Latency reversal and viral clearance to cure HIV-1

Abstract

Research toward a cure for human immunodeficiency virus type 1 (HIV-1) infection has joined prevention and treatment efforts in the global public health agenda. A major approach to HIV eradication envisions antiretroviral suppression, paired with targeted therapies to enforce the expression of viral antigen from quiescent HIV-1 genomes, and immunotherapies to clear latent infection. These strategies are targeted to lead to viral eradication--a cure for AIDS. Paired testing of latency reversal and clearance strategies has begun, but additional obstacles to HIV eradication may emerge. Nevertheless, there is reason for optimism that advances in long-acting antiretroviral therapy and HIV prevention strategies will contribute to efforts in HIV cure research and that the implementation of these efforts will synergize to markedly blunt the effect of the HIV pandemic on society.

Fig. 1. HIV latency

Cellular pathways that enforce HIV latency are targets for LRAs. The escape of the integration provirus from the latent state is restricted at several levels: epigenetic silencing of the proviral promoter, transcription complex formation, transcript initiation, and transcription complex processivity. Examples of inhibitors and inducers currently under study as potential LRAs are displayed.

Fig. 2. Persistent, latent infection of memory CD4 cells decays slowly over time

Residual HIV replication and proliferation of latently infected cells might increase the frequency of latent infection, but these forces must be slightly outweighed by those that naturally deplete latent infection because a slow decay of latent infection is uniformly seen in stably treated patients. The goal of antilatency therapy is to effectively accelerate the clearance of persistent infection across all reservoirs of persistent infection. This data, collected over 10 years ago (35), has recently been precisely reproduced in a contemporary patient cohort using improved ART (36). [Adapted by permission from Macmillan Publishers, Nature Med. 2003.]