Abstract:
The human immunodeficiency virus type 1 (HIV-1) utilizes its primary membrane glycoprotein, gp120, to infect CD4+ cells predominantly of the T-helper lymphocyte phenotype. Infection of CD4+ cells in vitro leads to pronounced cytopathic effect, syncytium formation, and cell death. In vivo infection by HIV-1 leads to CD4+ cell depletion and AIDS. In an effort to identify regions of the gp120 that are amenable to vaccine development, a sensitive assay for HIV-1 neutralizing antibodies was developed. During analysis of HIV-1 antibody-positive sera for anti-HIV-1 activity, it was determined that several fresh sera not only failed to inactivate HIV-1 but actually accelerated HIV-1 infection in vitro. Subsequent studies on this infection-enhancing activity of HIV-1 antibody-positive serum demonstrated the activity was comprised of two factors: the first was an anti-HIV gamma globulin while the second appeared to be the alternative pathway of complement. Such complement-mediated, antibody-dependent enhancement (ADE) of HIV-1 infection in vitro has, thus far, been demonstrated using MT-2 cells, a lymphoblastoid cell line expressing CD4 and a complement receptor, CR2. In this cell line, ADE of HIV-1 infection was characterized by accelerated rates of viral RNA and protein synthesis and progeny infectious virus release. Antibodies conferring ADE were found in HIV-1 infected chimpanzees as well as the majority of HIV-1 antibody-positive humans. Additional results suggest that ADE may be isolate specific and that glycosylation of HIV-1 gp120 plays an important role in fixation of complement and subsequently in ADE. These findings, combined with results from an envelope fragment affinity column, pENV9, suggest that the gp120 or gp160 envelope precursor protein is necessary for ADE of HIV-1 infection. The comparative roles of N-glycosylation and ADE are discussed in reference to modalities of therapy in AIDS and a mechanism for ADE of HIV-1 infection in vitro is proposed. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD89-10869)
Keywords: Acquired Immunodeficiency Syndrome/*IMMUNOLOGY/MICROBIOLOGY Animal Antigens, CD4/IMMUNOLOGY Cell Line Chimpansee troglodytes Complement/*IMMUNOLOGY Cytopathogenic Effect, Viral CD4-Positive T-Lymphocytes/IMMUNOLOGY/MICROBIOLOGY Human HIV Antibodies/*IMMUNOLOGY HIV Envelope Protein gp120/*IMMUNOLOGY HIV-1/*IMMUNOLOGY/PHYSIOLOGY THESIS 900530
M9051025
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