Existence of Replication-Competent Minor Variants with Different Coreceptor Usage in Plasma from HIV-1-Infected Individuals
Existence of Replication-Competent Minor Variants with Different Coreceptor Usage in Plasma from HIV-1-Infected Individuals
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DOI：
10.1128/jvi.00193-20
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发表时间：
2020-06-01
影响因子：
5.4
通讯作者：
Takiguchi, Masafumi
中科院分区：
文献类型：
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作者：
Maeda, Yosuke;Takemura, Taichiro;Takiguchi, Masafumi
HIV-1进入细胞由其主要受体CD 4和辅助受体CCR 5或CXCR 4介导，后者具有病毒包膜糖蛋白gp 120。一般来说，使用CCR 5的HIV-1变异体（称为R5）在感染的大部分过程中占主导地位，而使用CXCR 4的HIV-1变异体（利用CCR 5和CXCR 4 [R5 X4，或双重]或CXCR 4单独[X4]的变异体）出现在一半HIV-1感染个体的晚期感染中，并与疾病进展相关。虽然X4变异体在某些情况下也出现在急性期感染期间，但这些变异体此后明显下降到无法检测的水平。在这项研究中，复制能力的X4变异体是从感染HIV-1毒株CRF01_AE的药物治疗初治个体的血浆中分离出来的，CRF01_AE主要携带R5变异体的病毒RNA（vRNA）。下一代测序（NGS）证实，X4变体的序列确实存在于这些个体的血浆vRNA中，作为少数群体。另一方面，在一个具有X4变体占优势的混合感染的个体中，仅从血浆中分离出R5复制能力变体。这些结果表明存在的复制能力的变体与不同的辅助受体的使用作为minor population.IMPORTANCE的辅助受体开关的HIV-1从R5到CXCR 4使用的变体（R5 X4或X4）已观察到约一半的HIV-1感染的个体在感染后期的CD 4细胞计数和疾病进展的损失。然而，现阶段使用CXCR 4的变异体出现的机制尚不清楚。在本研究中，从主要携带R5变体vRNA的HIV-1感染者的血浆样本中分离出使用CXCR 4的X4变体。使用下一代测序将X4变体的序列检测为次要群体。综上所述，当在感染过程中维持具有复制能力的使用CXCR 4的变体作为少数群体时，后期感染中使用CXCR 4的变体可能出现。本研究可能支持的假设，即R5到X4转换是介导的扩展预先存在的X4变异在某些情况下。
Cell entry by HIV-1 is mediated by its principal receptor, CD4, and a coreceptor, either CCR5 or CXCR4, with viral envelope glycoprotein gp120. Generally, CCR5-using HIV-1 variants, called R5, predominate over most of the course of infection, while CXCR4-using HIV-1 variants (variants that utilize both CCR5 and CXCR4 [R5X4, or dual] or CXCR4 alone [X4]) emerge at late-stage infection in half of HIV-1-infected individuals and are associated with disease progression. Although X4 variants also appear during acute-phase infection in some cases, these variants apparently fall to undetectable levels thereafter. In this study, replication-competent X4 variants were isolated from plasma of drug treatment-naive individuals infected with HIV-1 strain CRF01_AE, which dominantly carries viral RNA (vRNA) of R5 variants. Next-generation sequencing (NGS) confirmed that sequences of X4 variants were indeed present in plasma vRNA from these individuals as a minor population. On the other hand, in one individual with a mixed infection in which X4 variants were dominant, only R5 replication-competent variants were isolated from plasma. These results indicate the existence of replication-competent variants with different coreceptor usage as minor populations.IMPORTANCE The coreceptor switch of HIV-1 from R5 to CXCR4-using variants (R5X4 or X4) has been observed in about half of HIV-1-infected individuals at late-stage infection with loss of CD4 cell count and disease progression. However, the mechanisms that underlie the emergence of CXCR4-using variants at this stage are unclear. In the present study, CXCR4-using X4 variants were isolated from plasma samples of HIV-1-infected individuals that dominantly carried vRNA of R5 variants. The sequences of the X4 variants were detected as a minor population using next-generation sequencing. Taken together, CXCR4-using variants at late-stage infection are likely to emerge when replication-competent CXCR4-using variants are maintained as a minor population during the course of infection. The present study may support the hypothesis that R5-to-X4 switching is mediated by the expansion of preexisting X4 variants in some cases.