Mefford Megan E, Kunstman Kevin, Wolinsky Steven M, Gabuzda Dana
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA, USA.
Northwestern University Medical School, Chicago, IL, USA.
Virology. 2015 Jul;481:210-22. doi: 10.1016/j.virol.2015.01.032. Epub 2015 Mar 20.
Macrophages express low levels of the CD4 receptor compared to T-cells. Macrophage-tropic HIV strains replicating in brain of untreated patients with HIV-associated dementia (HAD) express Envs that are adapted to overcome this restriction through mechanisms that are poorly understood. Here, bioinformatic analysis of env sequence datasets together with functional studies identified polymorphisms in the β3 strand of the HIV gp120 bridging sheet that increase M-tropism. D197, which results in loss of an N-glycan located near the HIV Env trimer apex, was detected in brain in some HAD patients, while position 200 was estimated to be under positive selection. D197 and T/V200 increased fusion and infection of cells expressing low CD4 by enhancing gp120 binding to CCR5. These results identify polymorphisms in the HIV gp120 bridging sheet that overcome the restriction to macrophage infection imposed by low CD4 through enhanced gp120-CCR5 interactions, thereby promoting infection of brain and other macrophage-rich tissues.
与T细胞相比，巨噬细胞表达的CD4受体水平较低。在患有HIV相关痴呆（HAD）的未治疗患者大脑中复制的嗜巨噬细胞HIV毒株表达的包膜蛋白（Env）能够通过一些尚不清楚的机制来克服这种限制。在此，对Env序列数据集进行生物信息学分析并结合功能研究，确定了HIV gp120桥接片层β3链中的多态性，这些多态性增加了对巨噬细胞的嗜性。在一些HAD患者的大脑中检测到D197，它导致HIV Env三聚体顶端附近一个N-聚糖缺失，而200位被估计处于正选择状态。D197和T/V200通过增强gp120与CCR5的结合，增加了低表达CD4细胞的融合和感染。这些结果确定了HIV gp120桥接片层中的多态性，这些多态性通过增强gp120-CCR5相互作用克服了低CD4对巨噬细胞感染的限制，从而促进了大脑和其他富含巨噬细胞组织的感染。
