CCR5 and CXCR4 chemokine receptor expression and beta-chemokine productionduring early T cell repopulation induced by highly active anti-retroviral therapy

Expression of chemokine receptors and beta-chemokine production by peripher al blood mononuclear cells (PBMC) were determined in HIV-1-infected individ uals before and after highly active anti-retroviral therapy (HAART) and the ir relationship to viral load, T cell phenotype and the expression of immun ological activation markers was examined. We found that the expression of C CR5 is upregulated in HIV-1-infected individuals while CXCR4 appears down-r egulated on both CD4 and CD8 T cells compared with normal controls. These a lterations are associated with the high levels of viral load. In addition, a relationship was observed between the degree of immune activation and che mokine receptor expression on T cells. However, after 3 months of combined anti-retroviral regimen, expression of CXCR4 significantly increased while CCR5 decreased when compared with pretherapy determinations. This was seen in strict association with a dramatic decrease of viral load and an increas e of both CD45RA(+)/CD62L(+) (naive) and CD45RA(-)/CDS2L(+) or CD45RA(+)/CD 62L(-) (memory)T cells accompanied by a significant decrease of the express ion of immune activation markers such as HLA-DR and CD38. At enrolment, bot h spontaneous and lectin-induced RANTES, macrophage inflammatory protein-1 alpha (MIP-1 alpha) and MIP-1 beta production by PBMC were higher in HIV-l- infected individuals compared with normal controls, although differences fo r MIP-1 beta were not statistically significant. However, RANTES and MIP-1 alpha production decreased during HAART at levels closer to that determined with normal controls, while MIP-1 beta production was less consistently mo dified. These data indicate that the expression of chemokine receptors CCR5 and CXCR4 and the production of beta-chemokines are altered in HIV-infecte d individuals, and suggest that their early modifications during HAART refl ect both the peripheral redistribution of naive/memory T cell compartments and the decrease in levels of T cell activation. Such modifications in the expression of host determinants of viral tropism and the production of anti -viral molecules may play a role in the emergence of virus variants when a failure of HAART occurs.