Massive Secretion by T Cells Is Caused by HIV Nef in Infected Cells and by Nef Transfer to Bystander Cells

Abstract

The HIV Nef protein mediates endocytosis of surface receptors that correlates with disease progression, but the link between this Nef function and HIV pathogenesis is not clear. Here, we report that Nef-mediated activation of membrane trafficking is bidirectional, connecting endocytosis with exocytosis as occurs in activated T cells. Nef expression induced an extensive secretory activity in infected and, surprisingly, also in noninfected T cells, leading to the massive release of microvesicle clusters, a phenotype observed in vitro and in 36%-87% of primary CD4 T cells from HIV-infected individuals. Consistent with exocytosis in noninfected cells, Nef is transferred to bystander cells upon cell-to-cell contact and subsequently induces secretion in an Erk1/2-dependent manner. Thus, HIV Nef alters membrane dynamics, mimicking those of activated T cells and causing a transfer of infected cell signaling (TOS) to bystander cells. This mechanism may help explain the detrimental effect on bystander cells seen in HIV infection.

HIV Type 1 Nef Is Released from Infected Cells in CD45+Microvesicles and Is Present in the Plasma of HIV-Infected Individuals

“…In fact, a recent study indicates that HIV-1-infected T cells undergo a Nef-dependent massive increase in exocytosis of microvesicles containing Nef and/or FasL. 62 This report supports our study and suggests that Nef microvesicles may play a factor in HIV-induced T cell apoptosis. Ultimately, Nef microvesicles make an attractive therapeutic target that could inhibit the loss of CD4 þ T-lymphocytes, thereby extending the asymptomatic period of HIV-1 infection and attenuating HIV-1 disease.…”

HIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo

“…Indeed, B-cell dysfunction characterized already at early stages of HIV-1 infection by the lack of highaffinity antibodies is increasingly recognized as a hallmark of AIDS pathogenesis (38,39). Nef is suggested to contribute to this phenomenon by impairing antigen presentation and prevention of B-cell class switching following transfer from infected cells (40)(41)(42)(43). The results presented herein, in line with those from other laboratories (44,45), suggest that Nef also suppresses B-cell help by HIV-1-infected T lymphocytes.…”

HIV-1 Nef compensates for disorganization of the immunological synapse by inducing trans-Golgi network–associated Lck signaling

“…25,27,28,30 Erk signaling is also targeted by Nef via an independent mechanism involving the NAKC complex that elevates HIV-1 transcription and exosome release. 48 Conceivably, the induction of TGN-associated Lck-Ras-Erk signaling represents a prerequisite for these subsequent functional Nef-Erk interactions. Erk signaling thus emerges as a major target of Nef-mediated host-cell manipulation.…”