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 cells1, 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)2. In a subsequent step, integration of the viral complementary DNA that is eventually formed is markedly impaired3,4. 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.
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We wish to thank A. Engelman (Dana-Farber Cancer Institute) for the pFlag-IN codon-optimized expression vector, L. Collavin (Laboratorio Nazionale CIB and University of Trieste) for the p-Cs2-JNK plasmid and F. Kirchhoff (Institute of Molecular Virology, Universitätsklinikum Ulm) for the HIV-2-Rod Luc clone. We are grateful to S. Kerbavcic for excellent editorial assistance and to M. Sturnega for the technical support in raising the rabbit phospho-integrase–specific antibody. This work was supported by grants from the Italian National Research Programme on AIDS of the Istituto Superiore di Sanità, Italy to M.G. and from the Associazione Italiana per la Ricerca sul Cancro to G.D.S.
The authors declare no competing financial interests.
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Manganaro, L., Lusic, M., Gutierrez, M. et al. Concerted action of cellular JNK and Pin1 restricts HIV-1 genome integration to activated CD4+ T lymphocytes. Nat Med 16, 329–333 (2010). https://doi.org/10.1038/nm.2102
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