A Review of Current Strategies Towards the Elimination of Latent HIV-1 and Subsequent HIV-1 Cure

Abstract

Background: During the past 35 years, highly effective ART has saved the lives of millions of people worldwide by suppressing viruses to undetectable levels. However, this does not translate to the absence of viruses in the body as HIV persists in latent reservoirs. Indeed, rebounded HIV has been recently observed in the Mississippi and California infants previously thought to have been cured. Hence, much remains to be learned about HIV latency, and the search for the best strategy to eliminate reservoir is the direction current research is taking. A systems-level approach that fully recapitulate the dynamics and complexity of HIV-1 latency in vivo and applicable in human therapy is prudent for HIV eradication to be more feasible. Objectives: The main barriers preventing the cure of HIV with antiretroviral therapy have been identified, progress has been made in the understanding of the therapeutic targets to which potentially eradicating drugs could be directed, integrative strategies have been proposed and clinical trials with various alternatives are underway. The aim of this review is to provide an update on the main advances in HIV eradication, with particular emphasis on the obstacles to HIV eradication and the different strategies proposed. We highlight the core challenges of each strategy and propose the most promising strategy and newresearch avenues in HIV eradication strategies. Methods: We conducted a systematic literature search of all English-language articles published between 2015 and 2019 using MEDLINE (PubMed) and Google scholar. Where available, medical subject headings (MeSH) were used as search terms and included: HIV, HIV latency, HIV reservoir, latency reactivation and HIV cure. Additional search terms consisted ofsuppression, persistence, establishment, generation, and formation. A total of 250 articles were found usingthe above search terms. Of these, 89 relevant articles related to HIV-1 latency establishment and eradication strategies were collected and reviewed, with no limitation of study design. Additional studies (commonly referenced and/or older and more recent articles of significance) were selected from bibliographies and references listed in the primary resources. Results : :In general, when exploring the literature, there are four main strategies heavily researched and provides promising strategies to the elimination of latent HIV: Haematopoietic Stem-Cell Transplantation, Shock and Kill Strategy, Gene-specific transcriptional activation using RNA-guided CRISPR-Cas9 system, and Block and Lock strategy. Most of these strategies studies are applicable in vitro, leaving many questions about the extent to which, or if any, these strategies are applicable to complex picture in vivo. However, the success of these strategies at least shows in part that HIV-1 can be cured, though some strategies are too invasive and expensive to become a standard of care for all HIV-infected patients. Conclusion: Recent advances hold promise for the ultimate cure of HIV infection. A systems-level approach that fully recapitulate the dynamics and complexity of HIV-1 latency in vivo and applicable in human therapy is prudent for HIV eradication to be more feasible. Future studies aimed at achieving a prolonged HIV remission state are more likely to be successful if they focus on a combination strategy including the block and kill, and stem cell approaches. These strategies propose a functional cure with minimal toxicity for patients. We believe that the cure of HIV infection will be attained in the short term if a strategy based on purging the reservoirs is complemented with an aggressive HAART strategy.

Therapeutic Potential of Marine Bioactive Peptides against Human Immunodeficiency Virus: Recent Evidence, Challenges, and Future Trends

“…The activation of these resting cells, particularly after prolonged periods of dormancy, results in proviral gene expression of HIV-1 and consequent renewal of viral infection [ 103 ]. The increasing emphasis has therefore been on exploring therapeutic interventions aimed at complete elimination of the latent proviruses (sterilized cure) [ 104 ]. Of particular research interest is what is commonly termed as the ‘shock and kill’ strategies, whereby the transcription of HIV-1 proviruses present in resting CD4+ T reservoir cells is de-repressed with the aid of small molecule drugs for the production of replicating virus, which could be inhibited through simultaneous administration of highly active antiretroviral therapy (HAART) [ 105 ].…”

Toward the unveiling of HIV-1 dynamics: Involvement of monocytes/macrophages in HIV-1 infection

“…In addition to these strategies, the "Shock and Kill" approach to reducing the size of reservoirs is a current challenge, whereby latency-reversing agents (LRAs) reactivate latently infected provirus (the shock) and induce cell death mediated by cytopathic effects, apoptosis, or CTL response (the kill), combined with ART treatment to prevent the occurrence of a new infection. This strategy is still under development (108), and some small-molecule chemical compounds, including histone deacetylase inhibitors (HDACi) (e.g., SAHA/vorinostat) (109), bromodomain and extraterminal domain inhibitors (BETi) (e.g., JQ1) (110), and protein kinase C (PKC) agonists [e.g., Prostratin, PEP-005 (ingenole-3-angelate) and bryostatin-1] (111), are being intensively investigated as candidate LRAs. Several groups have reported that using an LRA, active via a single mechanism, might not lead to effective viral reactivation in reservoir cells, and combinations of drug candidates with different mechanisms of action will be needed to enhance proviral activation.…”

“…Several groups have reported that using an LRA, active via a single mechanism, might not lead to effective viral reactivation in reservoir cells, and combinations of drug candidates with different mechanisms of action will be needed to enhance proviral activation. Currently, combining the BRD4 inhibitor (JQ1) and PKC agonist(s) (e.g., Prostratin, PEP-005) might be the most effective means of reactivating the HIV-1 provirus (7,108). Despite the potent effects of LRA or a combination of LRAs on ex vivo or in vitro analyses, multiple clinical trials have failed to reduce latent reservoir size sufficiently, and none have shown superior therapeutic effects compared with current cART (112).…”

Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HIV Replication and PD-1 Expression on CD4+ T Cells

“…Enormous reductions have been observed in rates of death and suffering when use is made of a potent ARV regimen, particularly in the early stages of the disease. However, there is still no cure for HIV infection, given the promises utilizing HAART and/or stem cell transplantation [ 1 , 2 ]. T cells play a crucial role in HIV infection; a robust T-cell response is associated with control of HIV infection; however, HIV-specific T cells are deleted or dysfunctional in HIV/AIDS [ 3 , 4 , 5 ].…”