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

• Type of Material: Article
• Authors: Steven Bosinger, Emory University; Simon P. Jochems, Emory University; Kathryn A. Folkner, Emory University; Timothy L. Hayes, Emory University; Nichole R. Klatt, NIH/NIAID; Guido Silvestri, Emory University
• Language: English
• Date: 2013-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2013, American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://jvi.asm.org/content/87/1/433
• Title of Journal or Parent Work: Journal of Virology
• Volume: 87
• Issue: 1
• Start Page: 433
• End Page: 443
• Grant/Funding Information: This work was supported by NIH grant R01-AI90797 to G.S. and by Office of Research Infrastructure Programs P51OD11107 and (formerly) NCCR P51RR169.
• Research Categories: Biology, Microbiology; Health Sciences, Immunology; Biology, Virology

Abstract

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 α- and θ-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.