Abstract
Tuberculosis (TB) is the leading cause of mortality among those infected with human immunodeficiency virus (HIV-1) worldwide. HIV-1 load and heterogeneity are increased both locally and systemically in active TB. Mycobacterium tuberculosis (MTB) infection supports HIV-1 replication through dysregulation of host cytokines, chemokines, and their receptors. However the possibility that mycobacterial molecules released from MTB infected macrophages directly interact with CD4+ T cells triggering HIV-1 replication has not been fully explored. We studied the direct effect of different MTB molecules on HIV-1 replication (R5-tropic strain Bal) in anti-CD3- stimulated CD4+ T cells from healthy donors in an antigen presenting cell (APC)-free system. PIM6, a major glycolipid of the mycobacterial cell wall, induced significant increases in the percent of HIV-1 infected T cells and the viral production in culture supernatants. In spite of structural relatedness, none of the other three major MTB cell wall glycolipids had significant impact on HIV-1 replication in T cells. Increased levels of IFN-γ in culture supernatants from cells treated with PIM6 indicate that HIV-1 replication is likely dependent on enhanced T cell activation. In HEK293 cells transfected with TLR2, PIM6 was the strongest TLR2 agonist among the cell wall associated glycolipids tested. PIM6 increased the percentage of HIV infected cells and viral particles in the supernatant in a T-cell-based reporter cell line (JLTRg-R5) transfected with TLR1 and TLR2 but not in the cells transfected with the empty vector (which lack TLR2 expression) confirming that PIM6-induced HIV-1 replication depends at least partially on TLR2 signaling.
Highlights
Tuberculosis (TB) is the largest single cause of death for people living with HIV-1 in low- and middle-income countries, accounting for one-quarter of the estimated 2 million HIV-1 related deaths worldwide [1,2,3,4]
We tested the effect of three Mycobacterium tuberculosis (MTB) crude subcellular fractions, i.e. whole cell lysate, cell wall and culture filtrate proteins on HIV-1 infection in CD4+ cells activated with anti-CD3 by measuring intracellular p24 expression by flow cytometry
To identify the factor(s) responsible for upregulation of HIV-1 replication, we focused on MTB cell wall associated glycolipids because they are known to be associated with exosomes isolated from supernatants of MTB infected macrophages [12,14]
Summary
Tuberculosis (TB) is the largest single cause of death for people living with HIV-1 in low- and middle-income countries, accounting for one-quarter of the estimated 2 million HIV-1 related deaths worldwide [1,2,3,4]. TB and HIV-1 disease are the two leading causes of infectious disease–associated mortality among adults worldwide [5,6]. TB is thought to be a major contributor in the immune activation that increases HIV-1 replication, compartmentalization and heterogeneity. Pulmonary TB enhances HIV-1 replication and heterogeneity in the lung [7]. TB is associated with increased systemic viral replication and heterogeneity, decreased CD4+ cell counts, more rapid progression to acquired immune deficiency syndrome (AIDS), and increased mortality [8,9]. It has been clearly established that TB has a major impact in viral replication and disease progression in HIV-1 infected individuals. The molecular mechanisms that drive HIV-1 disease progression in people with active TB are not well understood
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