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- Open Access
Activation of HIV-1 expression and replication by cGMP dependent protein kinase type 1-β (PKG1β)
© Lee et al; licensee BioMed Central Ltd. 2007
Received: 25 October 2007
Accepted: 13 December 2007
Published: 13 December 2007
The effect of cGMP (cyclic GMP) dependent protein kinase 1-β (PKG1-β) and cGMP analogues on transcriptional activity and replication of human immunodeficiency virus type 1 (HIV-1) was investigated. Transfection of PKG1β expression plasmid increased expression from an HIV-1 LTR-reporter as well as from an infectious HIV-1 molecular clone, pNL4-3. Treatment of HIV-1 AD8-infected monocyte derived macrophages (MDMs) with cGMP agonists and cGMP antagonists caused respectively increased and decreased virus replication. These findings provide evidence that cGMP and PKG serve to regulate HIV-1 infection in human cells.
Previously nitric oxide (NO) was postulated to have a negative effect on HIV-1 replication through a cGMP-independent route . However, it was not characterized as to how this cGMP-independent effect manifested mechanistically. On the other hand, it is well-accepted that a major intracellular signaling pathway for NO is through a cytosolic-guanylate cyclase linked cGMP-dependent protein kinase, PKG, pathway . cGMP/PKG has been shown to activate abundantly both CREB  and NF-κB [4, 5]. Interestingly, to our knowledge, no systematic investigation of cGMP/PKG's activity on the HIV-1 LTR has been reported to date.
Optimal PKG activity is dependent on activation by cGMP . While over expression of exogenously transfected PKG offered significantly measureable effects (Figures 1, 2), we wished to understand next how cell endogenous PKG might act mechanistically in response to cGMP treatment. Elsewhere, it was reported that NF-κB p65, p52, and p50 are substrate proteins activated by PKG-mediated phosphorylation. Because expression of the HIV-1 LTR is regulated by NF-κB [12, 13], we asked if cGMP activated NF-κB in our experimental.
Here, we report evidence that both in the absence and presence of Tat the cGMP/PKG pathway can serve to modulate HIV-1 expression/replication. Understanding how HIV-1 LTR expression is affected by ambient cellular pathways [18–20] may help to address potential approaches for treating latent HIV-1 infection . The current findings may be important because cGMP is a ubiquitous second messenger that affects multiple cellular pathways in most, if not all, cells. Accordingly, cGMP-influenced pathways are likely to interdigitate with some of the signaling routes utilized by HIV-1 in infected cells . Additionally, because many cGMP chemical agonists and antagonists are available [23, 24], practical chemotherapeutic interventions in these pathways (if they should be useful for anti-viral purposes) could be amenable.
Work in Kuan-Teh Jeang's laboratory is supported in part by intramural funding from NIAID, NIH; and by the intramural AIDS targeted antiviral program (IATAP) from the Office of the Director, NIH. We thank Dr. S.M. Lohmann for PKG1β expression plasmid.
- Mannick JB, Stamler JS, Teng E, Simpson N, Lawrence J, Jordan J, Finberg RW: Nitric oxide modulates HIV-1 replication. J Acquir Immune Defic Syndr. 1999, 22: 1-9.View ArticlePubMedGoogle Scholar
- Denninger JW, Marletta MA: Guanylate cyclase and the .NO/cGMP signaling pathway. Biochim Biophys Acta. 1999, 1411: 334-350. 10.1016/S0005-2728(99)00024-9.View ArticlePubMedGoogle Scholar
- Gudi T, Casteel DE, Vinson C, Boss GR, Pilz RB: NO activation of fos promoter elements requires nuclear translocation of G-kinase I and CREB phosphorylation but is independent of MAP kinase activation. Oncogene. 2000, 19: 6324-6333. 10.1038/sj.onc.1204007.View ArticlePubMedGoogle Scholar
- He B, Weber GF: Phosphorylation of NF-kappaB proteins by cyclic GMP-dependent kinase. A noncanonical pathway to NF-kappaB activation. Eur J Biochem. 2003, 270: 2174-2185. 10.1046/j.1432-1033.2003.03574.x.View ArticlePubMedGoogle Scholar
- He B, Weber GF: Synergistic activation of the CMV promoter by NF-kappaB P50 and PKG. Biochem Biophys Res Commun. 2004, 321: 13-20. 10.1016/j.bbrc.2004.06.101.View ArticlePubMedGoogle Scholar
- Jeang KT, Berkhout B: Kinetics of HIV-1 long terminal repeat trans-activation. Use of intragenic ribozyme to assess rate-limiting steps. J Biol Chem. 1992, 267: 17891-17899.PubMedGoogle Scholar
- Jeang KT, Berkhout B, Dropulic B: Effects of integration and replication on transcription of the HIV-1 long terminal repeat. J Biol Chem. 1993, 268: 24940-24949.PubMedGoogle Scholar
- Brady J, Kashanchi F: Tat gets the "green" light on transcription initiation. Retrovirology. 2005, 2: 69-10.1186/1742-4690-2-69.PubMed CentralView ArticlePubMedGoogle Scholar
- Ammosova T, Berro R, Jerebtsova M, Jackson A, Charles S, Klase Z, Southerland W, Gordeuk VR, Kashanchi F, Nekhai S: Phosphorylation of HIV-1 Tat by CDK2 in HIV-1 transcription. Retrovirology. 2006, 3: 78-10.1186/1742-4690-3-78.PubMed CentralView ArticlePubMedGoogle Scholar
- Sandberg M, Natarajan V, Ronander I, Kalderon D, Walter U, Lohmann SM, Jahnsen T: Molecular cloning and predicted full-length amino acid sequence of the type I beta isozyme of cGMP-dependent protein kinase from human placenta. Tissue distribution and developmental changes in rat. FEBS Lett. 1989, 255: 321-329. 10.1016/0014-5793(89)81114-7.View ArticlePubMedGoogle Scholar
- Pilz RB, Broderick KE: Role of cyclic GMP in gene regulation. Front Biosci. 2005, 10: 1239-1268. 10.2741/1616.View ArticlePubMedGoogle Scholar
- Nabel G, Baltimore D: An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature. 1987, 326: 711-713. 10.1038/326711a0.View ArticlePubMedGoogle Scholar
- Berkhout B, Jeang KT: Functional roles for the TATA promoter and enhancers in basal and Tat-induced expression of the human immunodeficiency virus type 1 long terminal repeat. J Virol. 1992, 66: 139-149.PubMed CentralPubMedGoogle Scholar
- Vermeulen L, De WG, Notebaert S, Vanden BW, Haegeman G: Regulation of the transcriptional activity of the nuclear factor-kappaB p65 subunit. Biochem Pharmacol. 2002, 64: 963-970. 10.1016/S0006-2952(02)01161-9.View ArticlePubMedGoogle Scholar
- Peloponese JM, Yeung ML, Jeang KT: Modulation of nuclear factor-kappaB by human T cell leukemia virus type 1 Tax protein: implications for oncogenesis and inflammation. Immunol Res. 2006, 34: 1-12. 10.1385/IR:34:1:1.View ArticlePubMedGoogle Scholar
- Freed EO, Martin MA: HIV-1 infection of non-dividing cells. Nature. 1994, 369: 107-108. 10.1038/369107b0.View ArticlePubMedGoogle Scholar
- Rich EA, Orenstein JM, Jeang KT: A macrophage-tropic HIV-1 that expresses green fluorescent protein and infects alveolar and blood monocyte-derived macrophages. J Biomed Sci. 2002, 9: 721-726. 10.1007/BF02255001.View ArticlePubMedGoogle Scholar
- Agbottah E, Deng L, Dannenberg LO, Pumfery A, Kashanchi F: Effect of SWI/SNF chromatin remodeling complex on HIV-1 Tat activated transcription. Retrovirology. 2006, 3: 48-10.1186/1742-4690-3-48.PubMed CentralView ArticlePubMedGoogle Scholar
- Ariumi Y, Serhan F, Turelli P, Telenti A, Trono D: The integrase interactor 1 (INI1) proteins facilitate Tat-mediated human immunodeficiency virus type 1 transcription. Retrovirology. 2006, 3: 47-10.1186/1742-4690-3-47.PubMed CentralView ArticlePubMedGoogle Scholar
- Sorin M, Yung E, Wu X, Kalpana GV: HIV-1 replication in cell lines harboring INI1/hSNF5 mutations. Retrovirology. 2006, 3: 56-10.1186/1742-4690-3-56.PubMed CentralView ArticlePubMedGoogle Scholar
- Marcello A: Latency: the hidden HIV-1 challenge. Retrovirology. 2006, 3: 7-10.1186/1742-4690-3-7.PubMed CentralView ArticlePubMedGoogle Scholar
- Fassati A: HIV infection of non-dividing cells: a divisive problem. Retrovirology. 2006, 3: 74-10.1186/1742-4690-3-74.PubMed CentralView ArticlePubMedGoogle Scholar
- Bender AT, Beavo JA: Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev. 2006, 58: 488-520. 10.1124/pr.58.3.5.View ArticlePubMedGoogle Scholar
- Martelli A, Rapposelli S, Calderone V: NO-releasing hybrids of cardiovascular drugs. Curr Med Chem. 2006, 13: 609-625. 10.2174/092986706776055634.View ArticlePubMedGoogle Scholar
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