Inhibition of HIV-1 progeny virion release by cell-surface CD4 is relievedby expression of the viral Nef protein

Background: The human immunodeficiency virus type 1 (HIV-1) Nef protein is required for efficient virus replication in vivo and displays a number of d istinct and apparently unrelated biological activities in vitro. Of these, one of the most readily demonstrated is the efficient internalization and d egradation of cell-surface CD4, the receptor for the HIV-1 envelope protein . The biological purpose of this internalization has, however, remained unc lear. Results: Using human 293T cells expressing high levels of cell-surface CD4 or CD8, we demonstrate that CD4, but not CD8, can dramatically reduce the r elease of infectious virions bearing the HIV-1 envelope protein and induce a concomitant increase in the accumulation of cell-associated HIV-1 structu ral proteins. In contrast, CD4 had no effect on the release of HIV-1 bearin g a heterologous envelope protein unable to bind CD4. Nef expression totall y reversed CD4-mediaied inhibition but only ii the CD4 used remained suscep tible to Nef-induced internalization. Conclusions: These results support the hypothesis that cell-surface CD4 can interact with the envelope protein present on budding HIV-1 virions to inh ibit their release. The internalization and degradation of cell-surface CD4 induced by the viral Nef protein can fully reverse this inhibition and is, therefore, likely to facilitate the spread of virus in vivo. (C) Elsevier Science Ltd ISSN 0960-9822.