Figure 2.

RNA processing mechanisms linked to HIV-1 latency. (A) Regulation of HIV-1 vRNA splicing is involved in HIV-1 latency by multiple mechanisms such as: Tat protein levels and activity at the HIV-1 LTR TAR can be controlled by regulating Tat-containing mRNA splicing (ESE-Tat), and action of host factors that prevent Tat-TAR interaction by binding to TAR (SF3B1), and positively (SRP14) or negatively (HMGB3) regulate Tat mRNA processing and translation by binding to TIM-TAM RNA element. Viral RNA processing is also controlled by surveillance mechanisms that prevent Tat-TAR binding in the US vRNA (RRP6, MTR4, ZFC3H1), promote degradation of MS vRNA (N4BP1), and (B) regulate US vRNA stability (UPF1, UPF2 and SMG6). (B) Nucleocytoplasmic export of HIV-1 vRNA species is tightly regulated during latency: nuclear retention of US vRNA species is promoted by host proteins CRNKL1, MATR3 and PSF, and by binding of host proteins to instability sequences (INS) such as PSF, hnRNPA1 and PABP1. On the contrary, protein DDX3 and PTB positively regulate US vRNA and MS vRNA export respectively, and their absence leads to vRNA nuclear retention. (C) Modulation of viral protein synthesis can contribute to HIV-1 latency via: regulation of mTOR complex, DDX3 and CBC complex, and by microRNAs that directly target HIV-1 vRNA and lead to its degradation (miR28, miR125b, miR223, miR383, mimR196, miR1290, miR29a). RNA (vRNA) is represented as a red curved line. Single spliced (SS) 4kb viral RNA is represented as a purple curved line. Multiple spliced (MS) 2kb viral RNA is represented as a green curved line. Red flat-head arrows represent mechanisms reported in literature to promote HIV-1 latency. Green triangle-head arrows represent mechanisms reported in literature to prevent HIV-1 latency. TAR stands for trans-activating response element. RRE stands for Rev response element. INS stands for instability sequence. Red sign ∅ represents inhibition.