HIV-1 envelope subregion length variation during disease progression.
HIV-1 envelope subregion length variation during disease progression.
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DOI：
10.1371/journal.ppat.1001228
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发表时间：
2010-12-16
期刊：
影响因子：
6.7
通讯作者：
Mullins JI
中科院分区：
文献类型：
--
作者：
Curlin ME;Zioni R;Hawes SE;Liu Y;Deng W;Gottlieb GS;Zhu T;Mullins JI
HIV-1 Env蛋白的V3环是病毒辅助受体使用的主要决定因素，而V1 V2环区域被认为影响辅助受体结合并参与屏蔽Env糖蛋白gp 120的中和敏感区域免受抗体应答。V1 V2的功能特性和抗原性受氨基酸序列、序列长度和N-连接糖基化模式的变化的影响。然而，这些多态性与HIV发病机制的关系尚不完全清楚。我们检测了来自154名个体（152名为HIV-1 B亚型感染者）的5185个HIV-1 gp 120核苷酸序列片段和临床资料。将序列进行比对、翻译、手动编辑并分成V1 V2、C2、V3、C3、V4、C4和V5亚区。计算V1-V5和亚区长度，并对潜在的N-连接糖基化位点（PNLGS）进行计数。在横断面和纵向分析中，将环长度和PNLGS作为自感染以来的时间、CD 4计数、病毒载量和日历年的函数进行检查。V1 V2长度和PNLGS在慢性感染中显著增加，在晚期感染中下降。在横断面分析中，在1984年至2004年期间，早期和中期疾病受试者的V1 V2长度也按日历年增加。我们的观察表明，在传播时对环长度的选择很少;感染后，HIV-1通过增加V1 V2长度和/或在N连接糖基化位点添加碳水化合物部分来适应宿主免疫反应。V1 V2缩短在早期和晚期感染可能反映无效的宿主免疫。来自慢性病献血者的传播可能导致了在大流行期间观察到的V1 V2长度的适度增加。HIV包膜基因（env）编码病毒表面蛋白（Env），这些蛋白对病毒感染人类并导致人类疾病的基本过程至关重要。env的适应性决定了病毒可以感染哪些细胞，并允许病毒避免被免疫系统清除。Env是已知最易变的基因之一，它可以在单个个体中随时间发生显着变化。然而，Env-宿主细胞相互作用是复杂的且不完全理解的，并且这种病毒蛋白在感染期间的变化尚未被系统地描述。我们检测了来自154名HIV感染不同阶段但从未接受过抗逆转录病毒治疗的个体的大量env序列。我们发现，在慢性感染过程中，env V1 V2区延长，并变得更加严重的糖基化。然而，这些变化在疾病晚期部分逆转，可能是对宿主免疫系统减弱的反应。V1 V2长度也随着时间的推移而增加，这可能与B亚型流行中的HIV传播流行病学有关。这些结果提供了对HIV生物学的基本见解。
The V3 loop of the HIV-1 Env protein is the primary determinant of viral coreceptor usage, whereas the V1V2 loop region is thought to influence coreceptor binding and participate in shielding of neutralization-sensitive regions of the Env glycoprotein gp120 from antibody responses. The functional properties and antigenicity of V1V2 are influenced by changes in amino acid sequence, sequence length and patterns of N-linked glycosylation. However, how these polymorphisms relate to HIV pathogenesis is not fully understood. We examined 5185 HIV-1 gp120 nucleotide sequence fragments and clinical data from 154 individuals (152 were infected with HIV-1 Subtype B). Sequences were aligned, translated, manually edited and separated into V1V2, C2, V3, C3, V4, C4 and V5 subregions. V1-V5 and subregion lengths were calculated, and potential N-linked glycosylation sites (PNLGS) counted. Loop lengths and PNLGS were examined as a function of time since infection, CD4 count, viral load, and calendar year in cross-sectional and longitudinal analyses. V1V2 length and PNLGS increased significantly through chronic infection before declining in late-stage infection. In cross-sectional analyses, V1V2 length also increased by calendar year between 1984 and 2004 in subjects with early and mid-stage illness. Our observations suggest that there is little selection for loop length at the time of transmission; following infection, HIV-1 adapts to host immune responses through increased V1V2 length and/or addition of carbohydrate moieties at N-linked glycosylation sites. V1V2 shortening during early and late-stage infection may reflect ineffective host immunity. Transmission from donors with chronic illness may have caused the modest increase in V1V2 length observed during the course of the pandemic. The HIV envelope gene (env) encodes viral surface proteins (Env) that are vital to the basic processes used by the virus to infect and cause disease in humans. Adaptations in env determine which cells the virus can infect, and permit the virus to avoid elimination by the immune system. Env is one of the most variable genes known, and it can change dramatically over time in a single individual. However, Env-host cell interactions are complex and incompletely understood, and changes in this viral protein during infection have not yet been systematically described. We examined a large number of env sequences from 154 individuals at various stages of HIV infection but who had never received antiretroviral treatment. We found that the env V1V2 region lengthens during chronic infection and becomes more heavily glycosylated. However, these changes partially reverse during late-stage illness, possibly in response to a weakening host immune system. V1V2 lengths are also increasing over time in the epidemic at large, possibly related to the epidemiology of HIV transmission within the subtype B epidemic. These results provide fundamental insights into the biology of HIV.
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