Inhibition of HIV-1 progeny virion release by cell-surface CD4 is relieved by 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 distinct and apparently unrelated biological activities in vitro. Of these, one of the most readily demonstrated is the efficient internalization and degradation of cell-surface CD4, the receptor for the HIV-1 envelope protein. The biological purpose of this internalization has, however, remained unclear.


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 release of infectious virions bearing the HIV-1 envelope protein and induce a concomitant increase in the accumulation of cell-associated HIV-1 structural proteins. In contrast, CD4 had no effect on the release of HIV-1 bearing a heterologous envelope protein unable to bind CD4. Nef expression totally reversed CD4-mediated inhibition but only if the CD4 used remained susceptible 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 inhibit 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.
Ross
T M
TM
Yerkes Regional Primate Research Center, Division of Microbiology and Immunology, Emory University, Atlanta, Georgia 30329, USA.
Oran
A E
AE
Cullen
B R
BR
D015704:CD4 Antigens / Q000235:genetics / Q000502:physiology*; D016827:CD8 Antigens / Q000502:physiology; D002460:Cell Line; D015536:Down-Regulation; D015870:Gene Expression; D015686:Gene Products, env / Q000502:physiology; D015693:Gene Products, nef / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015754:Genes, nef; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D014162:Transfection; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus; D018909:src Homology Domains
D015704:CD4 Antigens; D016827:CD8 Antigens; D015686:Gene Products, env; D015693:Gene Products, nef; D054311:nef Gene Products, Human Immunodeficiency Virus