FUNCTIONAL ANALYSIS OF THE HTLV-III ENVELOPE: IMPLICATIONS FOR PATHOGENESIS, THERAPY, AND PROPHYLAXIS

Important note: Information in this article was accurate in 1988. The state of the art may have changed since the publication date.

FUNCTIONAL ANALYSIS OF THE HTLV-III ENVELOPE: IMPLICATIONS FOR PATHOGENESIS, THERAPY, AND PROPHYLAXIS

Vaccines 87. Modern Approaches to New Vaccines: Prevention of AIDS and Other Viral, Bacterial, and Parasitic Diseases. Chanock RM et al, eds. New York, Cold Spring Harbor Laboratory, p. 130-7, 1987.. Unique Identifier : AIDSLINE ICDB/88647966
Sodroski J; Goh WC; Rosen C; Terwilliger E; Dayton A; Campbell K; Haseltine W; Lab. of Biochemical Pharmacology, Dana-Farber Cancer Inst.,; Boston, MA 02115

Abstract: Acquired immune deficiency syndrome (AIDS) is characterized by marked depletion of the T4+ lymphocyte population in the peripheral blood and involution of the lymph nodes. Infection with the etiologic agent of AIDS (human T-lymphotropic virus type III/lymphadenopathy associated virus, HTLV-III/LAV) can also result in massive CNS degeneration, lymphadenopathy syndrome, AIDS-related complex (ARC), idiopathic thrombocytopenic purpura, and childhood pneumonitis. Given the strong etiologic link between HTLV-III infection and the development of AIDS and CNS degeneration, it is likely that the cytopathicity of the virus for T4-bearing cells in in vitro models is at least the primary event in in vivo pathogenesis. To study the viral determinants of T4-cell killing, the ability of wild-type and mutant HTLV-III proviruses to generate replicating, cytopathic viruses in T4+ lymphocyte cultures was studied. In addition to gag, pol, and env genes typical of retroviruses, HLTV-III possesses at least four additional genes. Mutations within the tat or art trans-activator genes of HTLV-III destroy the ability of the provirus to generate replicating viruses. Experiments demonstrate that the carboxy-terminal 43 amino acids of the envelope protein are not required for T4+ lymphocyte killing by HTLV-III. High-level transient gene expression was used as a means of defining cytopathic determinants. Syncytium formation is induced by the HTLV-III envelope glycoprotein via a specific interaction with the T4 surface protein. In HTLV-III infection, the level of expression of the HTLV-III envelope protein, the level of expression of the T4 molecule, and the ability of these two proteins to interact are the factors that govern the efficiency of membrane fusion and determine whether an infected cell will be killed or produce viral particles in the absence of cell killing. A model for membrane fusion by the HTLV-III envelope is diagrammed. In the case of HTLV-III, ARC, and AIDS-patient antisera, although containing high titers of antibodies capable of immunoprecipitating the HTLV-III envelope, exhibit only very weak activity with respect to virus neutralization or syncytium inhibition. Apparently, antibodies directed against the immunodominant epitopes do not significantly interfere with the critical functions of the HTLV-III envelope, ie, T4 binding and membrane fusion. (34 Refs)

Keywords: Acquired Immunodeficiency Syndrome/*IMMUNOLOGY/PREVENTION & CONTROL/THERAPY Antibodies, Viral/IMMUNOLOGY Antibody Formation AIDS-Related Complex/IMMUNOLOGY Cloning, Molecular Cytopathogenic Effect, Viral Gene Expression Regulation *Genes, Viral Human HIV/*GENETICS/IMMUNOLOGY T-Lymphocytes, Helper-Inducer/IMMUNOLOGY T-Lymphocytes, Suppressor-Effector/IMMUNOLOGY Viral Envelope Proteins/*GENETICS/IMMUNOLOGY MEETING PAPER

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