HIV-1 Latency and Eradication: Past, Present and Future

Abstract

Background: It is well established that antiretroviral therapy (ART), while highly effective in controlling HIV replication, cannot eliminate virus from the body. Therefore, the majority of HIV-1-infected individuals remain at risk for developing AIDS due to persistence of infected reservoir cells serving as a source of virus re-emergence. Several reservoirs containing replication competent HIV-1 have been identified, most notably CD4+ T cells. Cells of the myeloid lineage, which are the first line of defense against pathogens and participate in HIV dissemination into sanctuary organs, also serve as cellular reservoirs of HIV-1. In latently infected resting CD4+ T cells, the integrated copies of proviral DNA remain in a dormant state, yet possess the ability to produce replication competent virus after cellular activation. Studies have demonstrated that modification of chromatin structure plays a role in establishing persistence, in part suggesting that latency is, controlled epigenetically.

Conclusion: Current efforts to eradicate HIV-1 from this cell population focus primarily on a "shock and kill" approach through cellular reactivation to trigger elimination of virus producing cells by cytolysis or host immune responses. However, studies revealed several limitations to this approach that require more investigation to assess its clinical application. Recent advances in gene editing technology prompted use of this approach for inactivating integrated proviral DNA in the genome of latently infected cells. This technology, which requires a detailed understanding of the viral genetics and robust delivery, may serve as a powerful strategy to eliminate the latent reservoir in the host leading to a sterile cure of AIDS.

Figure 1

Shock and kill approach aiming to reactivate latently infected cells by HDAC inhibition including suberoylanilide hydroxamic acid (SAHA), the BET bromodomain protein inhibitor (BET151), and anti-CTLA4 antibody and induce subsequent cell death due to viral toxicity and/or host immune defense while HIV-1 replication is inhibited by ART.

Figure 2

ART therapy reduces mutation rate of the LTR by an average of 1.1 mutations per Kb per year. A) A histogram of the average mutation rate per patient while naive to therapy (blue) and after virologic control on cART (green). B) A cumulative normalized histogram of the same data in A) showing the fraction of patients with a mutation rate. Fourty two non-drug using patients that currently have undetectable viral load and at least 5 years in the study were selected. from the Drexel Medicine CNS AIDS Research and Eradication Study (CARES) Cohort. The LTR region was PCR amplified from genomic DNA isolated from PBMCs and phylogenetic trees were constructed to estimate the time varying mutation rate of the virus.

Figure 3

Strategy for CRISPR/Cas9 mediated cleavage of the HIV-1 genome. Guide RNAs (gRNAs) targeting the U3 region of the LTR can recruit Cas9 to the viral DNA sequence integrated in the host chromosome and results in cleavage of the viral DNA at the designated sites and introduces InDel mutations. Cleavage at both the 5′ and 3′ LTRs can lead to removal of the complete coding region of HIV-1 from the host genome and lead to eradication of HIV-1 from the host [133, 134].

Figure 4

HIV-1, thirty years of latency: from discovery to excision.