Both clinical and experimental evidence suggest that HHV-6A may foster the progression of HIV disease toward AIDS. Following the recognition of HHV-6 primary tropism for CD4+ T cells (Lusso 1988), Lusso and colleagues proposed the hypothesis of HHV-6 and HIV-1 working together to deplete CD4+ T cells leading to more immunosuppression and thus catalyzing the progression toward full-blown AIDS. This theory was later corroborated by the observation of synergistic cytopathic effects in primary CD4+ T lymphocytes coinfected in vitro with HHV-6A and HIV-1 (Lusso 1989). HHV-6 not only upregulates the expression of the primary HIV receptor CD4, but also induces functional CD4 in cells that physiologically do not express it (Lusso 1991Flamand 1998). Through this unique mechanism, HHV-6 may significantly enhance the range of cells susceptible to HIV-1 in vivo, and thus further its spread in coinfected hosts. 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 (Flamand 1991Inagi 1996;Arena 1997).

The first conclusive in vivo evidence that HHV-6A acts as a promoting factor in the progression of immunodeficiency virus disease was observed in experimental coinfection studies in pigtailed macaques (Lusso 2007). Coinfection with HHV-6A was shown to dramatically accelerate the immunological and clinical progression toward AIDS in monkeys infected with a pathogenic simian immunodeficiency virus (SIV) strain. Furthermore, the progression of SIV toward RANTES resistance in macaques has been shown to progress more rapidly to AIDS upon coinfection with HHV-6A (Biancotto 2009). Despite these results, further in vivo animal model and patient studies are needed to definitively establish the role of HHV-6A in AIDS.

Several clinical observations also suggest a significant role of HHV-6 in AIDS progression. For example, HHV-6 has been frequently isolated from HIV-infected patients (Salahuddin 1986Levy 1990Agut 1988) and widespread HHV-6 infection is documented in patients with AIDS at post-mortem examination (Corbellino 1993Knox and Carrigan 1994). Additionally, sustained HHV-6 replication has been observed in the lymph nodes of HIV-infected patients associated with increased HIV-1 load (Knox and Carrigan 1996Emery 1999), HHV-6 is frequently reactivated in early symptomatic HIV-1 infected patients (Secchiero 1995), and the disease progression is accelerated in infants with early acquisition of HHV-6 infection (Kositanont 1999). Interestingly, HHV-6 reactivation/re-infection seems to occur before the time when other opportunistic infections usually appear. It is also remarkable that treatment with the potent HHV-6 inhibitor, foscarnet, significantly prolonged the survival of a group of AIDS patients (Studies of Ocular Complications of AIDS Research Group, 1992). Ensoli and colleagues (Ensoli 1989) showed that HHV-6 is a potent transactivator of the Long Terminal Repeat (LTR) of HIV, SIV, and HIV-2. While HHV-6 by itself causes significant immunologic damage and dysregulation, the combination of active HIV and HHV-6 leads to more severe immunosuppression in AIDS patients, thereby enhancing the progression of the disease.

Key Papers: HHV-6 & HIV/AIDS Progression



Understanding the association between ciHHV-6 and HIV disease: a cross-sectional study


HHV-6A infection and immunopathogenesis in humanized Rag2-/-yc-/- mice


Immunomodulation and immunosuppression by HHV-6A and HHV-6B


Evolution of SIV toward RANTES resistance in macaques rapidly progressing to AIDS upon coinfection with HHV-6A


Human herpesvirus 6A accelerates AIDS progression in macaques.


Interactions between beta-herpesviruses and human immunodeficiency virus in vivo: evidence for increased human immunodeficiency viral load in the presence of human herpesvirus 6.


Human herpesvirus 6: report of emerging pathogen in five patients with HIV/AIDS and review of the literature.


Primary infection of human herpesvirus 6 in children with vertical infection of human immunodeficiency virus type 1.


Human herpesvirus 6 in AIDS.


Potential herpesvirus interaction during HIV type 1 primary infection


Disseminated active HHV-6 infections in patients with AIDS.


Disseminated human herpesvirus 6 infection in AIDS.


Induction of CD4 and susceptibility to HIV-1 infection in human CD8+ T lymphocytes by human herpesvirus 6.


Productive dual infection of human CD4+ T lymphocytes by HIV-1 and HHV-6.


Human herpes virus-6 increases HIV-1 expression in co-infected T cells via nuclear factors binding to the HIV-1 enhancer.