AEGiS-12IAC: Isolation of MIP-1 alpha-resistant macrophage-tropic HIV-1 selected by passage in cell culture.

12th International AIDS Conference

Geneva, Switzerland - June 28-July 3, 1998

Isolation of MIP-1 alpha-resistant macrophage-tropic HIV-1 selected by passage in cell culture.

Int Conf AIDS 1998 Jun 28-Jul 3; 12:4 (abstract no. 11110)

Maeda Y, Matsushita SM, Foda MB, Nanke KN, Maeda HM, Harada SH;;; Kumamoto University, Japan.

BACKGROUND: It has been shown that chemokine receptors, CXCR4 and CCR5, serve as the major coreceptors for T- and macrophage-tropic human immunodeficiency virus (HIV-1) isolate, respectively, and the natural ligands for CCR5, including MIP-1 alpha, MIP-1 beta-, and RANTES, block macrophage-tropic but not T-tropic HIV-1 infection. It has been also shown that the disease progression in HIV-1-infected individuals is associated with the change in the coreceptor usage from CCR5 to CXCR4, and with a loss of sensitivity to these CC-chemokines. Recent data showed that the change of coreceptor was associated with changes in the third variable (V3) region of env gene. However, little is known which region in HIV-1 is responsible for the reduced sensitivity to the CC-chemokines in vivo.

METHODS: In order to elucidate its molecular mechanism, a variant of macrophage-tropic HIV with reduced sensitivity to MIP-1 alpha has been selected by passage of virus in CCR5-expressed MOLT-4#8 cells in the presence of increasing amount of MIP-1 alpha. The sensitivities of these variants were determined using CCR5-expressed CD4-HeLa/LTR-beta-gal (MAGI/CCR5) cells.

RESULTS: The variant from a macrophage-tropic infectious clone, JR-FL, had moderately decreased sensitivity (fourfold) to MIP-1 alpha compared with wild type JR-FL. This resistant variant had also decreased sensitivity to MIP-1 beta and RANTES, but did not change the cellular tropism, suggesting that this variant is still using CCR5 for its coreceptor. Analyses of the env sequences of the isolate had V(p)M substitution at codon 166 in the second variable (V2) region, whereas no remarkable changes were observed in the V3 region.

CONCLUSIONS: These results indicated that the CC-chemokines-resistant mutant could emerge from macrophage-tropic HIV-1 without any changes in the V3 region in vitro.

Keywords: AEGIS, Macrophage Inflammatory Protein-1, HIV-1, Macrophages, RANTES, HIV Infections, Receptors, Chemokine, Antigens, CD4, Chemokines, CC, Human, In Vitro, immunology, ICA12
980628
11110