Mycobacterium tuberculosis promotes HIV trans-infection and suppresses major histocompatibility complex class II antigen processing by dendritic cells.
Mycobacterium tuberculosis is a leading killer of HIV-infected individuals worldwide, particularly in sub-Saharan Africa, where it is responsible for up to 50% of HIV-related deaths. Infection by HIV predisposes individuals to M. tuberculosis infection, and coinfection accelerates the progression of both diseases. In contrast to most other opportunistic infections associated with HIV, an increased risk of M. tuberculosis infection occurs during early-stage HIV disease, long before CD4 T cell counts fall below critical levels. We hypothesized that M. tuberculosis infection contributes to HIV pathogenesis by interfering with dendritic cell (DC)-mediated immune control. DCs carry pathogens like M. tuberculosis and HIV from sites of infection into lymphoid tissues, where they process and present antigenic peptides to CD4 T cells. Paradoxically, DCs can also deliver infectious HIV to T cells without first becoming infected, a process known as trans-infection. Lipopolysaccharide (LPS)-activated DCs sequester HIV in pocketlike membrane invaginations that remain open to the cell surface, and individual virions are delivered from the pocket into T cells at the site of contact during trans-infection. Here we report that M. tuberculosis exposure increases HIV trans-infection and induces viral sequestration within surface-accessible compartments identical to those seen in LPS-stimulated DCs. At the same time, M. tuberculosis dramatically decreases the degradative processing and major histocompatibility complex class II (MHC-II) presentation of HIV antigens to CD4 T cells. Our data suggest that M. tuberculosis infection promotes a shift in the dynamic balance between antigen processing and intact virion presentation, favoring DC-mediated amplification of HIV infections.
Reuter
Morgan A
MA
Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4960, USA.
Pecora
Nicole D
ND
Harding
Clifford V
CV
Canaday
David H
DH
McDonald
David
D
D017951:Antigen Presentation; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D015536:Down-Regulation; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D009000:Monocytes / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000502:physiology*; D014397:Tuberculosis, Pulmonary / Q000150:complications / Q000276:immunology*
D000949:Histocompatibility Antigens Class II