Lentiviral Nef Proteins Manipulate T Cells in a Subset-Specific Manner

• Type of Material: Article
• Authors: Hangxiang Yu, Ulm University Medical Center; Mohammad Khalid, Ulm University Medical Center; Anke Heigele, Ulm University Medical Center; Jan Schmoekel, Ulm University Medical Center; Shariq Usmani, Ulm University Medical Center; Johannes van der Merwe, Ulm University Medical Center; Jan Muench, Ulm University Medical Center; Guido Silvestri, Emory University; Frank Kirchhoff, Ulm University Medical Center
• Language: English
• Date: 2015-02-15
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2015, American Society for Microbiology.
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.03104-14
• Title of Journal or Parent Work: Journal of Virology
• ISSN: 0022-538X
• Volume: 89
• Issue: 4
• Start Page: 1986
• End Page: 2001
• Grant/Funding Information: This work was supported by grants from the Deutsche Forschungsgemeinschaft (Leibniz award to F.K. and KFO167), the Hector foundation, an ERC advanced grant to F.K., and the European FP7 “HIT HIDDEN HIV” (305762).
• Keywords: Life Sciences & Biomedicine; AIDS; HUMAN LYMPHOID-TISSUE; Virology; AFRICAN-GREEN MONKEYS; IMMUNOLOGICAL SYNAPSE; INFECTION; HIV NEF; Science & Technology; DOWN-MODULATION; SIMIAN IMMUNODEFICIENCY VIRUS; PATHOGENESIS; REPLICATION
• Research Categories: Biology, Virology; Physics, Molecular; Biology, Cell

Abstract

The role of the accessory viral Nef protein as a multifunctional manipulator of the host cell that is required for effective replication of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) in vivo is well established. It is unknown, however, whether Nef manipulates all or just specific subsets of CD4+ T cells, which are the main targets of virus infection and differ substantially in their state of activation and importance for a functional immune system. Here, we analyzed the effect of Nef proteins differing in their T cell receptor (TCR)-CD3 downmodulation function in HIV-infected human lymphoid aggregate cultures and peripheral blood mononuclear cells. We found that Nef efficiently downmodulates TCR-CD3 in naive and memory CD4+ T cells and protects the latter against apoptosis. In contrast, highly proliferative CD45RA+ CD45RO+ CD4+ T cells were main producers of infectious virus but largely refractory to TCR-CD3 downmodulation. Such T cell subset-specific differences were also observed for Nef-mediated modulation of CD4 but not for enhancement of virion infectivity. Our results indicate that Nef predominantly modulates surface receptors on CD4+ T cell subsets that are not already fully permissive for viral replication. As a consequence, Nef-mediated downmodulation of TCR-CD3, which distinguishes most primate lentiviruses from HIV type 1 (HIV-1) and its vpu-containing simian precursors, may promote a selective preservation of central memory CD4+ T cells, which are critical for the maintenance of a functional immune system.