Lentiviral Nef proteins manipulate T cells in a subset-specific manner.

UNLABELLED: 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. IMPORTANCE: The Nef proteins of human and simian immunodeficiency viruses manipulate infected CD4(+) T cells in multiple ways to promote viral replication and immune evasion in vivo. Here, we show that some effects of Nef are subset specific. Downmodulation of CD4 and TCR-CD3 is highly effective in central memory CD4(+) T cells, and the latter Nef function protects this T cell subset against apoptosis. In contrast, highly activated/proliferating CD4(+) T cells are largely refractory to receptor downmodulation but are main producers of infectious HIV-1. Nef-mediated enhancement of virion infectivity, however, was observed in all T cell subsets examined. Our results provide new insights into how primate lentiviruses manipulate their target cells and suggest that the TCR-CD3 downmodulation function of Nef may promote a selective preservation of memory CD4(+) T cells, which are critical for immune function, but has little effect on activated/proliferating CD4(+) T cells, which are the main targets for viral replication.