Role of monocytes in the pathogenesis of HIV-1 infection.

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Peripheral blood monocytes and tissue macrophages play critical roles in both the natural history and the pathogenesis of HIV-1 infection. This thesis mainly focused on the study of a potential defensive role of macrophages in HIV-1 infection. HIV-1 expression in monocyte-derived macrophages (MDM) infected in vitro is known to be inhibited by lypopolysaccharide (LPS), the main component of the bacterial cell wall. However, the mechanisms are not completely understood. We show herein that LPS protects primary macrophages from infection by CCR5-dependent HIV-1 isolates. Inhibition was largely mediated by the release of the C-C chemokines RANTES, MIP-1ɑ and MTP-1s. Indeed, (a) addition of LPS to MDM resulted in the vigorous production of RANTES, MDMa and MIP-1s; (b) high levels of CCR5, the C-C chemokine receptor, were expressed by MDM at the time of infection; (c) antibody- mediated depletion of RANTES, MIP-1ɑ and MIP-1s blocked HIV-1 infection as effectively as LPS itself. CXCR4 mediates the entry of syncytia-inducing strains, both primary and T cell line-adapted. The ability of SI HIV-1 isolates to infect primary human macrophages has been disputed. Here, we report that CXCR4 expression on human MDM was variable but consistently significant. Primary CXCR4- dependent HIV-1 strains infected MDM productively and were specifically blocked by SDF 1. By contrast MDM supported the entry but not the replication of CXCR4-dependent TCLA HIV strains. Thus, monocyte/macrophages support the entry and replication not only of CCRS-dependent, but also of CXCR4-dependent primary HIV-1 isolates. Because CXCR4 is a functional coreceptor for HIV-1 infection of human macrophages, we investigated whether LPS also affects the replication of CXCR4-dependent HIV-1 isolates. Our results show that LPS inhibits the replication of X4 HIV-1 isolates in MDM through the release of novel soluble suppressive factor(s) that are as of yet uncharacterized.