Matija Peterlin
Dept of Medicine, Microbiology and Immunology, University of California, San Francisco, CA 94143-0703, USA
Abstract:
HIV established a latent reservoir before seroconversion, as evidenced by circulating PMBCs that harbor non-replicating proviruses that can be detected by promoter proximal but not distal transcripts. Ratios of short to long tanscripts also mark proviral latency in tissues, e.g. SHIV-infected rhesus macaques, where the major reservoir of the virus appears to be in the gut. These differential transcripts also mark transcriptional interference, as now 3’ LTRs are no longer occluded and transcribe only promoter proximal transcripts. To activate HIV transcription in latently infected cells, the positive transcription elongation factor b (P-TEFb) must be recruited to the LTR. This targeting can occur via NF-kB, Brd4 or Tat. The activation of NF-kB, which binds double- and single-stranded DNA tightly, also antagonizes TI. There are many ways to activate P-TEFb, which include stress, UV light and cellular signaling. An unexpected way is via HMBA and SAHA. HMBA is a weak class II HDACi. SAHA or vorinostat is a potent pan-HDACi that inhibits class I and II HDACs. It has been approved for the treatment of cutaneous lymphoma in humans. HMBA and SAHA lead to a rapid activation of P-TEFb, which induces HIV transcription. Tat is made and sustains effects of these drugs. In a complicated scenario, HMBA and SAHA release P-TEFb from its inactive complex with 7SK snRNA and Hexim by first inactivating HDAC6, followed by tubulin and HSP90 acetylation, PI3K and Akt activation. Akt then phosphorylates two residues in Hexim that release P-TEFb. Free P-TEFb also increases the synthesis of Hexim so that inactive P-TEFb complexes reform quickly. This finding explains why cells treated with HMBA and SAHA stop proliferating and undergo terminal differentiation. Importantly, by competing with Hexim for RNA- and CycT1-binding, Tat steals P-TEFb from the inactive complex, thus HIV transcription is maintained even in these quiescent cells. This finding might represent an Achilles heel of the virus, as its unique RNA-binding transactivator Tat assures that short bursts of P-TEFb activation are translated into sustained viral gene expression, which renders HIV susceptible to elimination by the immune system and HAART.
