Ruhanya Vurayai, Jacobs Graeme Brendon, Paul Robert H, Joska John A, Seedat Soraya, Nyandoro George, Glashoff Richard Helmuth, Engelbrecht Susan
Division of Medical Virology, Department of Pathology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Department of Medical Microbiology, University of Zimbabwe, Harare, Zimbabwe.
AIDS Res Hum Retroviruses. 2023 Apr;39(4):166-175. doi: 10.1089/AID.2022.0022. Epub 2023 Jan 13.
There is increasing evidence that HIV-1 viral protein R (Vpr) plays an important role in the pathogenesis of cognitive impairment. We investigated the relationship between HIV-1 subtype C Vpr sequence variation and HIV-associated neurocognitive impairment as measured by global deficit score (GDS) in treatment-naive individuals. We used different bioinformatic tools and statistical models to correlate vpr variation and cognitive function. We identified a tyrosine at position 45 (45Y) as a signature for neurocognitive impairment and histidine (45H) as a signature in the non-impaired individuals. The presence of signature 45Y was associated by 3.66 times higher GDS, 525 times higher plasma viral load, 15.84 times higher proviral load, and 60% lower absolute CD4-T cell count compared with those without the signature. Additionally, we identified four conserved Vpr fragment sequences, PEDQGPQREPYNEWTLE (5-21), LGQYIY (42-47), TYGDTW (49-54), and PEDQGPQREPYNEW (5-18), that were associated with higher plasma viral load and proviral load. The implication of these findings is that variation of Vpr leads to neurocognitive impairment in HIV infection and worsens the progression of disease in general by promoting the production of provirus, promoting HIV replication and depletion of CD4+ T cells in the periphery.
越来越多的证据表明，HIV-1病毒蛋白R（Vpr）在认知障碍的发病机制中起重要作用。我们调查了在未经治疗的个体中，HIV-1 C亚型Vpr序列变异与通过整体缺陷评分（GDS）衡量的HIV相关神经认知障碍之间的关系。我们使用了不同的生物信息学工具和统计模型来关联vpr变异与认知功能。我们确定第45位的酪氨酸（45Y）是神经认知障碍的标志，而组氨酸（45H）是未受影响个体的标志。与没有该标志的个体相比，标志45Y的存在与GDS高3.66倍、血浆病毒载量高525倍、前病毒载量高15.84倍以及绝对CD4-T细胞计数低60%相关。此外，我们确定了四个保守的Vpr片段序列，PEDQGPQREPYNEWTLE（5-21）、LGQYIY（42-47）、TYGDTW（49-54）和PEDQGPQREPYNEW（5-18），它们与更高的血浆病毒载量和前病毒载量相关。这些发现的意义在于，Vpr的变异导致HIV感染中的神经认知障碍，并通过促进前病毒的产生、促进HIV复制和外周CD4+ T细胞的耗竭，总体上使疾病进展恶化。
