title: 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 occurrence 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 show here that the M. tuberculosis proline-proline-glutamic acid (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 the NF-κB signaling pathway. In silico docking analyses and mutation experiments have revealed that the N-terminal domain of Rv1168c specifically interacts with LRR motifs 15-20 of TLR2, and this site of interaction is different from that of Rv1196 protein (LRR motifs 11-15), 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.
authors.affiliation: Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics, Gruhakalpa Building, Nampally, Hyderabad 500001, India.
authors.forename: Khalid Hussain
authors.initials: KH
authors.lastname: Bhat
authors.forename: Chinta Krishna
authors.initials: CK
authors.lastname: Chaitanya
authors.forename: Nazia
authors.initials: N
authors.lastname: Parveen
authors.forename: Raja
authors.initials: R
authors.lastname: Varman
authors.forename: Sudip
authors.initials: S
authors.lastname: Ghosh
authors.forename: Sangita
authors.initials: S
authors.lastname: Mukhopadhyay
mesh_terms: D020816:Amino Acid Motifs; D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D015658:HIV Infections / Q000150:complications / Q000235:genetics / Q000378:metabolism; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology / Q000821:virology; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014376:Tuberculosis / Q000150:complications / Q000235:genetics / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016328:NF-kappa B; C530985:Rv1168c protein, Mycobacterium tuberculosis; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2