title: TLR2-Modulating Lipoproteins of the Mycobacterium tuberculosis Complex Enhance the HIV Infectivity of CD4+ T Cells.
abstract: Co-infection with Mycobacterium tuberculosis accelerates progression from HIV to AIDS. Our previous studies showed that M. tuberculosis complex, unlike M. smegmatis, enhances TLR2-dependent susceptibility of CD4+ T cells to HIV. The M. tuberculosis complex produces multiple TLR2-stimulating lipoproteins, which are absent in M. smegmatis. M. tuberculosis production of mature lipoproteins and TLR2 stimulation is dependent on cleavage by lipoprotein signal peptidase A (LspA). In order to determine the role of potential TLR2-stimulating lipoproteins on mycobacterial-mediated HIV infectivity of CD4+ T cells, we generated M. smegmatis recombinant strains overexpressing genes encoding various M. bovis BCG lipoproteins, as well as a Mycobacterium bovis BCG strain deficient in LspA (ΔlspA). Exposure of human peripheral blood mononuclear cells (PBMC) to M. smegmatis strains overexpressing the BCG lipoproteins, LprF (p<0.01), LprH (p<0.05), LprI (p<0.05), LprP (p<0.001), LprQ (p<0.005), MPT83 (p<0.005), or PhoS1 (p<0.05), resulted in increased HIV infectivity of CD4+ T cells isolated from these PBMC. Conversely, infection of PBMC with ΔlspA reduced HIV infectivity of CD4+ T cells by 40% relative to BCG-infected cells (p<0.05). These results may have important implications for TB vaccination programs in areas with high mother-to-child HIV transmission.
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Ciaran
authors.initials: C
authors.lastname: Skerry
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Lee G
authors.initials: LG
authors.lastname: Klinkenberg
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Page
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.|Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Petros C
authors.initials: PC
authors.lastname: Karakousis
mesh_terms: D000328:Adult; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D002478:Cells, Cultured; D004198:Disease Susceptibility; D055879:Gene Knock-In Techniques; D005798:Genes, Bacterial; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism*; D009163:Mycobacterium bovis / Q000235:genetics / Q000378:metabolism*; D020102:Mycobacterium smegmatis / Q000235:genetics / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D021382:Protein Sorting Signals; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014774:Virulence
chemical_list: D001426:Bacterial Proteins; D008074:Lipoproteins; D021382:Protein Sorting Signals; D011993:Recombinant Fusion Proteins; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D016282:Aspartic Acid Endopeptidases; C095652:signal peptidase II