Dynamic Modulation of Expression of Lentiviral Restriction Factors in Primary CD4(+) T Cells following Simian Immunodeficiency Virus Infection

• Type of Material: Article
• Authors: Andrew R. Rahmberg, Harvard University; Premeela A. Rajakumar, Harvard Medical School; James M. Billingsley, Harvard Medical School; Robert Johnson, Emory University
• Language: English
• Date: 2017-04-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2017 American Society for Microbiology.
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.02189-16
• Title of Journal or Parent Work: Journal of Virology
• ISSN: 0022-538X
• Volume: 91
• Issue: 7
• Grant/Funding Information: This study was supported by National Institutes of Health (NIH) grants P51 OD011103 and P51 OD011132 and the Emory Center for AIDS Research (P30AI050409), as well as funding from the Mucosal Immunology Group (http://public.hivmucosalgroup.org), which is supported by a supplement to the HVTN Laboratory Program (UM1AI068618).
• Keywords: Virology; Life Sciences & Biomedicine; simian immunodeficiency virus; IN-VIVO; RHESUS MACAQUES; REVERSE TRANSCRIPTION; CD4(+) T lymphocytes; VIF; HIV-1 INFECTION; PROTEIN; interferon-stimulated genes; MEMORY; GENE-EXPRESSION; Science & Technology; VIRAL REPLICATION; gut-associated lymphoid tissue; restriction factors; SIV INFECTION
• Research Categories: Biology, Virology; Health Sciences, Epidemiology; Health Sciences, General

Abstract

Although multiple restriction factors have been shown to inhibit HIV/SIV replication, little is known about their expression in vivo. Expression of 45 confirmed and putative HIV/SIV restriction factors was analyzed in CD4 + T cells from peripheral blood and the jejunum in rhesus macaques, revealing distinct expression patterns in naive and memory subsets. In both peripheral blood and the jejunum, memory CD4 + T cells expressed higher levels of multiple restriction factors compared to naive cells. However, relative to their expression in peripheral blood CD4 + T cells, jejunal CCR5 + CD4 + T cells exhibited significantly lower expression of multiple restriction factors, including APOBEC3G, MX2, and TRIM25, which may contribute to the exquisite susceptibility of these cells to SIV infection. In vitro stimulation with anti- CD3/CD28 antibodies or type I interferon resulted in upregulation of distinct subsets of multiple restriction factors. After infection of rhesus macaques with SIVmac239, the expression of most confirmed and putative restriction factors substantially increased in all CD4 + T cell memory subsets at the peak of acute infection. JejunalCCR5 + CD4 + T cells exhibited the highest levels of SIV RNA, corresponding to the lower restriction factor expression in this subset relative to peripheral blood prior to infection. These results illustrate the dynamic modulation of confirmed and putative restriction factor expression by memory differentiation, stimulation, tissue microenvironment and SIV infection and suggest that differential expression of restriction factors may play a key role in modulating the susceptibility of different populations of CD4 + T cells to lentiviral infection.