The 'in's and out's' of macrophage HIV infection: How HIV interacts with and exploits the endosomal/exosomal pathway in macrophages.

摘要

HIV infection of macrophages leads to defects in their innate immune function, resulting in opportunistic infections and changes in cytokine expression that cause neurotoxicity. We investigated several aspects of the innate macrophage response against pathogens, involving engulfment via pattern recognition receptors (PRRs), degradation, and presentation via MHC Class II molecules, on the HIV life cycle in macrophages. One PRR, the macrophage mannose receptor (MMR), binds terminal mannosyl residues on surface glycoproteins, a pattern found on the HIV envelope glycoprotein. We found that HIV association with macrophages is mostly mannose-dependent and MMR-mediated. Macrophages also mediate MMR-dependent transmission of HIV to co-cultured T-cells. The transmission is enhanced by inhibitors of endocytosis, indicating that endocytosis of virus plays a significant role in HIV infection.; The normal MMR endocytic pathway involves lysosomal delivery, a process disadvantageous for HIV. We hypothesized that CCR5-using viruses, those that productively infect macrophages, may be able to bypass this endocytic pathway through cross-talk between CCR5 and MMR. We examined whether MMR localized to lipid rafts, cholesterol rich regions of the plasma membrane where CCR5 has been shown to reside, since co-localization might facilitate CCR5/MMR cross-talk. MMR does have raft localization in primary macrophages and, interestingly, so does CD45, a non-raft marker in T-cells. Based on the plasma membrane raft budding model, we then tested whether CD45 and other macrophage raft markers were incorporated into virus particles. Surprisingly, neither CD45 nor CD14, a GPI-anchored raft marker, were incorporated into virions, suggesting a budding mechanism distinct from the raft model. The pattern of host molecules incorporated by HIV is reminiscent of those in exosomes, vesicles formed at the MHC Class II compartment membrane. Phenotypic analysis of the exosomes from primary macrophages showed heavy enrichment of tetraspannin proteins and MHC Class II and a lack of CD14 or CD45 enrichment, supporting the idea that HIV is utilizing the existing exosomal pathway for budding in macrophages. The exosomal model of HIV budding has important implications for understanding virus transmission and pathogenesis. It may also provide the basis for novel therapeutic and vaccine approaches for this important human pathogen.