Kuwata Takeo, Byrum Russell, Whitted Sonya, Goeken Robert, Buckler-White Alicia, Plishka Ronald, Iyengar Ranjini, Hirsch Vanessa M
Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
J Virol. 2007 Sep;81(17):8891-904. doi: 10.1128/JVI.00614-07. Epub 2007 Jun 27.
A subset of simian immunodeficiency virus (SIV)-infected macaques progresses rapidly to disease with transient SIV-specific immune responses and high viral loads. Unique SIV variants with convergent Env mutations evolve in these rapid progressor (RP) macaques. To address the pathogenic significance of RP-specific variants, we generated infectious molecular clones from the terminal-phase plasma of an RP macaque. Inoculation of macaques with a representative clone, SIVsmH635FC, resulted in a persistent viremia, comparable to that produced by pathogenic SIVsmE543-3, and a chronic disease with progressive loss of CD4(+) T cells. However, SIVsmH635FC did not reproduce the rapid-disease phenomenon. Molecular analyses of viruses from these macaques revealed rapid reversion to the wild-type SIVsmE543-3 sequence at two RP-specific sites and slower reversion at another three sites. SIVsmH635FC infection was not sufficient to cause rapid progression even following coinoculation with SIVsmE543-3, despite acute depletion of memory CD4(+) T cells. SIVsmH635FC competed efficiently during primary infection in the coinoculated macaques, but SIVsmE543-3 predominated after the development of SIV-specific immune responses. These data suggest that the replication fitness of the RP variant was similar to that of SIVsmE543-3 in a naïve host; however, SIVsmH635FC was at a disadvantage following the development of SIV-specific immune responses. Consistent with these findings, neutralization assays revealed that SIVsmH635FC was highly sensitive to neutralization but that the parental SIVsmE543-3 strain was highly resistant. This study suggests that the evolution of RP-specific variants is the result of replication in a severely immunocompromised host, rather than the direct cause of rapid progression.
感染猿猴免疫缺陷病毒（SIV）的猕猴亚群会迅速发展为疾病，伴有短暂的SIV特异性免疫反应和高病毒载量。具有趋同Env突变的独特SIV变体在这些快速进展型（RP）猕猴中进化。为了探究RP特异性变体的致病意义，我们从一只RP猕猴的终末期血浆中生成了感染性分子克隆。用代表性克隆SIVsmH635FC接种猕猴，导致持续病毒血症，与致病性SIVsmE543 - 3产生的病毒血症相当，并引发慢性疾病，伴有CD4(+) T细胞逐渐减少。然而，SIVsmH635FC并未重现快速发病现象。对这些猕猴体内病毒的分子分析显示，在两个RP特异性位点迅速回复为野生型SIVsmE543 - 3序列，在另外三个位点回复较慢。即使与SIVsmE543 - 3共同接种，SIVsmH635FC感染也不足以导致快速进展，尽管记忆CD4(+) T细胞会急性耗竭。在共同接种的猕猴初次感染期间，SIVsmH635FC有效竞争，但在SIV特异性免疫反应发展后，SIVsmE543 - 3占主导。这些数据表明，RP变体在未感染宿主中的复制适应性与SIVsmE543 - 3相似；然而，在SIV特异性免疫反应发展后，SIVsmH635FC处于劣势。与这些发现一致，中和试验显示SIVsmH635FC对中和高度敏感，但亲本SIVsmE543 - 3毒株高度耐药。这项研究表明，RP特异性变体的进化是在严重免疫受损宿主中复制的结果，而非快速进展的直接原因。
Proc Natl Acad Sci U S A. 2004-8-17
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