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.