Joshi Anjali, Sedano Melina, Beauchamp Bethany, Punke Erin B, Mulla Zuber D, Meza Armando, Alozie Ogechika K, Mukherjee Debabrata, Garg Himanshu
Center of Excellence for Infectious Diseases, Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX 79905;
Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905;
J Immunol. 2016 Feb 15;196(4):1768-79. doi: 10.4049/jimmunol.1501588. Epub 2016 Jan 13.
The mechanism behind the selective depletion of CD4(+) cells in HIV infections remains undetermined. Although HIV selectively infects CD4(+) cells, the relatively few infected cells in vivo cannot account for the extent of CD4(+) T cell depletion, suggesting indirect or bystander mechanisms. The role of virus replication, Env glycoprotein phenotype, and immune activation (IA) in this bystander phenomenon remains controversial. Using samples derived from HIV-infected patients, we demonstrate that, although IA in both CD4(+) and CD8(+) subsets correlates with CD4 decline, apoptosis in CD4(+) and not CD8(+) cells is associated with disease progression. Because HIV-1 Env glycoprotein has been implicated in bystander apoptosis, we cloned full-length Envs from plasma of viremic patients and tested their apoptosis-inducing potential (AIP). Interestingly, AIP of HIV-1 Env glycoproteins were found to correlate inversely with CD4:CD8 ratios, suggesting a role of Env phenotype in disease progression. In vitro mitogenic stimulation of PBMCs resulted in upregulation of IA markers but failed to alter the CD4:CD8 ratio. However, coculture of normal PBMCs with Env-expressing cells resulted in selective CD4 loss that was significantly enhanced by IA. Our study demonstrates that AIP of HIV-1 Env and IA collectively determine CD4 loss in HIV infection.
HIV感染中CD4(+)细胞选择性耗竭背后的机制仍未明确。尽管HIV选择性感染CD4(+)细胞，但体内相对较少的被感染细胞并不能解释CD4(+) T细胞耗竭的程度，这表明存在间接或旁观者机制。病毒复制、Env糖蛋白表型和免疫激活（IA）在这种旁观者现象中的作用仍存在争议。利用来自HIV感染患者的样本，我们证明，尽管CD4(+)和CD8(+)亚群中的IA均与CD4下降相关，但CD4(+)而非CD8(+)细胞中的凋亡与疾病进展相关。由于HIV-1 Env糖蛋白与旁观者凋亡有关，我们从病毒血症患者的血浆中克隆了全长Env，并测试了它们的凋亡诱导潜力（AIP）。有趣的是，发现HIV-1 Env糖蛋白的AIP与CD4:CD8比值呈负相关，这表明Env表型在疾病进展中起作用。体外对PBMCs的促有丝分裂刺激导致IA标志物上调，但未能改变CD4:CD8比值。然而，正常PBMCs与表达Env的细胞共培养导致选择性CD4丢失，IA可显著增强这种丢失。我们的研究表明，HIV-1 Env的AIP和IA共同决定了HIV感染中CD4的丢失。
