Shankarappa R, Margolick J B, Gange S J, Rodrigo A G, Upchurch D, Farzadegan H, Gupta P, Rinaldo C R, Learn G H, He X, Huang X L, Mullins J I
Department of Microbiology, University of Washington School of Medicine, Seattle, Washington 98195-7740, USA.
J Virol. 1999 Dec;73(12):10489-502. doi: 10.1128/JVI.73.12.10489-10502.1999.
To understand the high variability of the asymptomatic interval between primary human immunodeficiency virus type 1 (HIV-1) infection and the development of AIDS, we studied the evolution of the C2-V5 region of the HIV-1 env gene and of T-cell subsets in nine men with a moderate or slow rate of disease progression. They were monitored from the time of seroconversion for a period of 6 to 12 years until the development of advanced disease in seven men. Based on the analysis of viral divergence from the founder strain, viral population diversity within sequential time points, and the outgrowth of viruses capable of utilizing the CXCR4 receptor (X4 viruses), the existence of three distinct phases within the asymptomatic interval is suggested: an early phase of variable duration during which linear increases ( approximately 1% per year) in both divergence and diversity were observed; an intermediate phase lasting an average of 1.8 years, characterized by a continued increase in divergence but with stabilization or decline in diversity; and a late phase characterized by a slowdown or stabilization of divergence and continued stability or decline in diversity. X4 variants emerged around the time of the early- to intermediate-phase transition and then achieved peak representation and began a decline around the transition between the intermediate and late phases. The late-phase transition was also associated with failure of T-cell homeostasis (defined by a downward inflection in CD3(+) T cells) and decline of CD4(+) T cells to </=200 cells/microliter. The strength of these temporal associations between viral divergence and diversity, viral coreceptor specificity, and T-cell homeostasis and subset composition supports the concept that the phases described represent a consistent pattern of viral evolution during the course of HIV-1 infection in moderate progressors. Recognition of this pattern may help explain previous conflicting data on the relationship between viral evolution and disease progression and may provide a useful framework for evaluating immune damage and recovery in untreated and treated HIV-1 infections.
为了解原发性人类免疫缺陷病毒1型（HIV-1）感染与获得性免疫缺陷综合征（AIDS）发生之间无症状期的高度变异性，我们研究了9名疾病进展速度中等或缓慢的男性中HIV-1 env基因C2-V5区域及T细胞亚群的演变情况。从血清转化时起对他们进行了6至12年的监测，直至7名男性发展为晚期疾病。基于对与奠基株病毒差异、连续时间点内病毒群体多样性以及能够利用CXCR4受体的病毒（X4病毒）增殖情况的分析，提示在无症状期内存在三个不同阶段：一个持续时间可变的早期阶段，在此期间观察到差异和多样性均呈线性增加（每年约1%）；一个平均持续1.8年的中期阶段，其特征是差异持续增加但多样性稳定或下降；以及一个晚期阶段，其特征是差异放缓或稳定，多样性持续稳定或下降。X4变异体在早期至中期转变时出现，然后在中期和晚期转变时达到峰值并开始下降。晚期转变还与T细胞内稳态的破坏（由CD3(+) T细胞的向下拐点定义）以及CD4(+) T细胞降至≤200个细胞/微升有关。病毒差异与多样性、病毒共受体特异性、T细胞内稳态及亚群组成之间这些时间关联的强度支持了这样一种概念，即所描述的阶段代表了HIV-1感染中等进展者病程中病毒进化的一致模式。认识到这种模式可能有助于解释先前关于病毒进化与疾病进展关系的相互矛盾的数据，并可能为评估未治疗和已治疗的HIV-1感染中的免疫损伤和恢复提供一个有用的框架。
