Proline-Proline-Glutamic acid (PPE) protein Rv1168c of Mycobacterium tuberculosis augments transcription from HIV-1 long terminal repeat promoter

Abstract

Cells of the monocyte/macrophage lineage are shown to play a role in the pathogenesis of Human Immunodeficiency Virus (HIV). The incidence of HIV type 1 (HIV-1) infection is found to be accelerated in people infected with Mycobacterium tuberculosis, but the mechanism by which mycobacterial protein(s) induces HIV-1 LTR trans-activation is not clearly understood. We describe here that the M. tuberculosis PPE protein, Rv1168c (PPE17) can augment transcription from HIV-1 LTR in monocyte/macrophage cells. Rv1168c interacts specifically with Toll-like receptor-2 (TLR2) resulting in downstream activation of nuclear factor-κB (NF-κB) resulting in HIV-1 LTR trans-activation. Another PPE protein, Rv1196 (PPE18) was also found to interact with TLR2, but had no effect on HIV-1 LTR trans-activation because of its inability to activate NF-κB signaling pathway. In silico docking analyses and mutation experiments have revealed that the N-terminal domain of Rv1168c specifically interacts with the Leucine Rich Repeats (LRR) 15∼20 domain of TLR2 and this site of interaction is different from that of Rv1196 protein (LRR 11∼15 domain), indicating that the site of interaction on TLR2 dictates the downstream signaling events leading to activation of NF-κB. This information may help in understanding the mechanism of pathogenesis of HIV-1 during M. tuberculosis co-infection.