Biancotto Angélique, Grivel Jean-Charles, Lisco Andrea, Vanpouille Christophe, Markham Phillip D, Gallo Robert C, Margolis Leonid B, Lusso Paolo
Laboratory of Molecular and Cellular Biophysics, National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
Retrovirology. 2009 Jul 2;6(Suppl 2):61. doi: 10.1186/1742-4690-6-61.
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.
进展为艾滋病通常与HIV-1向更高毒力和/或致病性的演变相关。有证据表明，HIV-1的一种毒力因子是对CCR5结合趋化因子的抗性，最显著的是RANTES，据信其在体内对HIV-1的控制中发挥作用。HIV-1可以通过从仅使用CCR5的表型转换为扩大的共受体特异性，或通过获得CCR5使用的替代方式来实现对RANTES的抗性。一种可能促进HIV-1向RANTES抗性演变的感染因子是人类疱疹病毒6A（HHV-6A），它在HIV-1感染患者中经常重新激活，并且是淋巴组织中一种有效的RANTES诱导剂。
从感染SIV（smE660）一年左右的食蟹猴（M. nemestrina）或感染SIV（smE660）和HHV-6A（GS）的双重感染食蟹猴中获得的SIV分离株，对其在人或猕猴淋巴组织中的生长能力以及对HHV-6A和RANTES介导的体外抑制的敏感性进行了表征。在4只HHV-6A共感染的猕猴中，有4只在感染后2年内都进展为全面的艾滋病，尽管它们保持仅使用CCR5共受体的特异性，但发现它们携带的SIV变体对HHV-6A和RANTES的敏感性均降低；来自其中两只动物的病毒在外源HHV-6A或RANTES存在时复制得更加旺盛。在HHV-6A共感染的猕猴中出现的SIV变体显示出整体体外复制能力降低，在添加外源RANTES后部分得到逆转，这与IL-2抑制和IFN-γ产生增强有关。相比之下，从两只单独感染的猕猴中获得的SIV分离株，它们都没有进展为艾滋病，仍保持对HHV-6A/RANTES的敏感性，而在单独感染的猕猴中唯一进展为艾滋病的个体产生了一种对HHV-6A/RANTES具有部分抗性且复制能力增强的SIV变体，这与共受体使用的扩大有关。
这些结果提供了在快速进展为艾滋病的猕猴中SIV向RANTES抗性演变的体内证据。对RANTES的抗性可能代表一种常见的毒力因子，使灵长类免疫缺陷逆转录病毒能够逃避宿主抗病毒防御的关键机制。
