Micci Luca, Alvarez Xavier, Iriele Robin I, Ortiz Alexandra M, Ryan Emily S, McGary Colleen S, Deleage Claire, McAtee Brigitte B, He Tianyu, Apetrei Cristian, Easley Kirk, Pahwa Savita, Collman Ronald G, Derdeyn Cynthia A, Davenport Miles P, Estes Jacob D, Silvestri Guido, Lackner Andrew A, Paiardini Mirko
Division of Microbiology & Immunology, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Tulane National Primate Research Center, Tulane University School of Medicine, Covington, Louisiana, United States of America.
PLoS Pathog. 2014 Oct 30;10(10):e1004467. doi: 10.1371/journal.ppat.1004467. eCollection 2014 Oct.
In rhesus macaques (RMs), experimental depletion of CD4+ T-cells prior to SIV infection results in higher viremia and emergence of CD4-independent SIV-envelopes. In this study we used the rhesus recombinant anti-CD4 antibody CD4R1 to deplete RM CD4+ T-cells prior to SIVmac251 infection and investigate the sources of the increased viral burden and the lifespan of productively infected cells. CD4-depleted animals showed (i) set-point viral load two-logs higher than controls; (ii) macrophages constituting 80% of all SIV vRNA+ cells in lymph node and mucosal tissues; (iii) substantial expansion of pro-inflammatory monocytes; (iv) aberrant activation and infection of microglial cells; and (v) lifespan of productively infected cells significantly longer in comparison to controls, but markedly shorter than previously estimated for macrophages. The net effect of CD4+ T-cell depletion is an inability to control SIV replication and a shift in the tropism of infected cells to macrophages, microglia, and, potentially, other CD4-low cells which all appear to have a shortened in vivo lifespan. We believe these findings have important implications for HIV eradication studies.
在恒河猴（RMs）中，在感染猴免疫缺陷病毒（SIV）之前对CD4 + T细胞进行实验性耗竭会导致更高的病毒血症以及不依赖CD4的SIV包膜的出现。在本研究中，我们使用恒河猴重组抗CD4抗体CD4R1在感染SIVmac251之前耗竭恒河猴CD4 + T细胞，并研究病毒载量增加的来源以及有效感染细胞的寿命。CD4耗竭的动物表现出：（i）设定点病毒载量比对照组高两个对数；（ii）巨噬细胞占淋巴结和粘膜组织中所有SIV vRNA +细胞的80％；（iii）促炎性单核细胞大量扩增；（iv）小胶质细胞异常激活和感染；以及（v）与对照组相比，有效感染细胞的寿命明显更长，但明显短于先前对巨噬细胞的估计。CD4 + T细胞耗竭的净效应是无法控制SIV复制，并且感染细胞的嗜性转变为巨噬细胞、小胶质细胞以及可能的其他CD4低细胞（所有这些细胞在体内的寿命似乎都缩短了）。我们认为这些发现对HIV根除研究具有重要意义。
