Differential effects of IL-4 and TNFalpha on HIV-1 expression depend on coreceptor usage

The main HIV-1 coreceptors, CCR5 and CXCR4, are expressed in different subsets of T lymphocytes. Cytokines have profound and complex effects on coreceptor expression as well as on HIV-1 replication. Some cytokines affect HIV differentially, depending on the coreceptor usage. We have previously shown that IL-4 differentially affects HIV-coreceptor expression in primary T-lymphocytes (upregulates CXCR4 and down-regulates CCR5), resulting in strong inhibition of NSI and activation of SI HIV-1 strains. In contrast, IL-4 does not affect CCR5 expression in primary macrophages but increases CXCR4 expression in these cells. A single treatment with IL-4 prior to infection results in 5-10-fold increase in the levels of SI HIV-1 production in macrophages. Similar to IL-4, TNFalpha, a cytokine known to activate HIV-1 expression at the transcriptional level, inhibits CCR5 expression in T-lymphocytes resulting in downregulation of NSI HIV-1 strains. Like IL-4, TNFalpha does not significantly affect the levels of CCR5 in primary macrophages, and the only effect that was observed in these cells was stimulation of HIV expression. Increased levels of TNFalpha have been demonstrated in most HIV-infected individuals. Increased levels of IL-4 have also been reported by several groups. IL-4 expression in Th2 cells is expected to decrease CCR5 levels. This is in agreement with the demonstration of more frequent expression of CCR5 in Th1 lymphocyte clones. Therefore, it is expected that NSI viruses will propagate mainly in Th1 cells, resulting in their preferential killing leading to the predominance of Th2 cells and responses. These results show that HIV-1 with different coreceptor preferences are regulated differently by cytokines and suggest a critical role for cytokines in the control of viral evolution and disease progression. Research sponsored by the National Cancer Institute, DHHS, under contact with ABL.

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