Baseline CD4+ T Cell Counts Correlates with HIV-1 Synonymous Rate in HLA-B*5701 Subjects with Different Risk of Disease Progression

HLA-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression, although risk of progression may vary among patients carrying this allele. The interplay between HIV-1 evolutionary rate variation and risk of progression to AIDS in HLA-B*5701 subjects was studied using longitudinal viral sequences from high-risk progressors (HRPs) and low-risk progressors (LRPs). Posterior distributions of HIV-1 genealogies assuming a Bayesian relaxed molecular clock were used to estimate the absolute rates of nonsynonymous and synonymous substitutions for different set of branches. Rates of viral evolution, as well as in vitro viral replication capacity assessed using a novel phenotypic assay, were correlated with various clinical parameters. HIV-1 synonymous substitution rates were significantly lower in LRPs than HRPs, especially for sets of internal branches. The viral population infecting LRPs was also characterized by a slower increase in synonymous divergence over time. This pattern did not correlate to differences in viral fitness, as measured by in vitro replication capacity, nor could be explained by differences among subjects in T cell activation or selection pressure. Interestingly, a significant inverse correlation was found between baseline CD4+ T cell counts and mean HIV-1 synonymous rate (which is proportional to the viral replication rate) along branches representing viral lineages successfully propagating through time up to the last sampled time point. The observed lower replication rate in HLA-B*5701 subjects with higher baseline CD4+ T cell counts provides a potential model to explain differences in risk of disease progression among individuals carrying this allele.

人类白细胞抗原B*5701（HLA-B*5701）是与人类免疫缺陷病毒1型（HIV-1）感染后疾病进展缓慢关联最强的宿主因子，但携带该等位基因的患者间疾病进展风险仍存在差异。本研究针对携带HLA-B*5701的受试者，利用高进展者（HRPs）与低进展者（LRPs）的纵向病毒序列，探究了HIV-1进化速率变异与艾滋病（AIDS）进展风险之间的相互作用。研究采用贝叶斯松弛分子钟（Bayesian relaxed molecular clock）假设下的HIV-1谱系后验分布，估算了不同分支集合的非同义替换与同义替换绝对速率。将病毒进化速率，以及通过新型表型检测评估的体外病毒复制能力，与多项临床参数进行相关性分析。结果显示，低进展者的HIV-1同义替换速率显著低于高进展者，尤其在内部分支集合中更为显著；低进展者体内病毒群体的同义分歧随时间增长的速度也更为缓慢。上述模式与体外复制能力所反映的病毒适配性差异无关，也无法通过受试者间T细胞活化或选择压力的差异解释。值得注意的是，基线CD4+ T细胞计数与代表成功延续至末次采样时间点的病毒谱系分支的平均HIV-1同义替换速率（与病毒复制速率正相关）呈显著负相关。本研究观察到基线CD4+ T细胞计数更高的HLA-B*5701携带者体内病毒复制速率更低，这为解释该等位基因携带者间疾病进展风险差异提供了潜在模型。