STRUCTURE AND FUNCTION OF THE HIV ENVELOPE: IMPLICATIONS FOR VACCINE DEVELOPMENT

Important note: Information in this article was accurate in 1991. The state of the art may have changed since the publication date.

STRUCTURE AND FUNCTION OF THE HIV ENVELOPE: IMPLICATIONS FOR VACCINE DEVELOPMENT

AIDS Vaccine Research and Clinical Trials. Putney SD and Bolognesi DP, eds. New York, Marcel Dekker, p. 93-106, 1990.. Unique Identifier : AIDSLINE ICDB/91676943
Sodroski J; Kowalski M; Haseltine W; Lab. of Human Retrovirology, Dana-Farber Cancer Inst., Boston, MA

Abstract: The HIV is surrounded by an envelope composed of a lipid bilayer, derived from the host cell as the virus buds, and envelope glycoproteins encoded by the virus. Cleavage of a precursor 160-kD glycoprotein by a cellular protease yields the exterior glycoprotein, gp120, and the transmembrane glycoprotein, gp41. Both proteins are expressed on the surface of the infected cell and are incorporated into the virion. The nature of the HIV envelope and its implications for development of an AIDS vaccine are reviewed, including HIV entry into the host cell, HIV cytopathicity, HIV cell-to-cell transmission, neutralizing antibody paradox, mutational analysis of envelope functions, mutations that affect gp120-CD4 binding, mutations that affect membrane fusion, membrane anchorage, gp120-gp41 association, proteolytic cleavage of the envelope precursor, mutants at the carboxyl terminus of gp41, a model for binding and fusion, and resolution of the neutralization paradox. The same regions of the HIV envelope important for cell-free virus entry appear to be critical for cell-to-cell transmission of virus. Except for the gp41 carboxyl terminus, the same regions defined to be important for viral replication are likely to be essential for syncytium formation, single-cell killing, and CD4-positive lymphocyte depletion. Thus, it would be reasonable to focus effort on the following regions and their respective functions: (1) the carboxy-terminal half of gp120 (CD4 binding), (2) the amino terminus of gp41 (membrane fusion), and (3) the amino terminal regions of gp120 and gp41 (gp120-gp41 association). These regions are well conserved among HIV-1 isolates and are conserved to a reasonable extent between HIV-1, HIV-2, and simian immunodeficiency virus. Thus, novel members of the family of CD4-tropic, immunodepletive retroviruses that the human population is likely to encounter in the near future may use common schemes for replication and pathogenesis. The ability of the human immune system to raise a vigorous humoral or cellular response to the region of gp120 and gp41 important for function is unknown. The CD4-binding region of gp120 is likely to be recessed, surrounded by glycosylated hypervariable regions that are functionally unimportant. The affinity of antibodies that recognize conserved regions within the CD4-binding pocket may be far less than the affinity of the CD4 receptor for gp120, making long-term blockade of infection or membrane fusion events unlikely. The masking features of the envelope glycoproteins render eliciting of the desired responses a formidable task. (38 Refs)

Keywords: Cytopathogenic Effect, Viral/IMMUNOLOGY DNA Mutational Analysis Human HIV/GENETICS/*IMMUNOLOGY HIV Antigens/*IMMUNOLOGY HIV Envelope Protein gp120/GENETICS/IMMUNOLOGY HIV Envelope Protein gp41/GENETICS/IMMUNOLOGY HIV Infections/*IMMUNOLOGY HIV-1/IMMUNOLOGY HIV-2/IMMUNOLOGY T-Lymphocytes, Cytotoxic/IMMUNOLOGY Viral Envelope Proteins/*IMMUNOLOGY Viral Vaccines/*IMMUNOLOGY MONOGRAPH REVIEW
912130
M91C4098

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