Interplay of Rad51 with NF-κB pathway stimulates expression of HIV-1.
Transcription from the HIV-1 promoter is controlled by a series of ubiquitous and inducible cellular proteins with the ability to enter the nucleus and interact with the promoter. A DNA sequence spanning nucleotides -120 to -80, which supports the association of the inducible NF-κB transcription factor, has received much attention. Here we demonstrate that the interplay between Rad51, a key regulator of the homologous recombination pathway of DNA repair and whose level is induced upon HIV-1 infection, with the NF-κB pathway, augments transcription of the viral promoter. Evidently, stimulation of the NF-κB pathway by PMA and/or TSA promotes association of Rad51 with the LTR DNA sequence and that the p65 subunit of NF-κB is important for this event. Our results also demonstrate that, similar to p65, Rad51 utilizes the NF-κB pathway to position itself in the nucleus as ectopic expression of an IκB mutant impedes its nuclear appearance and transcriptional activity upon the HIV-1 LTR. Treatment of peripheral blood mononuclear cells with small molecules that inhibit Rad51 activity results in greater than 50% decrease in the HIV-1 infection of cells. These observations provide evidence for the involvement of DNA repair factors in control of HIV-1 gene activation and offer a new avenue for the development of anti-viral therapeutics that affect viral gene transcription in latently infected cells.
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
Rafal
R
Kaminski
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
Hassen S
HS
Wollebo
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
Prasun K
PK
Datta
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
Martyn K
MK
White
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America; Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, United States of America.
Shohreh
S
Amini
Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania, United States of America.
Kamel
K
Khalili
D001253:Astrocytes / Q000166:cytology / Q000821:virology; D001921:Brain / Q000196:embryology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000378:metabolism; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D009154:Mutation; D011401:Promoter Regions, Genetic; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic; D051996:Transcription Factor RelA / Q000378:metabolism*; D015533:Transcriptional Activation
C498143:RELA protein, human; D051996:Transcription Factor RelA; C495153:RAD51 protein, human; D051135:Rad51 Recombinase