title: Nef-mediated downregulation of CD4 enhances human immunodeficiency virus type 1 replication in primary T lymphocytes.
abstract: The accessory protein Nef plays a crucial role in primate lentivirus pathogenesis. Nef enhances human immunodeficiency virus type 1 (HIV-1) infectivity in culture and stimulates viral replication in primary T cells. In this study, we investigated the relationship between HIV-1 replication efficiency in CD4(+) T cells purified from human blood and two various known activities of Nef, CD4 downregulation and single-cycle infectivity enhancement. Using a battery of reporter viruses containing point mutations in nef, we observed a strong genetic correlation between CD4 downregulation by Nef during acute HIV-1 infection of activated T cells and HIV-1 replication efficiency in T cells. In contrast, HIV-1 replication ability was not significantly correlated with the ability of Nef to enhance single-cycle virion infectivity, as determined by using viruses produced in cells lacking CD4. These results demonstrate that CD4 downregulation by Nef plays a crucial role in HIV-1 replication in activated T cells and underscore the potential for the development of therapies targeting this conserved activity of Nef.
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2363, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lundquist
authors.forename: Minoru
authors.initials: M
authors.lastname: Tobiume
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Derya
authors.initials: D
authors.lastname: Unutmaz
authors.forename: Christopher
authors.initials: C
authors.lastname: Aiken
mesh_terms: D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D015536:Down-Regulation; D015693:Gene Products, nef / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus
chemical_list: D015704:CD4 Antigens; D015693:Gene Products, nef; D054311:nef Gene Products, Human Immunodeficiency Virus