Efficient Nef-mediated downmodulation of TCR-CD3 and CD28 is associated with high CD4+ T cell counts in viremic HIV-2 infection.

Journal article

The role of the multifunctional accessory Nef protein in the immunopathogenesis of HIV-2 infection is currently poorly understood. Here, we performed comprehensive functional analyses of 50 nef genes from 21 viremic (plasma viral load, >500 copies/ml) and 16 nonviremic (<500) HIV-2-infected individuals. On average, nef alleles from both groups were equally active in modulating CD4, TCR-CD3, CD28, MHC-I, and Ii cell surface expression and in enhancing virion infectivity. Thus, many HIV-2-infected individuals efficiently control the virus in spite of efficient Nef function. However, the potency of nef alleles in downmodulating TCR-CD3 and CD28 to suppress the activation and apoptosis of T cells correlated with high numbers of CD4(+) T cells in viremic patients. No such correlations were observed in HIV-2-infected individuals with undetectable viral load. Further functional analyses showed that the Nef-mediated downmodulation of TCR-CD3 suppressed the induction of Fas, Fas-L, PD-1, and CTLA-4 cell surface expression as well as the secretion of gamma interferon (IFN-γ) by primary CD4(+) T cells. Moreover, we identified a single naturally occurring amino acid variation (I132T) in the core domain of HIV-2 Nef that selectively disrupts its ability to downmodulate TCR-CD3 and results in functional properties highly reminiscent of HIV-1 Nef proteins. Taken together, our data suggest that the efficient Nef-mediated downmodulation of TCR-CD3 and CD28 help viremic HIV-2-infected individuals to maintain normal CD4(+) T cell homeostasis by preventing T cell activation and by suppressing the induction of death receptors that may affect the functionality and survival of both virally infected and uninfected bystander cells.

Authors: Khalid, M; Yu, H; Sauter, D; Usmani, S; Schmokel, J

• Publication status: Published
• Journal: Journal of virology
• Volume: 86
• Issue: 9
• Pages: 4906-4920
• Publication date: 2012-05-01
• DOI: 10.1128/jvi.06856-11
• EISSN: 1098-5514
• ISSN: 0022-538X
• Language: English
• Keywords: Receptors, Death Domain; HIV-2; Antigens, CD28; Receptors, Cell Surface; Molecular Sequence Data; HIV Infections; Humans; Cell Line; Leukocytes, Mononuclear; Lymphocyte Activation; Protein Binding; Phylogeny; CD4 Lymphocyte Count; Gene Order; Models, Molecular; Proviruses; Down-Regulation; Protein Conformation; nef Gene Products, Human Immunodeficiency Virus; Viremia; Apoptosis; Gene Expression; Amino Acid Substitution; Receptor-CD3 Complex, Antigen, T-Cell; T-Lymphocytes