Kuang Xiaomei T, Li Xiaoguang, Anmole Gursev, Mwimanzi Philip, Shahid Aniqa, Le Anh Q, Chong Louise, Qian Hua, Miura Toshiyuki, Markle Tristan, Baraki Bemuluyigza, Connick Elizabeth, Daar Eric S, Jessen Heiko, Kelleher Anthony D, Little Susan, Markowitz Martin, Pereyra Florencia, Rosenberg Eric S, Walker Bruce D, Ueno Takamasa, Brumme Zabrina L, Brockman Mark A
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada.
Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
J Virol. 2014 Sep 1;88(17):10200-13. doi: 10.1128/JVI.01334-14. Epub 2014 Jun 25.
Host and viral factors influence the HIV-1 infection course. Reduced Nef function has been observed in HIV-1 controllers during the chronic phase, but the kinetics and mechanisms of Nef attenuation in such individuals remain unclear. We examined plasma RNA-derived Nef clones from 10 recently infected individuals who subsequently suppressed viremia to less than 2,000 RNA copies/ml within 1 year postinfection (acute controllers) and 50 recently infected individuals who did not control viremia (acute progressors). Nef clones from acute controllers displayed a lesser ability to downregulate CD4 and HLA class I from the cell surface and a reduced ability to enhance virion infectivity compared to those from acute progressors (all P<0.01). HLA class I downregulation activity correlated inversely with days postinfection (Spearman's R=-0.85, P=0.004) and positively with baseline plasma viral load (Spearman's R=0.81, P=0.007) in acute controllers but not in acute progressors. Nef polymorphisms associated with functional changes over time were identified in follow-up samples from six controllers. For one such individual, mutational analyses indicated that four polymorphisms selected by HLA-A31 and B37 acted in combination to reduce Nef steady-state protein levels and HLA class I downregulation activity. Our results demonstrate that relative control of initial HIV-1 viremia is associated with Nef clones that display reduced function, which in turn may influence the course of HIV-1 infection. Transmission of impaired Nef sequences likely contributed in part to this observation; however, accumulation of HLA-associated polymorphisms in Nef that impair function also suggests that CD8+ T-cell pressures play a role in this phenomenon.
Rare individuals can spontaneously control HIV-1 viremia in the absence of antiretroviral treatment. Understanding the host and viral factors that contribute to the controller phenotype may identify new strategies to design effective vaccines or therapeutics. The HIV-1 Nef protein enhances viral pathogenesis through multiple mechanisms. We examined the function of plasma HIV-1 RNA-derived Nef clones isolated from 10 recently infected individuals who subsequently controlled HIV viremia compared to the function of those from 50 individuals who failed to control viremia. Our results demonstrate that early Nef clones from HIV controllers displayed lower HLA class I and CD4 downregulation activity, as well as a reduced ability to enhance virion infectivity. The accumulation of HLA-associated polymorphisms in Nef during the first year postinfection was associated with impaired protein function in some controllers. This report highlights the potential for host immune responses to modulate HIV pathogenicity and disease outcome by targeting cytotoxic T lymphocyte (CTL) epitopes in Nef.
宿主和病毒因素会影响HIV-1感染进程。在慢性期的HIV-1病毒控制者中已观察到Nef功能降低，但这些个体中Nef衰减的动力学和机制仍不清楚。我们检测了10名近期感染个体的血浆RNA衍生的Nef克隆，这些个体在感染后1年内病毒血症抑制至低于2000 RNA拷贝/毫升（急性控制者），以及50名未控制病毒血症的近期感染个体（急性进展者）。与急性进展者相比，急性控制者的Nef克隆下调细胞表面CD4和I类HLA的能力较弱，增强病毒体感染性的能力也较低（所有P<0.01）。在急性控制者中，I类HLA下调活性与感染后天数呈负相关（斯皮尔曼相关系数R=-0.85，P=0.004），与基线血浆病毒载量呈正相关（斯皮尔曼相关系数R=0.81，P=0.007），而在急性进展者中则不然。在6名控制者的随访样本中鉴定出与功能随时间变化相关的Nef多态性。对于其中一名个体，突变分析表明，由HLA-A31和B37选择的四个多态性共同作用，降低了Nef稳态蛋白水平和I类HLA下调活性。我们的结果表明，对初始HIV-1病毒血症的相对控制与功能降低的Nef克隆相关，这反过来可能影响HIV-1感染进程。受损Nef序列的传播可能部分导致了这一观察结果；然而，Nef中与HLA相关的损害功能的多态性积累也表明CD8+T细胞压力在这一现象中起作用。
少数个体在无抗逆转录病毒治疗的情况下可自发控制HIV-1病毒血症。了解促成控制者表型的宿主和病毒因素可能会确定设计有效疫苗或治疗方法的新策略。HIV-1 Nef蛋白通过多种机制增强病毒致病性。我们检测了从10名近期感染个体中分离的血浆HIV-1 RNA衍生的Nef克隆的功能，这些个体随后控制了HIV病毒血症，并将其与50名未控制病毒血症个体的Nef克隆功能进行了比较。我们的结果表明，HIV控制者的早期Nef克隆显示出较低的I类HLA和CD4下调活性，以及增强病毒体感染性的能力降低。感染后第一年Nef中与HLA相关的多态性积累与一些控制者的蛋白功能受损有关。本报告强调了宿主免疫反应通过靶向Nef中的细胞毒性T淋巴细胞（CTL）表位来调节HIV致病性和疾病结局的潜力。
