Abstract
Low vitamin D levels in human immunodeficiency virus type-1 (HIV) infected persons are associated with more rapid disease progression and increased risk for Mycobacterium tuberculosis infection. We have previously shown that 1α,25-dihydroxycholecalciferol (1,25D3), the active form of vitamin D, inhibits HIV replication in human macrophages through the induction of autophagy. In this study, we report that physiological concentrations of 1,25D3 induce the production of the human cathelicidin microbial peptide (CAMP) and autophagic flux in HIV and M. tuberculosis co-infected human macrophages which inhibits mycobacterial growth and the replication of HIV. Using RNA interference for Beclin-1 and the autophagy-related 5 homologue, combined with the chemical inhibitors of autophagic flux, bafilomycin A1, an inhibitor of autophagosome-lysosome fusion and subsequent acidification, and SID 26681509 an inhibitor of the lysosome hydrolase cathepsin L, we show that the 1,25D3-mediated inhibition of HIV replication and mycobacterial growth during single infection or dual infection is dependent not only upon the induction of autophagy, but also through phagosomal maturation. Moreover, through the use of RNA interference for CAMP, we demonstrate that cathelicidin is essential for the 1,25D3 induced autophagic flux and inhibition of HIV replication and mycobacterial growth. The present findings provide a biological explanation for the benefits and importance of vitamin D sufficiency in HIV and M. tuberculosis-infected persons, and provide new insights into novel approaches to prevent and treat HIV infection and related opportunistic infections.
Highlights
Human immunodeficiency virus type-1 (HIV) is a global health problem that has infected 60 million people and caused 25 million deaths worldwide
Through the use of RNA interference for the human cathelicidin microbial peptide we demonstrate that cathelicidin is essential for the 1a,25dihydroxycholecalciferol induced autophagic flux and inhibition of HIV replication and mycobacterial growth
Despite much progress in the care and treatment of persons infected with HIV and those suffering from tuberculosis, the two pathogens are inextricably linked as important causes of morbidity and mortality worldwide
Summary
Human immunodeficiency virus type-1 (HIV) is a global health problem that has infected 60 million people and caused 25 million deaths worldwide. One-third of HIV-infected individuals are co-infected with Mycobacterium tuberculosis, a leading cause of death among people living with HIV. It has been proposed that the increase in M. tuberculosis pathology associated with HIV infection is caused by the disruption of the local immune response within the tuberculosis granulomas, decreasing their ability to contain M. tuberculosis leading to increased mycobacterial replication, dissemination and clinical disease [1,2,3,4,5]. Several studies have linked vitamin D deficiency (25-hydroxycholecalciferol (25D3) deficiency) with an increased risk for susceptibility to tuberculosis and active disease both in the presence [6] and absence of HIV infection [7,8,9,10,11,12,13,14]. Few studies have examined the association between vitamin D status and HIV disease progression and survival.
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