Concerted action of cellular JNK and Pin1 restricts HIV-1 genome integration to activated CD4+ T lymphocytes

TY - JOUR

T1 - Concerted action of cellular JNK and Pin1 restricts HIV-1 genome integration to activated CD4+ T lymphocytes

AU - Manganaro, Lara

AU - Lusic, Marina

AU - Gutierrez, Maria Ines

AU - Cereseto, Anna

AU - Del Sal, Giannino

AU - Giacca, Mauro

PY - 2010/3/1

Y1 - 2010/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77949264933&partnerID=8YFLogxK

U2 - 10.1038/nm.2102

DO - 10.1038/nm.2102

M3 - Article

C2 - 20173753

AN - SCOPUS:77949264933

SN - 1078-8956

VL - 16

SP - 329

EP - 333

JO - Nature Medicine

JF - Nature Medicine

IS - 3

ER -