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Review
. 2015 Aug;36(8):908-16.
doi: 10.1038/aps.2015.22. Epub 2015 Jun 1.

Progress and challenges in the use of latent HIV-1 reactivating agents

Hong-tao Shang  1 , Ji-wei Ding  2 , Shu-ying Yu  1 , Tao Wu  1 , Qiu-li Zhang  1 , Fu-jun Liang  3
Affiliations
Review

Progress and challenges in the use of latent HIV-1 reactivating agents

Hong-tao Shang et al. Acta Pharmacol Sin. 2015 Aug.

Abstract

Highly active antiretroviral therapy (HAART) can effectively suppress the replication of human immunodeficiency virus-1 (HIV-1) and block disease progression. However, chronic HIV-1 infection remains incurable due to the persistence of a viral reservoir, including the transcriptionally silent provirus in CD4(+) memory T cells and the sanctuary sites that are inaccessible to drugs. Reactivation and the subsequent elimination of latent virus through virus-specific cytotoxic effects or host immune responses are critical strategies for combating the disease. Indeed, a number of latency reactivating reagents have been identified through mechanism-directed approaches and large-scale screening, including: (1) histone deacetylase inhibitors (HDACi); (2) cytokines and chemokines; (3) DNA methyltransferase inhibitors (DNMTI); (4) histone methyltransferase inhibitors (HMTI); (5) protein kinase C (PKC) activators; (6) P-TEFb activators; and (7) unclassified agents, such as disulfram. They have proved to be efficacious in latent cell line models and CD4(+) T lymphocytes from HIV-1-infected patients. This review comprehensively summarizes the recent progress and relative challenges in this field.

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Figures

Figure 1
Figure 1
Multifactorial mechanisms governing HIV-1 latency and latency-reversing agents based on their pharmaceutical targets. Different compounds have been identified that reactivate HIV-1 transcription. In the cytoplasm, PKC agonists such as prostratin and brystatin 1 can activate PKC, which leads to the subsequent phosphorylation and degradation of NF-κB inhibitor IκB-α, followed by the freeing of p65/p50 and accumulation of p65/p50 in the nucleus. The binding of p65/p50 to the HIV LTR enhances initial transcription. Disulfram promotes the degradation of PTEN and upregulates HIV-1 transcription upon activation of the Akt pathway. Cytokines such as IL-7 and IL-15, which are involved in the JAK/STAT pathway, also have a positive effect on latent virus reactivation. In the nucleus, the recruitment of the P-TEFb complex, comprised of CDK9 and cyclin T1, by HIV Tat is the prerequisite for transcription initiation. JQ1, by binding to Brd4, can release P-TEFb and thereby promote transcription elongation. HDACi inhibits deacetylation of histones and non-histone transcription factors, allowing for acetylation by the HATs, which is required for a more favorable chromatin structure. In addition, DNMTIs, of which Aza-CdR is the prototype, and HMTIs, including DNZep and chaetocin, reactivate HIV-1 transcription by targeting DNMT and HMT, respectively.
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