ADAPTATION TO PROMISCUOUS USAGE OF CC AND CXC-CHEMOKINE CORECEPTORS IN-VIVO CORRELATES WITH HIV-1 DISEASE PROGRESSION

Objective: To study coreceptor usage of sequential primary HIV-1 isola tes in a longitudinal follow-up cohort of HIV-1-infected men to unders tand its contribution to pathogenesis of HIV disease. Design: Viral co receptor usage of sequential primary isolates from HIV-1-infected indi viduals was examined at various timepoints and data was compared with CD4 cell counts, rates of disease progression and beta-chemokine produ ction. Methods: Fifty-eight sequential primary isolates were obtained from four rapid progressors, six late progressors, and three long-term nonprogressors (LTNP) and their coreceptor usage was examined by infe ction of peripheral blood mononuclear cells (PBMC) from donors with wi ld-type or non-functional CC-chemokine receptor (CCR)-5, and by infect ion of GHOST4 cells expressing CD4 and various chemokine receptors [CC R-1-CCR-5, CXC-chemokine receptor (CXCR)-4, BOB/GPR15/ BONZO/STRL33]. Production of RANTES and macrophage inflammatory protein (MIP)-1 beta was examined using unstimulated or phytohemagglutinin (PHA)-stimulated PBMC isolated from these individuals at multiple timepoints during in fection. Results: A switch from single CCR-5 coreceptor usage to multi ple coreceptor usage occurred in all four rapid progressors and three out of six late progressors. In addition to the commonly used corecept ors CXCR-4, CCR-5, and CCR-3, some of the viruses isolated from patien ts in the terminal stage of infection also used CCR-1, CCR-2b, CCR-4, and BOB as coreceptors. The emergence of viral variants capable of uti lizing multiple coreceptors generally preceded CD4 cell decline to < 2 00 x 10(6)/l and correlated with the onset of AIDS. In contrast, three LTNP maintained exclusive usage of CCR-5 over a period of 7-12 years post-infection. Endogenous production of RANTES and MIP-1 beta by PBMC from LTNP was not significantly different from rapid and late progres sors. However, PHA-driven production of both chemokines was significan tly higher in LTNP, suggesting that in vivo activating stimuli might c urtail HIV replication by inducing these chemokines. Conclusions: Vira l variants capable of utilizing a broad range of coreceptors correlate d with HIV-1 disease progression. In contrast, LTNP maintain exclusive usage of CCR-5 and produce higher levels of beta-chemokines. Thus, bo th viral and host determinants leading to the emergence of viral varia nts capable of using an expanded range of coreceptors may be likely de terminants of disease progression. (C) 1998 Lippincott Williams & Wilk ins.