In vivo coinfection with HHV6 and SIV in pigtailed macaques Macaca nemestrina accelerated immunological and clinical progression to AIDS

Chimpanzees (Pan troglodytes) represent the first choice for in vivo coinfection studies due to their evolutionary closeness to humans and their marked susceptibility to HIV-1 (Alter et al., 1984) and, at least in vitro, to HHV-6 (Lusso et al., 1990).

However, their high cost, limited supply and endangered status have so far impeded the performance of HHV-6 studies in this species. Since in vitro studies have shown that another nonhuman primate, the pig-tailed macaque (Macaca nemestrina), is highly susceptible to HHV-6 infection (Lusso et al., 1994), this species was chosen for an in vivo study of experimental coinfection performed in 1994-1996 at the National Cancer Institute in Bethesda, Maryland (Lusso et al., unpublished). The prototype HHV-6 subgroup A strain (GS) and a pathogenic SIV strain (smE660) were employed in these experiments. Three groups of four young adult animals were infected by intravenous injection with either SIV alone (group 1), HHV-6 alone (group 2) or both viruses (group 3), and then followed longitudinally for several virological, im-munological and clinical parameters. The infections in group 3 were performed sequentially, with a 14-day interval between SIV injection and the subsequent HHV-6 superinfection. As expected, since the animals were immunocompetent before the inoculations, infection with HHV-6 alone resulted in only transient viremia without any evident short- and long-term clinical consequences. Consistent with previous studies using the SIVsmE660 strain, infection with SIV alone induced a progressive immunological deterioration with a rapid loss of circulating CD4+ T cells, but clinical progression to full-blown AIDS occurred in only one out of four animals within the 32 months of the study. By contrast, HHV-6 coinfection induced a dramatic acceleration of the clinical progression, with the appearance of AIDS-defining conditions in all the animals before termination of the study. The mean time to euthanasia for AIDS-related conditions was 20 + 6.7 months in coinfected animals vs. >27 months in those infected with SIV alone. The depletion of circulating CD4 + and, more strikingly, CD8+ T lymphocytes in peripheral blood was more rapid in coinfected animals. SIV antigenemia and HHV-6 plasma viremia were both positive during the early phase of the coinfection. Morever, simultaneous replication of SIV and HHV-6 was documented by in situ hybridization in lymph nodes. These data provided the first conclusive evidence in a relevant primate model in vivo that co-infection with HHV-6 A significantly accelerates the progression of SIV disease.

The potential mechanisms underlying the accelerated disease progression in HHV-6-SIV-coinfected macaques were recently investigated through an extensive biological characterization of the SIV isolates obtained from singly and dually infected animals between 10 and 12 months post-inoculation. Strikingly, while the SIV isolates derived from singly-infected macaques were regularly sensitive to inhibition by RANTES, in agreement with their dependence on CCR5 for entry, all the isolates derived from coinfected macaques showed a marked RANTES resistance, and in two cases even RANTES dependence, as they grew more efficiently in the presence of RANTES (Biancotto et al., unpublished). These results are consistent with the model derived from the observations made in human lymphoid tissue ex vivo: HHV-6 may exert a selective pressure through the induction of RANTES in vivo, driving SIV to become resistant to RANTES-mediated inhibition. Although the use of alternative coreceptors cannot be totally, ruled out these SIV isolates were unable to grow in CCR5-A32/A32 T cells and thus may have learnt how to engage CCR5 in a different manner, which is insensitive to or even dependent on the presence of the bound inhibitor. Likewise, HIV-1 resistance to CCR5-targeted inhibitors was shown to develop without a change in coreceptor usage (Kuhmann et al., 2004).

In conclusion, coinfection studies in macaques have provided an intriguing model for elucidating the interactions between HHV-6 and primate immunodeficiency viruses in vivo. The accelerated induction of SIV disease observed in co-infected animals represents the first conclusive in vivo evidence of the role of HHV-6 as a progression cofactor in AIDS. Moreover, the phenotypic changes detected in SIV isolates derived after about 1 year of HHV-6 coinfection in vivo reveal the footprints of RANTES induction by HHV-6, providing a proof-of-principle of the model derived from ex vivo studies in lymphoid tissue.

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