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 1991; Flamand 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 1991; Inagi 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 1986; Levy 1990; Agut 1988) and widespread HHV-6 infection is documented in patients with AIDS at post-mortem examination (Corbellino 1993; Knox 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 1996; Emery 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.