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Mol Med. 1997 May; 3(5): 339–346.
PMCID: PMC2230081

The critical role of p38 MAP kinase in T cell HIV-1 replication.


BACKGROUND: Replication of HIV-1 in human T lymphocytes requires the activation of host cellular proteins. This study identifies p38 mitogen-activated protein kinase (MAPK) as one such kinase necessary for HIV-1 replication in T cells. MATERIALS AND METHODS: Primary human T lymphocytes were infected with the LAI strain of HIV-1 and Jurkat cells were infected with the RF strain of HIV-1. HIV replication was measured by reverse transcriptase activity. Cellular expression of endogenous p38 MAPK protein was analyzed using immunoprecipitation. Blockade of p38 MAPK expression was achieved using antisense oligonucleotides to p38 MAPK and the guanylhydrazone compound CNI-1493, an inhibitor of p38 MAPK activation. RESULTS: HIV-1 infection of both primary human T lymphocytes and a T cell line rapidly activated the cellular p38 MAPK pathway, which remained activated for the duration of the culture. Addition of phosphothioated antisense oligonucleotides to p38 MAPK specifically inhibited viral replication. Blockade of p38 MAPK activation by addition of CNI-1493 also inhibited HIV-1 viral replication of primary T lymphocytes in a dose- and time-dependent manner. Stimulation of p38 MAPK activation did not occur with the addition of heat-inactivated virus, suggesting that viral internalization, and not just membrane binding, is necessary for p38 MAPK activation. CONCLUSIONS: These results indicate that activation of the p38 MAPK cascade is critical for HIV-1 replication in primary T lymphocytes, and that blockade of this signal transduction pathway may be a novel therapeutic approach to the treatment of HIV-1 infection.

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  • Collier AC, Coombs RW, Schoenfeld DA, Bassett RL, Timpone J, Baruch A, Jones M, Facey K, Whitacre C, McAuliffe VJ, et al. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. AIDS Clinical Trials Group. N Engl J Med. 1996 Apr 18;334(16):1011–1017. [PubMed]
  • Eron JJ, Benoit SL, Jemsek J, MacArthur RD, Santana J, Quinn JB, Kuritzkes DR, Fallon MA, Rubin M. Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. North American HIV Working Party. N Engl J Med. 1995 Dec 21;333(25):1662–1669. [PubMed]
  • Deeks S, Volberding P. An approach to antiretroviral treatment of HIV disease. Combined antiretroviral therapy: the emerging role. Hosp Pract (1995) 1995 Aug;30 (Suppl 1):23–31. [PubMed]
  • Fauci AS, Pantaleo G, Stanley S, Weissman D. Immunopathogenic mechanisms of HIV infection. Ann Intern Med. 1996 Apr 1;124(7):654–663. [PubMed]
  • Heguy A, Stewart AA, Haley JD, Smith DE, Foulkes JG. Gene expression as a target for new drug discovery. Gene Expr. 1995;4(6):337–344. [PubMed]
  • Duh EJ, Maury WJ, Folks TM, Fauci AS, Rabson AB. Tumor necrosis factor alpha activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-kappa B sites in the long terminal repeat. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5974–5978. [PubMed]
  • Osborn L, Kunkel S, Nabel GJ. Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2336–2340. [PubMed]
  • Han J, Lee JD, Bibbs L, Ulevitch RJ. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science. 1994 Aug 5;265(5173):808–811. [PubMed]
  • Lee JC, Laydon JT, McDonnell PC, Gallagher TF, Kumar S, Green D, McNulty D, Blumenthal MJ, Heys JR, Landvatter SW, et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature. 1994 Dec 22;372(6508):739–746. [PubMed]
  • Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ. Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem. 1995 Mar 31;270(13):7420–7426. [PubMed]
  • Sen J, Kapeller R, Fragoso R, Sen R, Zon LI, Burakoff SJ. Intrathymic signals in thymocytes are mediated by p38 mitogen-activated protein kinase. J Immunol. 1996 Jun 15;156(12):4535–4538. [PubMed]
  • Han J, Richter B, Li Z, Kravchenko V, Ulevitch RJ. Molecular cloning of human p38 MAP kinase. Biochim Biophys Acta. 1995 Mar 16;1265(2-3):224–227. [PubMed]
  • Bianchi M, Ulrich P, Bloom O, Meistrell M, 3rd, Zimmerman GA, Schmidtmayerova H, Bukrinsky M, Donnelley T, Bucala R, Sherry B, et al. An inhibitor of macrophage arginine transport and nitric oxide production (CNI-1493) prevents acute inflammation and endotoxin lethality. Mol Med. 1995 Mar;1(3):254–266. [PMC free article] [PubMed]
  • Bianchi M, Bloom O, Raabe T, Cohen PS, Chesney J, Sherry B, Schmidtmayerova H, Calandra T, Zhang X, Bukrinsky M, et al. Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone. J Exp Med. 1996 Mar 1;183(3):927–936. [PMC free article] [PubMed]
  • Cohen PS, Nakshatri H, Dennis J, Caragine T, Bianchi M, Cerami A, Tracey KJ. CNI-1493 inhibits monocyte/macrophage tumor necrosis factor by suppression of translation efficiency. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):3967–3971. [PubMed]
  • Lu X, Wu X, Plemenitas A, Yu H, Sawai ET, Abo A, Peterlin BM. CDC42 and Rac1 are implicated in the activation of the Nef-associated kinase and replication of HIV-1. Curr Biol. 1996 Dec 1;6(12):1677–1684. [PubMed]
  • Nunn MF, Marsh JW. Human immunodeficiency virus type 1 Nef associates with a member of the p21-activated kinase family. J Virol. 1996 Sep;70(9):6157–6161. [PMC free article] [PubMed]
  • Sawai ET, Khan IH, Montbriand PM, Peterlin BM, Cheng-Mayer C, Luciw PA. Activation of PAK by HIV and SIV Nef: importance for AIDS in rhesus macaques. Curr Biol. 1996 Nov 1;6(11):1519–1527. [PubMed]
  • Freshney NW, Rawlinson L, Guesdon F, Jones E, Cowley S, Hsuan J, Saklatvala J. Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell. 1994 Sep 23;78(6):1039–1049. [PubMed]
  • Zervos AS, Faccio L, Gatto JP, Kyriakis JM, Brent R. Mxi2, a mitogen-activated protein kinase that recognizes and phosphorylates Max protein. Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10531–10534. [PubMed]
  • Trono D. HIV accessory proteins: leading roles for the supporting cast. Cell. 1995 Jul 28;82(2):189–192. [PubMed]
  • Yang X, Goncalves J, Gabuzda D. Phosphorylation of Vif and its role in HIV-1 replication. J Biol Chem. 1996 Apr 26;271(17):10121–10129. [PubMed]
  • Heinzinger NK, Bukrinsky MI, Haggerty SA, Ragland AM, Kewalramani V, Lee MA, Gendelman HE, Ratner L, Stevenson M, Emerman M. The Vpr protein of human immunodeficiency virus type 1 influences nuclear localization of viral nucleic acids in nondividing host cells. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7311–7315. [PubMed]
  • Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science. 1995 Nov 24;270(5240):1326–1331. [PubMed]
  • Flory E, Hoffmeyer A, Smola U, Rapp UR, Bruder JT. Raf-1 kinase targets GA-binding protein in transcriptional regulation of the human immunodeficiency virus type 1 promoter. J Virol. 1996 Apr;70(4):2260–2268. [PMC free article] [PubMed]
  • Kaplan G, Moreira AL. TNF alpha regulation of HIV1: biology and therapy. Res Immunol. 1994 Oct-Dec;145(8-9):685–690. [PubMed]

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