The microvesicle component of HIV-1 inocula modulates dendritic cell infection and maturation and enhances adhesion to and activation of T lymphocytes

• Published in: PLoS pathogens 2013-10, Vol.9 (10), p.e1003700-e1003700
• Main Authors: Mercier, Sarah K, Donaghy, Heather, Botting, Rachel A, Turville, Stuart G, Harman, Andrew N, Nasr, Najla, Ji, Hong, Kusebauch, Ulrike, Mendoza, Luis, Shteynberg, David, Sandgren, Kerrie, Simpson, Richard J, Moritz, Robert L, Cunningham, Anthony L
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; Adhesion; AIDS; Cell Adhesion - immunology; Cells, Cultured; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - pathology; Dendritic Cells - virology; Health aspects; HIV; HIV (Viruses); HIV Infections - immunology; HIV Infections - pathology; HIV-1 - immunology; Host-parasite relationships; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Lymphocyte Activation; Lymphocytes; Monocytes - immunology; Monocytes - pathology; Physiological aspects; Proteomics; T-Lymphocytes - immunology; T-Lymphocytes - pathology
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1003700

HIV-1 is taken up by immature monocyte derived dendritic cells (iMDDCs) into tetraspanin rich caves from which the virus can either be transferred to T lymphocytes or enter into endosomes resulting in degradation. HIV-1 binding and fusion with the DC membrane results in low level de novo infection that can also be transferred to T lymphocytes at a later stage. We have previously reported that HIV-1 can induce partial maturation of iMDDCs at both stages of trafficking. Here we show that CD45⁺ microvesicles (MV) which contaminate purified HIV-1 inocula due to similar size and density, affect DC maturation, de novo HIV-1 infection and transfer to T lymphocytes. Comparing iMDDCs infected with CD45-depleted HIV-1BaL or matched non-depleted preparations, the presence of CD45⁺ MVs was shown to enhance DC maturation and ICAM-1 (CD54) expression, which is involved in DC∶T lymphocyte interactions, while restricting HIV-1 infection of MDDCs. Furthermore, in the DC culture HIV-1 infected (p24⁺) MDDCs were more mature than bystander cells. Depletion of MVs from the HIV-1 inoculum markedly inhibited DC∶T lymphocyte clustering and the induction of alloproliferation as well as limiting HIV-1 transfer from DCs to T lymphocytes. The effects of MV depletion on these functions were reversed by the re-addition of purified MVs from activated but not non-activated SUPT1.CCR5-CL.30 or primary T cells. Analysis of the protein complement of these MVs and of these HIV-1 inocula before and after MV depletion showed that Heat Shock Proteins (HSPs) and nef were the likely DC maturation candidates. Recombinant HSP90α and β and nef all induced DC maturation and ICAM-1 expression, greater when combined. These results suggest that MVs contaminating HIV-1 released from infected T lymphocytes may be biologically important, especially in enhancing T cell activation, during uptake by DCs in vitro and in vivo, particularly as MVs have been detected in the circulation of HIV-1 infected subjects.