R5 variants of human immunodeficiency virus type 1 preferentially infect CD62L- CD4+ T cells and are potentially resistant to nucleoside reverse transcriptase inhibitors.

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Journal of Virology (Impact Factor: 4.44). 02/2006; 80(2):854-65. DOI: 10.1128/JVI.80.2.854-865.2006
Source: PubMed


The persistence of human immunodeficiency virus type 1 (HIV-1) in memory CD4+ T cells is a major obstacle to the eradication of the virus with current antiretroviral therapy. Here, we investigated the
effect of the activation status of CD4+ T cells on the predominance of R5 and X4 HIV-1 variants in different subsets of CD4+ T cells in ex vivo-infected human lymphoid tissues and peripheral blood mononuclear cells (PBMCs). In these cell systems,
we examined the sensitivity of HIV replication to reverse transcriptase inhibitors. We demonstrate that R5 HIV-1 variants
preferentially produced productive infection in HLA-DR− CD62L− CD4+ T cells. These cells were mostly in the G1b phase of the cell cycle, divided slowly, and expressed high levels of CCR5. In contrast, X4 HIV-1 variants preferentially
produced productive infection in activated HLA-DR+ CD62L+ CD4+ T cells, which expressed high levels of CXCR4. The abilities of the nucleoside reverse transcriptase inhibitors (NRTI) zidovudine
and lamivudine to stop HIV-1 replication were 20 times greater in activated T cells than in slowly dividing HLA-DR− CD62L− CD4+ T cells. This result, demonstrated both in a highly physiologically relevant ex vivo lymphoid tissue model and in PBMCs,
correlated with higher levels of thymidine kinase mRNA in activated than in slowly dividing HLA-DR− CD62L− CD4+ T cells. The non-NRTI nevirapine was equally efficient in both cell subsets. The lymphoid tissue and PBMC-derived cell systems
represent well-defined models which could be used as new tools for the study of the mechanism of resistance to HIV-1 inhibitors
in HLA-DR− CD62L− CD4+ T cells.

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