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

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 modulatingCD4, 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 indownmodulating 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. Furtherfunctional 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 selectivelydisrupts 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 inductionof death receptors that may affect the functionality and survival of both virally infected and uninfected bystander cells.

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