Important note: Information in this article was accurate in 1988. The state of the art may have changed since the publication date.
MOLECULAR MECHANISMS OF PATHOGENESIS BY HTLV-III
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. 138-42, 1987.. Unique Identifier : AIDSLINE ICDB/88647967 Wong-Staal F; Gallo RC; Lab. of Tumor Cell Biology, NCI, Bethesda, MD 20892
Abstract:
The etiological agent of acquired immune deficiency syndrome (AIDS), referred to as human T-lymphotropic virus type III (HTLV-III), lymphadenopathy virus (LAV), or human immunodeficiency virus (HIV), is a member of the retrovirus family. HTLV-III shares with HTLV-I and HTLV-II its target cell tropism for the T4 helper cell, as well as a number of other characteristics including impairment of T-cell function and modes of transmission. The underlying defect in HTLV-III-infected patients is the depletion of T4 cells, leading to severe immunosuppression. The genetic structure of HTLV-III is by far the most complex among retroviruses. In addition to the three structural genes (gag, pol, env) necessary for replication of all retroviruses, the genome of HTLV-III contains at least four genes (sor, tat-3, trs/art, and 3 orf). It appears that HTLV-III expression is regulated at multiple levels. The interplay of the regulatory genes may modulate the lytic and latent phases of infection and assure efficient viral expression when cells are immune-activated. One practical implication of this finding is that the investigator has multiple targets for inhibiting viral expression. For example, antagonists of tat-3 and trs should also be effective antiviral agents. In a series of experiments originally designed to determine the role of 3 orf in viral replication and cytopathicity, deletions of various sizes in this gene were constructed and transfected into normal T lymphocytes or different T-cell lines. All mutants with deletions exclusively in 3 orf were highly replicative and cytopathic. Two mutants with deletions extending into the carboxyl terminus of the neighboring env gene did not exert overall cytopathic effect (CPE) while maintaining their replicative capacity. These infected cells produced copious amounts of virus, retained full trans-activating function, contained high levels of unintegrated DNA, and formed syncytia, indicating that although each of these parameters may contribute to CPE, none is sufficient in itself. These results point to the env gene as a critical determinant for CPE. The env gene of HTLV-III encodes a precursor protein of 160 kD, which is then cleaved into the major extracellular envelope protein (gp120) and the small envelope protein (gp41). The exact roles of gp120, gp41, T4, and other viral and cellular factors in the pathogenesis of HTLV-III remain to be determined. (21 Refs)
Keywords: Acquired Immunodeficiency Syndrome/ETIOLOGY/IMMUNOLOGY *Cloning, Molecular *Cytopathogenic Effect, Viral Gene Expression Regulation Human HIV/*GENETICS/IMMUNOLOGY/PHYSIOLOGY T-Lymphocytes, Helper-Inducer/IMMUNOLOGY Viral Envelope Proteins/GENETICS *Virus Replication MEETING PAPER
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Important note: Information in this article was accurate in 1988. The state of the art may have changed since the publication date.
