Transcriptional Profiling of Experimental CD8⁺Lymphocyte Depletion in Rhesus Macaques Infected with Simian Immunodeficiency Virus SIVmac239

Abstract

c CD8 ؉ T cells inhibit virus replication in SIV-infected rhesus macaques. However, it is unclear to what extent the viral suppression mediated by CD8؉ T cells reflects direct killing of infected cells as opposed to indirect, noncytolytic mechanisms. In this study, we used functional genomics to investigate noncytolytic mechanisms of in vivo viral suppression mediated by CD8؉ lymphocytes. Eight chronically SIVmac239-infected rhesus macaques underwent CD8؉ lymphocyte depletion, and RNA from whole blood was obtained prior to depletion, during the nadir of CD8 ؉ cell depletion, and after CD8 ؉ lymphocyte numbers had rebounded. We observed significant downregulation of the expression of genes encoding factors that can suppress SIV replication, including the CCR5-binding chemokine CCL5/RANTES and CCL4 and several members of the tripartite motif-containing (TRIM) family. Surprisingly, we also noted a strong, widespread downregulation of ␣-and -defensins with anti-HIV activity, which are not expressed by CD8 ؉ T cells. After cessation of depleting antibody treatment, we observed induction of a transcriptional signature indicative of B lymphocyte activation. Validation experiments demonstrated that animals during this period had elevated levels of B cells coupled with higher expression of the proliferative marker Ki67, indicating that CD8 ؉ depletion triggered a potent expansion of B cell numbers. Collectively, these data identify antiviral pathways perturbed by in vivo CD8؉ T cell depletion that may contribute to noncytolytic control of SIV replication.

Long-Term Control of Simian Immunodeficiency Virus (SIV) in Cynomolgus Macaques Not Associated with Efficient SIV-Specific CD8+T-Cell Responses

“…CD8 ϩ T cells can inhibit HIV/SIV infection through noncytolytic soluble factors (47). Several reports have suggested that these mechanisms may play a major role in the CD8-mediated partial control of SIV infection during primary infection in macaques (48)(49)(50). In vitro infection of mitogen-activated PBMCs has been widely used to reveal the presence of strong activities of these various soluble antiviral factors.…”

The dynamics of simian immunodeficiency virus after depletion of CD8+ cells

“…These studies were taken as strong, if not the main, evidence for an important effect of CD8+ cells in controlling the virus—and likely were one of the key aspects for the rational to develop CD8+ T‐cell‐based vaccines . Subsequent studies used this experimental approach to try to characterize in more detail the biology of HIV/SIV infection and the mechanisms of action of the CD8+ cells . For example, the contrasting results of depleting these cells in pathogenic models of SIV versus natural hosts of SIV, which do not develop overt disease, were analyzed in multiple studies …”

“…26 Subsequent studies used this experimental approach to try to characterize in more detail the biology of HIV/ SIV infection and the mechanisms of action of the CD8+ cells. [41][42][43][44][45][46][47] For example, the contrasting results of depleting these cells in pathogenic models of SIV versus natural hosts of SIV, which do not develop overt disease, were analyzed in multiple studies. [48][49][50][51] One of the most common uses of CD8+ cell depletion is to investigate the effects of vaccine protocols.…”

The Effect of Chloroquine on Immune Activation and Interferon Signatures Associated with HIV-1

“…We have observed in the nonhuman primate model after depletion of CD8 T cells that even modest (0.5 log) increases in viremia increase ISG expression. 30 It is interesting that, in this study, we observed an ''uncoupling'' of ISG expression and plasma viremia. We also observed a modest but consistent decrease in CD38 and CCR5 RNAs.…”