MYCOBACTERIUM-TUBERCULOSIS ENHANCES HUMAN IMMUNODEFICIENCY VIRUS-1 REPLICATION BY TRANSCRIPTIONAL ACTIVATION AT THE LONG TERMINAL REPEAT

Tuberculosis has emerged as an epidemic fueled by the large number of individuals infected with the human immunodeficiency virus, especially those who are injecting drug users. We found a striking increase from 4- to 208-fold in p24 levels in bronchoalveolar lavage fluid from inv olved sites of Mycobacterium tuberculosis infection vs uninvolved site s in three HIV+ patients. We used an in vitro cell culture model to de termine if tuberculosis could activate replication of HIV-1. Mononucle ar phagocyte cell lines U937 and THP-1 infected with HIV-1(JR-CSF), in vitro and stimulated with live M. tuberculosis H37Ra, had a threefold increase in p24 in culture supernatants. Using the HTV-1 long termina l repeat with a chloramphenicol acetyltransferase (CAT) reporter const ruct, live M, tuberculosis increased transcription 20-fold in THP-1 ce lls, and cell wall components stimulated CAT expression to a lesser ex tent. The nuclear factor-kappa B enhancer element was responsible for the majority of the increased CAT activity although two upstream nucle ar factor-IL6 sites may also contribute to enhanced transcription, Ant ibodies to TNF-alpha and IL-1 inhibited the increase in CAT activity o f the HIV-1 long terminal repeat by M. tuberculosis from 21-fold to 8- fold. Stimulation of HIV-1 replication by M, tuberculosis may exacerba te dysfunction of the host immune response in dually infected individu als.