AEGiS-07IAC: Regulation of silent and productive HIV-1 infection in primary monocytes by two distinct genetic determinants.

7th International AIDS Conference

Florence, Italy — June 16-21, 1991

Regulation of silent and productive HIV-1 infection in primary monocytes by two distinct genetic determinants.

Int Conf AIDS 1991 Jun 16-21; 7:42 (abstract no. M.A.80)
Westervelt P, Trowbridge DB, Gendelman HE, Ratner L; Departments of Medicine & Molecular Microbiology, Washington University School of Medicine, St. Louis, MO

OBJECTIVE: Determination of the molecular basis for HIV-1 tropism for primary human monocytes.

METHODS: Recombinant proviral clones were constructed by reciprocal DNA fragment exchange between a monocyte-tropic clone (ADA) and two full-length molecular clones (HXB2 and NL4-3) incapable of infection or replication in primary monocytes ("no infection" phenotype). Infection and replication were assayed for by serial determinations of reverse transcriptase activity in culture supernatants and by virus recovery from infected monocytes following cocultivation with fresh uninfected peripheral blood mononuclear cells (PBMC's).

RESULTS: Our data indicate that at least two viral genes, env and vpr, play central roles in HIV-1 infection and replication in monocytes and mediate the expression of three distinct replication phenotypes. The env determinant has been fine mapped to amino acids No. 240-333 of the mature ADA gp120 protein, encoding the entire V3 loop but excluding the CD4 binding domain. Virions derived from recombinant HXB2-based clones containing the env determinant infected primary monocytes and were recovered consistently at 24 days post-infection by co-cultivation with fresh uninfected PBMC's, despite their failure to generate detectable virus replication levels in monocytes ("silent infection"). Incorporation of the env determinant in recombinant NL4-3-based clones, which unlike HXB2 encode a full-length vpr protein, resulted in the generation of virions which replicated to high levels in primary monocytes ("productive infection"). Inactivation of vpr by mutagenesis converted the productive infection phenotype in monocytes to that of silent infection.

CONCLUSIONS: These findings suggest that an env determinant is required for HIV-1 infection of primary monocytes, while subsequent replication levels (silent vs. productive infection) are determined, at least in part, by vpr. Further elucidation of these phenotypes in vitro should contribute toward a better understanding of in vivo phenomena such as disease latency and progression to AIDS.

Keywords: AEGIS, Monocytes, HIV Infections, HIV-1, Virus Replication, RNA-Directed DNA Polymerase, Gene Products, vpr, Antigens, CD4, Genes, Viral, Acquired Immunodeficiency Syndrome, Human, In Vitro, virology, genetics, ICA7
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MA80