Functional adaptation of HIV accessory proteins towardimmune-mediated selective pressure

HIV-1 Gag、Pol和Env功能受损已在自发将血浆病毒血症抑制到50RNA拷贝/毫升的精英控制者(EC)中描述；然而，辅助蛋白Nef的活性仍未完全确定。我们检测了从45例EC和46例慢性进展者(CP)血浆中分离到的91个Nef序列下调人类白细胞抗原I类和CD4，上调人类白细胞抗原II类不变链(CD74)，增强病毒感染性，并刺激病毒在PBMC中复制的能力。总体而言，EC的Nef序列是功能性的；然而，EC的所有五种活性都显著低于CP。与非B*57表达的EC相比，表达HLA-B*57的EC的Nef表现出更差的CD4下调功能，并且EC特有的B*57相关Nef多态的数目与这些个体中5种Nef功能中的4种呈负相关。结果表明，病毒蛋白功能降低，部分原因是主机免疫选择压力，可能是EC表型的一个特征。

Impaired HIV-1 Gag, Pol, and Env function has been described inelite controllers (EC) who spontaneously suppress plasma viremia to < 50 RNA copies/mL;however, activity of the accessory protein Nef remains incompletely characterized. Weexamined the ability of 91 Nef sequences, isolated from plasma of 45 EC and 46 chronicprogressors (CP), to down-regulate HLA class I and CD4, up-regulate HLA class II invariantchain (CD74), enhance viral infectivity, and stimulate viral replication in PBMC. Ingeneral, EC Nef sequences were functional; however, all five activities weresignificantly lower in EC compared to CP. Nef from HLA-B*57-expressing EC exhibited poorerCD4 down-regulation function compared to non-B*57 EC, and the number of EC-specificB*57-associated Nef polymorphisms correlated inversely with 4 of 5 Nef functions in theseindividuals. Results indicate that decreased viral protein function, due in part to hostimmune selection pressures, may be a hallmark of the EC phenotype.