Defects In The Macrophage Galactose-Type Lectin Pathway Due To Hiv Infection

Abstract In the era of highly active antiretroviral therapy, HIV infection still produces 800,000 deaths and 1.2 million new infections per year. People living with HIV (PLWH) are vulnerable to several co-morbidities and co-infections, due to depletion of CD4+T cells and other incompletely characterized immune disturbances. To address the mechanisms involved, lung mRNAs from humanized mice co-infected with HIV and Mycobacterium tuberculosis (Mtb) were screened. Macrophage Galactose-type Lectin (MGL) was differentially regulated in co-infected animals. When MGL protein was quantified in biobanked frozen human lung specimens from 47 HIV-infected decedents, it was lower in the lung specimens with actively replicating HIV-1, as compared to those lacking detectable viral load. Lung MGL levels were negatively correlated with HIV RNA copies in the lung, and in the spleen, which is a key lymphoid organ that influences systemic immunity. Peripheral blood leukocytes from HIV infected patients showed that MGL activation was abnormal in those cells; comparable results were obtained in cultured HIV-infected macrophages. Molecular silencing of MGL in human monocyte-derived macrophages in vitro produced increased growth of Mtb, suggesting that lower MGL expression in PLWH could compromise their innate immunity to opportunistic pathogens such as Mtb. Macrophage MGL is a novel target to elucidate how HIV infection disrupts innate immunity and increases vulnerability to tuberculosis.