Strategies to eradicate HIV from infected patients: elimination of latent provirus reservoirs

Abstract

35 years since identification of HIV as the causative agent of AIDS, and 35 million deaths associated with this disease, significant effort is now directed towards the development of potential cures. Current anti-retroviral (ART) therapies for HIV/AIDS can suppress virus replication to undetectable levels, and infected individuals can live symptom free so long as treatment is maintained. However, removal of therapy allows rapid re-emergence of virus from a highly stable reservoir of latently infected cells that exist as a barrier to elimination of the infection with current ART. Prospects of a cure for HIV infection are significantly encouraged by two serendipitous cases where individuals have entered remission following stem cell transplantation from compatible HIV-resistant donors. However, development of a routine cure that could become available to millions of infected individuals will require a means of specifically purging cells harboring latent HIV, preventing replication of latent provirus, or destruction of provirus genomes by gene editing. Elimination of latently infected cells will require a means of exposing this population, which may involve identification of a natural specific biomarker or therapeutic intervention to force their exposure by reactivation of virus expression. Accordingly, the proposed "Shock and Kill" strategy involves treatment with latency-reversing agents (LRA) to induce HIV provirus expression thus exposing these cells to killing by cellular immunity or apoptosis. Current efforts to enable this strategy are directed at developing improved combinations of LRA to produce broad and robust induction of HIV provirus and enhancing the elimination of cells where replication has been reactivated by targeted immune modulation. Alternative strategies may involve preventing re-emergence virus from latently infected cells by "Lock and Block" intervention, where transcription of provirus is inhibited to prevent virus spread or disruption of the HIV provirus genome by genome editing.

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

“…Of note, this strategy does not discriminate between replication-competent and defective proviruses. Several classes of LRAs have been developed and studied (reviewed in Kim et al, 2018;Spivak and Planelles, 2018;Sadowski and Hashemi, 2019). These include: PKC agonists, MAPK agonists, CCR5 antagonist, Tat vaccine, SMAC mimetics, inducers of P-TEFb release, activators of Akt pathway, benzotriazole derivatives, epigenetic modifiers (including HDACis, HMTis, and DNMTis), and immunomodulatory LRAs (including TLR agonists, IL-15 agonist and immune checkpoint inhibitors) (summarized in Table 1).…”

Broadly active zinc finger protein-guided transcriptional activation of HIV

“…The ZFP-362 activator of HIV described here may prove useful in the development of a functional cure for HIV infection. For instance, the ZFP-362 activator could be used in a "shock-and-kill" strategy to activate latent virus while maintaining ART, leading to the death of the latently infected cells [2]. Alternatively, ZFP-362 could be used to induce sustained expression of HIV to allow for or enhance chimeric antigen T cell (CAR) targeting of infected cells.…”

“…Activation and purging of provirus from macrophages, monocytes, and T-cells, with ~ 1 infected cell per million cells, has been an ongoing experimental struggle, the goal being to nd latency reversing agents (LRAs) that can be used along with antiretroviral therapy (ART). This "shock-andkill" approach aims to eliminate the reservoir by inducing HIV-1 activation resulting in death of the infected cell [2]. Several LRAs are known to activate latent provirus in patients [3], but LRAs are broad effectors of cellular processes and, therefore, inherent off-target effects are expected.…”

Trends in antiviral strategies

“…In retroviruses and hepadnaviruses, the viral DNA is not only hidden from antiviral drugs, but it can serve as an archive of genomes whose replication can be reactivated upon treatment discontinuation. If combination therapy could be coupled with an efficient elimination of the proviral reservoirs in host DNA (De Crignis and Mahmoudi, 2014;Sadowski and Hashemi, 2019), HIV-1 could probably be eliminated from the infected organism, as achieved in the case of HCV infections in many patients treated with direct-acting antiviral agents (DAAs).…”