7th International AIDS Conference Florence, Italy — June 16-21, 1991

Int Conf AIDS 1991 Jun 16-21; 7:21 (abstract no. M.A.5)
Cheng-Mayer C, Shioda T, Levy JA; Cancer Research Institute, University of California, School of Medicine, San Francisco, California 94143-0128

OBJECTIVE: To identify genetic regions of HIV-1 that control the pathogenic properties of the virus.

METHODS: Recombinant viruses were generated between two sequential isolates (HIV-1SF2, HIV-1SF13) that are highly related at the genomic level and yet display distinct in vitro biological properties.

RESULTS: The sequential isolates (HIV-1SF2, HIV-1SF13), molecularly cloned and sequenced, were found to be closely related at the genomic level (greater than 97% overall sequence homology). However, when compared to the earlier isolate (HIV-1SF2mc), the later isolate (HIV-1SF13mc) replicated faster and to higher titers in PMC, Hut78, MT-4 and Jurkat cells and was highly cytopathic. It induced plaque in the MT-4 cell line. Moreover, HIV-1SF13mc displayed a wide host range; productively infected primary macrophages, the CEM and U937 cell lines, and CD4-negative fibroblastoid cells. Studies with recombinants showed that a 0.48kb StuI/MstII fragment, encompassing the V3 domain of gp120, determines cytopathogenicity in PMC and the Hut78 and MT-4 cell lines. This same region also contains the major determinant of macrophage tropism. A 0.39kb MstII/StyI fragment, encompassing the V4, V5 and CD4 binding domains of gp120, contains the major determinant for entry into the Jurkat, CEM and U937 cells. A 0.29kb RI/Hind III fragment, encompassing the first coding exons of tat and rev, determines the rate of virus replication in the Hut78, Jurkat and MT-4 cell lines. A single aa change in this region of tat, however, appears to be responsible for the difference observed between HIV-1SF2mc and HIV-1SF13mc.

CONCLUSIONS: Our studies showed that small genetic regions of HIV-1 control biological properties of the virus that correlate with its virulence in the host. Specifically, a single aa change in tat appears to affect the replicative rate of HIV-1. Studies with other site-directed mutants are in progress to identify specific amino acid changes in the envelope gp120 that determine the different host range properties of HIV-1.

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