HHV-6 as a Progression Factor in AIDS

There is both clinical and experimental evidence which suggests that HHV-6A may foster the progression of HIV disease toward AIDS. Following the recognition of HHV-6 primary tropism for CD4+ T cells, the hypothesis of HHV-6 and HIV-1 working together to deplete CD4+ T cells leading to more immunosuppression and therefore catalyzing the progression toward full-blown AIDS was proposed (Lusso, et al., 1988). 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 et al., 1989). HHV-6 can not only upregulate the expression of the primary HIV receptor CD4, but also induce functional CD4 in cells that physiologically do not express it (Lusso et al., 1991a, Flammand et al., 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 co-infected hosts. Several studies have also shown that HHV-6 infection increases production of inflammatory cytokines, such as TNF-a, IL-Ib and IL-8  that  enhance in vitro expression of HIV-1 (Flamand et al., 1991; Inagi et al., 1996; Arena et al., 1997).

Several clinical observations have also suggested the role of HHV-6 in AIDS progression. For example, HHV-6 was frequently isolated from HIV infected patients (Salahuddin et al., 1986; Dowing et al., 1987, Tedder et al., 1987, Lopez et al., 1988, Levy et al. 1990, Agut et al.1988) and widespread HHV-6 infection is documented in patients with AiDS at post-mortem examination (Corbellino et al., 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 et al., 1999), HHV-6 is frequently reactivated in early symptomatic HIV-1 infected patients (Secchiero et al., 1995), and the disease progression is accelerated in infants with early acquisition of HHV-6 infection (Kositanont et al., 1999). Interestingly, HHV-6 reactivation/reinfection 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 among a group of AIDS patients (Studies of Ocular Complications of AIDS Research Group, 1992).  Ensoli et al., 1989, showed that HHV-6 is a potent transactivator of LTR of HIV, SIV, and HIV-2. While HHV-6 by itself causes significant immunologic damage and dysregulation, when HIV and HHV-6 are active the combination leads to more severe immunosuppression in AIDS patients, thereby enhancing the progression of the disease.