Curing HIV: Seeking to Target and Clear Persistent Infection

Abstract

Human immunodeficiency virus type 1 (HIV-1) infection persists despite years of antiretroviral therapy (ART). To remove the stigma and burden of chronic infection, approaches to eradicate or cure HIV infection are desired. Attempts to augment ART with therapies that reverse viral latency, paired with immunotherapies to clear infection, have advanced into the clinic, but the field is still in its infancy. We review foundational studies and highlight new insights in HIV cure research. Together with advances in ART delivery and HIV prevention strategies, future therapies that clear HIV infection may relieve society of the affliction of the HIV pandemic.

Figure 1.

Proviral silencing and latency is founded and enforced via multiple restrictions to expression. (A) Epigenetic modifiers, such as histone deacetylases (HDACs) and histone lysine methyltransferases (HKMTs), are recruited to HIV-1 LTR promoter, notably by the PRC2 complex. This results in histone modifications within chromatin at the HIV promoter that limit the ability of RNA polymerase to initiate transcription. (B) Sequestration of essential transcription factors like NFAT and NF-kB, and the pTEF-b cyclin complex, are sequestered in resting CD4⁺ T cells by cellular regulatory complexes (IkB and HEXIM/7skRNA, respectively). (C) Transcriptional interference can occur by promoter occlusion, when a host gene polymerase positioned upstream of the provirus reads through the HIV-1 LTR, causing displacement of necessary transcription factors. Alternatively convergent transcription abort viral expression when the proviral and the host gene RNA Pol II complexes are in opposite orientation, and collide. (D) In the absence of sufficient viral Tat transactivator, viral transcripts are paused. The switch to processive elongation requires the kinase activity of P-TEFb along with the recruitment of processivity factors that constitute the superelongation complex (SEC). Tat efficiently transactivates HIV transcription by recruiting P-TEFb and the SEC to the paused RNAP II complex at the TAR hairpin.

Figure 2.

A model of the dynamic, latent reservoir. Viruses enter the latent, persistent reservoir from the earliest days of infection, but most do not persist due to a short half-life of the host cells or immune activation or both. Early viruses are serially replaced by viruses that circulate later in infection, prior to ART initiation (dotted line). Upon ART initiation, viruses no longer enter the reservoir as replication is blocked. But the exit rate of infected cells is much decreased, perhaps due to the dampening of generalized immune activation and/or increases in CD4 cell half-life. The slower loss of persistently infected cells is thereafter nearly matched by homeostatic proliferation, resulting in the slow decay of latent viruses.

Figure 3.

Persistence and proliferation in latency. Both homeostatic and antigen-driven proliferation appears contribute to the persistence of proviral infection. One model that fits current observations holds that while more differentiated, activated, effector cells may have a shorter lifespan, they may be continually replaced by clonal proliferation of less differentiated memory cell populations.

Figure 4.

Potential and demonstrated sites of HIV reservoirs. Anatomic sites with demonstrated recovery of replication-competent virus in humans following years of suppressive ART are highlighted in bold. Potential replication-competent anatomic reservoir sites are in regular font. These sites represent tissues/organs where HIV nucleic acid has been detected either in humans or animal models but recovery of rebound-competent virus in humans after years of suppressive ART has not been demonstrated.