the linear dsDNA genome circularizing by end to end covalent linkages. This process was first reported for the herpes simplex virus.[24] Once circularized, HHV-6 begins to express what are known as "immediate early" genes. These gene products are believed to be transcription activators[7] and may be regulated by the expression of viral micro RNAs.[26] 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.[23]

HHV-6's replication results in the formation of concatemers, which are long molecules that contain several repeats of a DNA sequence.[33] These long concatemers are then cleaved between the pac-1 and pac-2 regions for packaging of the genome into individual virions.[24]

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.[34]

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.[15] Only one other virus, Marek's disease virus, is known to achieve latency in this fashion.[7] 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[35] of chromosomes 9, 17, 18, 19, and 22, but has also occasionally been found in chromosomes 10 and 11.[33] Nearly 70 million individuals are suspected to carry chromosomally integrated HHV-6.[15][33]

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.[35] For instance, the U94 protein is believed to repress genes that are involved in cellular lysis (apoptosis) and also may aid in telomeric integration.[23] Once stored in human telomeres, the virus is reactivated intermittently.[35]

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.[36]

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.[23]

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.[13] It has been demonstrated that HHV-6 fosters the progression of HIV-1 upon coinfection in T cells.[37] 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,[38] IL-1 beta, and IL-8.[39] A more recent in vivo study shows HHV-6A coinfection to dramatically accelerate the progression from HIV to AIDS in pigtailed macaques.[40]

HHV-6 has also been demonstrated to transactivate Epstein–Barr virus.[31]

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[41][42] 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.[13]

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.

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.[13][43] Studies have found seroprevalence varying "from approximately 39 to 80% among ethnically diverse adult populations from Tanzania, Malaysia, Thailand, and Brazil."[13] 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.[13]

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%),[13] 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.[23]

Vertical transmission has also been described, and occurs in approximately 1% of births in the United States.[7][44] This form is easily identifiable as the viral genome is contained within every cell of an infected individual.

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.[50] 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.[51]

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.[52]

Several similar studies followed. A study from October 2014 supported the role of long-term HHV-6 infection with demyelination in progressive neurological diseases.[53]

Chronic fatigue syndrome (CFS) is a debilitating illness,[54] the 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.[55] 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 (${\displaystyle P<10^{-8}}$).[56] 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.[55][57][58]

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,[57][59][60][61][62][63] although a few have not.[58][64]

In summary, active infection with HHV-6 is present in a substantial fraction of patients with CFS. Moreover, HHV-6 is known to infect cells of the nervous system and immune system, organ systems with demonstrable abnormalities in CFS. Despite this association, it remains unproven that reactivated HHV-6 infection is a cause of CFS.

Hashimoto's thyroiditis is the most common thyroid disease and is characterized by abundant lymphocyte infiltrate and thyroid impairment. Recent research suggests a potential role for HHV-6 (possibly variant A) in the development or triggering of Hashimoto's thyroiditis.[65]

The role of HHV-6 during pregnancy leading to inflammation in the amniotic cavity has been studied.[66]

HHV-6A DNA was found in the endometrium of almost half of a group of infertile women, but in none of the fertile control group. Natural killer cells specific for HHV-6A, and high uterine levels of certain cytokines, were also found in the endometrium of the infertile women positive for HHV-6A. The authors suggest that HHV-6A may prove to be an important factor in female infertility.[67]

Many human oncogenic viruses have been identified. For instance, HHV-8 is linked to Kaposi's sarcoma,[68] the Epstein–Barr virus to Burkitt's lymphoma, and HPV to cervical cancer. In fact, the World Health Organization estimated (2002) that 17.8% of human cancers were caused by infection.[69] The typical methods whereby viruses initiate oncogenesis involve suppressing the host's immune system, causing inflammation, or altering genes.

HHV-6 has been detected in lymphomas, leukemias, cervical cancers, and brain tumors.[14] Various medulloblastoma cell lines as well as the cells of other brain tumors have been demonstrated to express the CD46 receptor. Viral DNA has also been identified in many other non-pathological brain tissues, but the levels are lower.[14]

The human P53 protein functions as a tumor suppressor. Individuals who do not properly produce this protein experience a higher incidence of cancer, a phenomenon known as Li-Fraumeni syndrome. One of HHV-6's gene products, the U14 protein, binds P53 and incorporates it into virions. Another gene product, the ORF-1 protein, can also bind and inactivate P53. Cells expressing the ORF-1 gene have even been shown to produce fibrosarcomas when injected into mice.[14]

Another product of HHV-6, the immediate early protein U95, has been shown to bind nuclear factor-kappa B. Deregulation of this factor is associated with cancer.[14]

HHV-6 induced ocular inflammation has been reported three times. All three were reported in elderly individuals, two during 2007 and one during 2011. The first two were reported in Japan and France, the most recent one in Japan.[70][71][72]

These were believed to have occurred as a result of a reactivation, as anti-HHV-6 IgM antibody levels were low.[72]

Epilepsy of the mesial temporal lobe is associated with HHV-6 infection. Within this region of the brain exists three structures: the amygdala, hippocampus, and parahippocampal gyrus. Mesial temporal lobe epilepsy (MTLE) is the most common form of chronic epilepsy and its underlying mechanism is not fully understood.[73]

Researchers consistently report having found HHV-6 DNA in tissues that were removed from patients with MTLE. Studies have demonstrated a tendency for HHV-6 to aggregate in the temporal lobe,[74] with the highest concentrations in astrocytes of the hippocampus.[73]

However, one group of researchers ultimately concluded that HHV-6 may not be involved in MTLE related to Mesial Temporal Sclerosis.[75]

The virus is a common cause of liver dysfunction and acute liver failure in liver transplant recipients, and has recently been linked to periportal confluent necrosis. Furthermore, HHV-6 DNA is often detectable only in the biopsy tissues as DNA levels fall below the level of detection in blood in persistent cases.[76]