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Genetic variation among HIV-1 gp120 genes: macrophage tropism revisited.


Diss Abstr Int [B]; 55(11):4714 1995. Unique Identifier : AIDSLINE

Cell-type specific tropisms was reported for HIV-1. Only 10-20% of isolates are able to infect neoplastic CD4+ cells, an ability which correlates with disease progression. Preferential tropism for macrophages was also described, a behavior appearing reciprocally linked to neoplastic cell tropism. The relevance of these phenomena to virus replication in vivo remains controversial, especially because field isolates replicate in both normal T lymphocytes and normal macrophages in vitro. Studies focused on identifying the genetic determinants of specific tropisms have indicated the critical determinants reside within the gp120 envelope gene. To ascertain whether macrophage tropism in vitro reflects virus substrain compartmentalization in vivo, the gp120 genes from selected HIV-1 isolates were molecularly cloned, sequenced, and evaluated in comparison with other isolates exhibiting similar and different tropisms. Compared were a family of HIV-1IIIB viruses, brain and peripheral blood T-cell-derived isolates recovered concomitantly from three patients and two sequential isolates recovered from the same patient obtained over three years, one being neoplastic T-cell tropic and the other recovered from monocytes. The HIV-1IIIB family was used to investigate variation associated with passage in vivo. The parental HIV-1IIIB replicates well in neoplastic CD4+ cells, but poorly in macrophages. Passage of HIV-1IIIB through human and chimpanzee hosts resulted in reacquisition of macrophage tropism, without loss of neoplastic T-cell tropism. Four altered sites were found as a consequence of in vivo passage. The one likely responsible for macrophage tropism is located V3 loop tip. It contains functional thrombin-tryptase and cathepsin E cleavage sites. Any sequence variation among the isolates exceeded short-termed cultured- and PCR-dependent variations. Overall, the results indicate that no significant genetic dichotomy exists in vivo between HIV-1 isolates replicating within T lymphocytes versus mononuclear phagocytes. The same substrain can be present within both the T lymphocyte and macrophage compartments within different tissues at the same time. Also, no consistent pattern of determinants is associated with T-cell or macrophage origin, but adaptation to neoplastic cells results in selection of variants not necessarily representative of those in vivo. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AADAA-I9510410)

HIV Envelope Protein gp120/*GENETICS Human Macrophages/IMMUNOLOGY/*PHYSIOLOGY T-Lymphocytes/PHYSIOLOGY *Variation (Genetics) Virus Replication THESIS


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