Unidade dos Retrovírus e Infecções Associadas, Centro de Patogénese Molecular, Faculdade de Farmácia de Lisboa, Lisboa, Portugal.
Retrovirology. 2013 Oct 24;10:110. doi: 10.1186/1742-4690-10-110.
Differently from HIV-1, HIV-2 disease progression usually takes decades without antiretroviral therapy and the majority of HIV-2 infected individuals survive as elite controllers with normal CD4⁺ T cell counts and low or undetectable plasma viral load. Neutralizing antibodies (Nabs) are thought to play a central role in HIV-2 evolution and pathogenesis. However, the dynamic of the Nab response and resulting HIV-2 escape during acute infection and their impact in HIV-2 evolution and disease progression remain largely unknown. Our objective was to characterize the Nab response and the molecular and phenotypic evolution of HIV-2 in association with Nab escape in the first years of infection in two children infected at birth.
CD4⁺ T cells decreased from about 50% to below 30% in both children in the first five years of infection and the infecting R5 viruses were replaced by X4 viruses within the same period. With antiretroviral therapy, viral load in child 1 decreased to undetectable levels and CD4+ T cells recovered to normal levels, which have been sustained at least until the age of 12. In contrast, viral load increased in child 2 and she progressed to AIDS and death at age 9. Beginning in the first year of life, child 1 raised high titers of antibodies that neutralized primary R5 isolates more effectively than X4 isolates, both autologous and heterologous. Child 2 raised a weak X4-specific Nab response that decreased sharply as disease progressed. Rate of evolution, nucleotide and amino acid diversity, and positive selection, were significantly higher in the envelope of child 1 compared to child 2. Rates of R5-to-X4 tropism switch, of V1 and V3 sequence diversification, and of convergence of V3 to a β-hairpin structure were related with rate of escape from the neutralizing antibodies.
Our data suggests that the molecular and phenotypic evolution of the human immunodeficiency virus type 2 envelope are related with the dynamics of the neutralizing antibody response providing further support for a model in which Nabs play an important role in HIV-2 pathogenesis.
与 HIV-1 不同，HIV-2 疾病的进展通常在没有抗逆转录病毒治疗的情况下需要数十年的时间，并且大多数 HIV-2 感染者作为精英控制器存活，其 CD4+T 细胞计数正常，血浆病毒载量低或无法检测到。中和抗体（Nabs）被认为在 HIV-2 的进化和发病机制中起核心作用。然而，在急性感染期间，Nab 反应的动态以及由此产生的 HIV-2 逃逸及其对 HIV-2 进化和疾病进展的影响在很大程度上仍然未知。我们的目的是在两名出生时感染的儿童感染的头几年中，描述 Nab 反应以及与 Nab 逃逸相关的 HIV-2 的分子和表型进化。
在感染的前五年中，两个孩子的 CD4+T 细胞从约 50%下降到低于 30%，在此期间，感染的 R5 病毒被 X4 病毒取代。在抗逆转录病毒治疗下，孩子 1 的病毒载量降至无法检测的水平，CD4+T 细胞恢复正常水平，至少持续到 12 岁。相比之下，孩子 2 的病毒载量增加，她在 9 岁时进展为艾滋病并死亡。从出生后的第一年开始，孩子 1 产生了高滴度的抗体，这些抗体比 X4 更有效地中和原发性 R5 分离株，无论是自身的还是异源的。孩子 2 产生了较弱的 X4 特异性 Nab 反应，随着疾病的进展急剧下降。与孩子 2 相比，孩子 1 的包膜中的进化率、核苷酸和氨基酸多样性以及正选择显著更高。R5 至 X4 嗜性转换、V1 和 V3 序列多样化以及 V3 向 β-发夹结构收敛的速率与从中和抗体逃逸的速率相关。
我们的数据表明，HIV-2 包膜的分子和表型进化与中和抗体反应的动态有关，为 Nabs 在 HIV-2 发病机制中起重要作用的模型提供了进一步的支持。
