Abstract
Progression to AIDS is often associated with the evolution of HIV-1 toward increased virulence and/or pathogenicity. Evidence suggests that a virulence factor for HIV-1 is resistance to CCR5-binding chemokines, most notably RANTES, which are believed to play a role in HIV-1 control in vivo. HIV-1 can achieve RANTES resistance either by phenotypic switching from an exclusive CCR5 usage to an expanded coreceptor specificity, or by the acquisition of alternative modalities of CCR5 usage. An infectious agent that might promote the evolution of HIV-1 toward RANTES resistance is human herpesvirus 6A (HHV-6A), which is frequently reactivated in HIV-1-infected patients and is a potent RANTES inducer in lymphoid tissue. SIV isolates obtained from pig-tailed macaques (M. nemestrina) after approximately one year of single infection with SIV(smE660) or dual infection with SIV(smE660) and HHV-6A(GS) were characterized for their growth capacity and sensitivity to HHV-6A- and RANTES-mediated inhibition in human or macaque lymphoid tissues ex vivo. Four out of 4 HHV-6A-coinfected macaques, all of which progressed to full-blown AIDS within 2 years of infection, were found to harbor SIV variants with a reduced sensitivity to both HHV-6A and RANTES, despite maintaining an exclusive CCR5 coreceptor specificity; viruses derived from two of these animals replicated even more vigorously in the presence of exogenous HHV-6A or RANTES. The SIV variants that emerged in HHV-6A-coinfected macaques showed an overall reduced ex vivo replication capacity that was partially reversed upon addition of exogenous RANTES, associated with suppressed IL-2 and enhanced IFN-gamma production. In contrast, SIV isolates obtained from two singly-infected macaques, none of which progressed to AIDS, maintained HHV-6A/RANTES sensitivity, whereas the only AIDS progressor among singly-infected macaques developed an SIV variant with partial HHV-6A/RANTES resistance and increased replication capacity, associated with expanded coreceptor usage. These results provide in vivo evidence of SIV evolution toward RANTES resistance in macaques rapidly progressing to AIDS. RANTES resistance may represent a common virulence factor allowing primate immunodeficiency retroviruses to evade a critical mechanism of host antiviral defense.
Highlights
Progression to AIDS is often associated with the evolution of HIV-1 toward increased virulence and/or pathogenicity
These results provide the first demonstration of SIV evolution toward RANTES resistance under the influence of a coinfecting microbe, illustrating a potential mechanism for the accelerated progression to full-blown AIDS seen in human herpesvirus 6A (HHV-6A)-coinfected macaques
Altered replicative capacity of SIV isolated from HHV-6Acoinfected macaques For the purpose of this study, we selected 7 SIV isolates obtained after approximately 1 year of inoculation from three macaques singly-infected with SIV and 4 macaques coinfected with HHV-6A and SIV
Summary
Progression to AIDS is often associated with the evolution of HIV-1 toward increased virulence and/or pathogenicity. While coinfection with some agents has been associated with reduced HIV-1 loads and delayed AIDS progression [2,3,4,5], most of these microbes accelerate the clinical course either by inducing opportunistic diseases or by enhancing the level of HIV-1 replication [6]. In vivo studies have documented: i) widespread HHV-6 infection in patients with full-blown AIDS at post-mortem examination [13,14]; ii) frequent reactivation of HHV-6 in early symptomatic HIV-1infected subjects [15]; iii) vigorous HHV-6 replication in lymph nodes of HIV-1-infected subjects, associated with an increased local HIV-1 load [16,17]; and iv) accelerated progression of HIV-1 disease in infants who acquire HHV6 within the first year of life [18]. We recently provided evidence that in vivo coinfection with HHV-6A accelerates the course of simian immunodeficiency virus (SIV) disease in pig-tailed macaques (M. nemestrina) [19]
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