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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.

Original publication

DOI

10.1128/JVI.06856-11

Type

Journal article

Journal

J Virol

Publication Date

05/2012

Volume

86

Pages

4906 - 4920

Keywords

Amino Acid Substitution, Apoptosis, CD28 Antigens, CD4 Lymphocyte Count, Cell Line, Down-Regulation, Gene Expression, Gene Order, HIV Infections, HIV-2, Humans, Leukocytes, Mononuclear, Lymphocyte Activation, Models, Molecular, Molecular Sequence Data, Phylogeny, Protein Binding, Protein Conformation, Proviruses, Receptor-CD3 Complex, Antigen, T-Cell, Receptors, Cell Surface, Receptors, Death Domain, T-Lymphocytes, Viremia, nef Gene Products, Human Immunodeficiency Virus