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.
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