HIV-1 Nef Disrupts Maturation of CD4+ T Cells through CD4/Lck Modulation

Abstract

The HIV-1 Nef protein is a major determinant of HIV-1 pathogenicity. It has been found to induce thymocyte depletion, but the mechanisms involved are not completely understood. Also, nothing is known about its effects on thymocyte selection. We used the CD4C/HIVNef transgenic (Tg) mice, which develop a profound CD4+ T cell lymphopenia, to study their thymic development. We report that HIV-1 Nef causes depletion of double-positive thymocytes and impairs selection and lineage commitment of CD4+ single-positive thymocytes. This latter defect could be relieved by increasing the affinity of the TCR–MHC interaction or by allowing CD4+ T cell maturation to proceed in absence of the CD4 tail, in double-Tg (Nef × CD4tailless) mice or in the presence of constitutively active Tg LckY505F. These rescue strategies also resulted in reversal of peripheral CD4+ T cell lymphopenia. Our data indicate that impairment of Lck-mediated CD4 coreceptor signaling by Nef is an important in vivo mechanism of HIV-1 pathogenesis.