Human herpesvirus 6A accelerates AIDS progression in macaques

Institute of Human Virology, University of Maryland, Baltimore, Baltimore, Maryland, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2007; 104(12):5067-72. DOI: 10.1073/pnas.0700929104
Source: PubMed


Although HIV is the necessary and sufficient causative agent of AIDS, genetic and environmental factors markedly influence the pace of disease progression. Clinical and experimental evidence suggests that human herpesvirus 6A (HHV-6A), a cytopathic T-lymphotropic DNA virus, fosters the progression to AIDS in synergy with HIV-1. In this study, we investigated the effect of coinfection with HHV-6A on the progression of simian immunodeficiency virus (SIV) disease in pig-tailed macaques (Macaca nemestrina). Inoculation of HHV-6A resulted in a rapid appearance of plasma viremia associated with transient clinical manifestations and followed by antibody seroconversion, indicating that this primate species is susceptible to HHV-6A infection. Whereas animals infected with HHV-6A alone did not show any long-term clinical and immunological sequelae, a progressive loss of CD4(+) T cells was observed in all of the macaques inoculated with SIV. However, progression to full-blown AIDS was dramatically accelerated by coinfection with HHV-6A. Rapid disease development in dually infected animals was heralded by an early depletion of both CD4(+) and CD8(+) T cells. These results provide in vivo evidence that HHV-6A may act as a promoting factor in AIDS progression.

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Available from: Angélique Biancotto
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    • "HHV-6B is also implicated in a majority of pediatric cases of febrile status epilepticus (Epstein et al., 2012). HHV-6A active replication on the other hand is associated with autoimmune diseases such as Hasimoto's thyroiditis (Caselli et al., 2012) and enhances disease progression in HIV infected individuals (Ablashi et al., 1998; Boutolleau et al., 2004; Lusso et al., 2007). Both HHV-6B and HHV-7 are believed to be transmitted by exposure to saliva. "
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    ABSTRACT: Human herpesvirus-6 (HHV-6) and -7 (HHV-7) are Roseoloviruses within the Betaherpesvirus family, which have a high prevalence and suspected involvement in a number of diseases. Using CODEHOP-based PCR, we identified homologs of both viruses in saliva of pig-tailed macaques, provisionally named MneHV-6 and MneHV-7. This finding supports the existence of two distinct Roseolovirus lineages before the divergence of humans and macaques. Using specific qPCR assays, high levels of MneHV-6 and MneHV-7 DNA were detected in macaque saliva, although the frequency was greater for MneHV-7. A blood screen of 283 macaques revealed 10% MneHV-6 DNA positivity and 25% MneHV-7 positivity, with higher prevalences of MneHV-6 in older females and of MneHV-7 in younger males. Levels of MneHV-6 were increased in animals coinfected with MneHV-7, and both viruses were frequently detected in salivary gland and stomach tissues. Our discovery provides a unique animal model to answer unresolved questions regarding Roseolovirus pathology.
    Full-text · Article · Dec 2014 · Virology
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    • "Furthermore, this model has been used to analyze coinfection with HHV-6A and simian immunodeficiency virus (SIV), a simian counterpart of HIV-1 typically used for experimental infection in macaques (Lusso et al., 2007). This approach provided the first in vivo data showing that HHV-6A infection can accelerate AIDS progression. "
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    ABSTRACT: Human herpesvirus (HHV)-6A and HHV-6B are two enveloped DNA viruses of β-herpesvirus family, infecting over 90% of the population and associated with several diseases, including exanthema subitum (for HHV-6B), multiple sclerosis and encephalitis, particularly in immunosuppressed patients. Animal models are highly important to better understand the pathogenesis of viral infections. Naturally developed neutralizing antibodies to HHV-6 or a related virus were found in different species of monkeys, suggesting their susceptibility to HHV-6 infection. Both HHV-6 DNA and infectious virus were detected in experimentally infected Cynomolgus and African green monkeys, although most animals remained clinically asymptomatic. Furthermore, HHV-6A infection was shown to accelerate the progression of AIDS (acquired immunodeficiency syndrome) in macaques and to lead to the development of neurological symptoms in the marmoset model. Humanized SCID (severe combined immunodeficiency) mice efficiently replicated HHV-6 and were also susceptible to coinfection with HHV-6 and HIV-1 (human immunodeficiency virus 1). As CD46 was identified as a receptor for HHV-6, transgenic mice expressing human CD46 may present a potentially interesting model for study certain aspects of HHV-6 infection and neuroinflammation.
    Full-text · Article · Jul 2013 · Frontiers in Microbiology
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    • "Serologic studies have found that by the age of two, greater than 90% of children have acquired a primary HHV-6A/B infection (Okuno et al., 1989; Zerr et al., 2005). HHV-6A has been associated with several adult diseases and various neurological disorders including encephalitis, ataxia, seizures, multiple sclerosis, Hashimoto's thyroiditis, and has been implicated as a cofactor in AIDS progression (Ablashi et al., 2010; Ahlqvist et al., 2005; Cameron et al., 2010; Caselli et al., 2012; De Bolle et al., 2005; Donati et al., 2003; Jones et al., 1994; Lusso et al., 2007, 1989; Yamashita and Morishima, 2005; Yao et al., 2010). Nevertheless, the causal link between human disease and HHV-6A infection remains to be fully elucidated. "
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    ABSTRACT: Human herpesvirus 6B (HHV-6B) is the causative agent of roseola infantum. HHV-6A and 6B can reactivate in immunosuppressed individuals and are linked with severe inflammatory response, organ rejection and central nervous system diseases. About 0.85% of the US and UK population carries an integrated HHV-6 genome in all nucleated cells through germline transmission. We have previously reported that the HHV-6A genome integrated in telomeres of patients suffering from neurological dysfunction and also in telomeres of tissue culture cells. We now report that HHV-6B also integrates in telomeres during latency. Detailed mapping of the integrated viral genomes demonstrates that a single HHV-6 genome integrates and telomere repeats join the left end of the integrated viral genome. When HEK-293 cells carrying integrated HHV-6A were exposed to the histone deacetylase inhibitor Trichostatin A, circularization and/or formation of concatamers were detected and this assay could be used to distinguish between lytic replication and latency.
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