Concerted action of cellular JNK and Pin1 restricts HIV-1 genome integration to activated CD4+ T lymphocytes.
Long-standing evidence indicates that quiescent human peripheral blood T lymphocytes (PBLs) do not support efficient HIV infection. In resting PBLs, reverse transcription of viral RNA takes longer than in activated cells, partially because formation of the late products of reverse transcription is decreased by RNA binding by apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G). In a subsequent step, integration of the viral complementary DNA that is eventually formed is markedly impaired. Here we show that cellular c-Jun N-terminal kinase (JNK), an enzyme that is not expressed in resting CD4+ T cells, regulates permissiveness to HIV-1 infection, and we unravel a new, sequential post-translational pathway of protein modification that regulates viral DNA integration. We found that, in activated T lymphocytes, viral integrase, which mediates HIV-1 cDNA integration into the host cell genome, is phosphorylated by JNK on a highly conserved serine residue in its core domain. Phosphorylated integrase, in turn, becomes a substrate for the cellular peptidyl prolyl-isomerase enzyme Pin1, which catalyzes a conformational modification of integrase. These concerted activities increase integrase stability and are required for efficient HIV-1 integration and infection. Lack of these modifications restricts viral infection in nonactivated, primary CD4+ T lymphocytes.
Manganaro
Lara
L
Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology, Area Science Park, Trieste, Italy.
Lusic
Marina
M
Gutierrez
Maria Ines
MI
Cereseto
Anna
A
Del Sal
Giannino
G
Giacca
Mauro
M
D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002478:Cells, Cultured; D004279:DNA, Viral / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D019427:HIV Integrase / Q000502:physiology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation / Q000502:physiology*; D048670:MAP Kinase Kinase 4 / Q000502:physiology*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000502:physiology*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D016662:Virus Integration / Q000502:physiology*
D004279:DNA, Viral; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D048670:MAP Kinase Kinase 4; D019427:HIV Integrase; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase