Early Selection in Gag by Protective HLA Alleles Contributes to Reduced HIV-1 Replication Capacity That May Be Largely Compensated for in Chronic Infection
Early Selection in Gag by Protective HLA Alleles Contributes to Reduced HIV-1 Replication Capacity That May Be Largely Compensated for in Chronic Infection
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DOI：
10.1128/jvi.01086-10
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发表时间：
2010-11-01
影响因子：
5.4
通讯作者：
Allen, Todd M.
中科院分区：
文献类型：
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作者：
Brockman, Mark A.;Brumme, Zabrina L.;Allen, Todd M.
允许逃避CD 8 T细胞应答的突变在HIV-1中很常见，并且可能通过降低病毒适应性来减弱发病机制。虽然这已被证明为个别情况下，HLA I类介导的选择对HIV-1的体外复制能力（RC）的后果的系统调查尚未进行。我们通过从66名急性/早期和803名慢性未治疗的B亚型感染者中产生表达血浆HIV-1 RNA衍生的GAG蛋白酶序列的重组病毒，并使用绿色荧光蛋白（GFP）报告CD 4 T细胞测定法测量其RC，来研究这个问题。在急性/早期感染中，来自表达保护性等位基因HLA-B *57、-B*5801和/或-B*13的个体的病毒显示出比来自缺乏这些等位基因的个体的病毒显著更低的RC（P < 0.05）。此外，急性/早期RC与HLA-B相关Gag多态性的存在呈负相关（R = -0.27; P = 0.03），表明在感染的最初几个月期间，原发性逃逸突变对适应性的累积效应。在感染的慢性阶段，RC和保护性HLA-B等位基因之间或与保护性等位基因限制的HLA-B相关多态性的存在之间未观察到强相关性，尽管检测这些相关性的统计能力增加。然而，RC与来自携带Gag T242 N突变的B*57表达个体的慢性病毒中已知的补偿突变的存在正相关（n = 50; R = 0.36; P = 0.01），这表明通过次级位点的突变来拯救适应性缺陷。鉴定了可能调节T242 N突变对RC影响的Gag中的其他突变。慢性感染组RC与CD_4细胞计数呈负相关（R = -0.17; P
Mutations that allow escape from CD8 T-cell responses are common in HIV-1 and may attenuate pathogenesis by reducing viral fitness. While this has been demonstrated for individual cases, a systematic investigation of the consequence of HLA class I-mediated selection on HIV-1 in vitro replication capacity (RC) has not been undertaken. We examined this question by generating recombinant viruses expressing plasma HIV-1 RNA-derived Gag-Protease sequences from 66 acute/early and 803 chronic untreated subtype B-infected individuals in an NL4-3 background and measuring their RCs using a green fluorescent protein (GFP) reporter CD4 T-cell assay. In acute/early infection, viruses derived from individuals expressing the protective alleles HLA-B*57, -B*5801, and/or -B*13 displayed significantly lower RCs than did viruses from individuals lacking these alleles (P < 0.05). Furthermore, acute/early RC inversely correlated with the presence of HLA-B-associated Gag polymorphisms (R = -0.27; P = 0.03), suggesting a cumulative effect of primary escape mutations on fitness during the first months of infection. At the chronic stage of infection, no strong correlations were observed between RC and protective HLA-B alleles or with the presence of HLA-B-associated polymorphisms restricted by protective alleles despite increased statistical power to detect these associations. However, RC correlated positively with the presence of known compensatory mutations in chronic viruses from B*57-expressing individuals harboring the Gag T242N mutation (n = 50; R = 0.36; P = 0.01), suggesting that the rescue of fitness defects occurred through mutations at secondary sites. Additional mutations in Gag that may modulate the impact of the T242N mutation on RC were identified. A modest inverse correlation was observed between RC and CD4 cell count in chronic infection (R = -0.17; P