Targeting and Reversing HIV Latency Using Novel 'Block and Lock' Strategies: A Comprehensive Review

Arnab Roy; Sandeep Prasad Verma; Nikita Kumari; Bikash Vishwakarma; Kristy Kumari; Sajid Ansari; Astha Topno; Shweta Kumari; Manshi Kumari; Purnima Kumari; Ajay Kumar; Shruti Kumari; Ananya Mishra; Priyanka Singh; Dibya Sahoo; Abhijit Kumar; Manu Sharma; Komal Singh; Sneha Singh; Smita Bharti; Sneha Sinha; Jasmine Kumari; Abhinav Kumar; Priyanshu Kumar Singh; Faiz Alam

doi:10.5281/zenodo.17789094

Review Paper | Open Access
Volume 02 | Issue 12 | Article Id IJSRT/250311176

Targeting and Reversing HIV Latency Using Novel 'Block and Lock' Strategies: A Comprehensive Review
Arnab Roy* Sandeep Prasad Verma Nikita Kumari Bikash Vishwakarma Kristy Kumari Sajid Ansari Astha Topno Shweta Kumari Manshi Kumari Purnima Kumari Ajay Kumar Shruti Kumari Ananya Mishra Priyanka Singh Dibya Sahoo Abhijit Kumar Manu Sharma Komal Singh Sneha Singh Smita Bharti Sneha Sinha Jasmine Kumari Abhinav Kumar Priyanshu Kumar Singh Faiz Alam
Sai Nath University, Ranchi, Jharkhand-835219, India

Abstract

The establishment of latent HIV reservoirs remains the principal barrier to achieving a cure for HIV infection. While antiretroviral therapy (ART) effectively suppresses viral replication, it cannot eliminate integrated proviral DNA that persists in a transcriptionally silent state within long-lived memory CD4+ T cells. The "Block and Lock" strategy has emerged as a promising alternative to the traditional "Shock and Kill" approach, aiming to permanently silence HIV transcription rather than reactivating latent virus. This review examines the molecular mechanisms underlying HIV latency, critically evaluates current Block and Lock strategies including didehydro-Cortistatin A (dCA) and Tat inhibitors, and discusses the translational challenges and future directions for achieving a functional HIV cure. Recent advances in our understanding of epigenetic regulation, the role of the viral transactivator Tat, and the heterogeneity of latent reservoirs provide new opportunities for therapeutic intervention.

Keywords

HIV latency, Block and Lock, latency-reversing agents, shock and kill, dCA, Tat inhibitors, HIV reservoir, functional cure, HIV transcription, epigenetic silencing

Introduction

Human Immunodeficiency Virus (HIV) infection continues to pose a significant global health challenge, affecting approximately 39 million people worldwide as of 2023 ([1]). While combination antiretroviral therapy (ART) has transformed HIV from a fatal disease into a manageable chronic condition, it requires lifelong adherence and does not constitute a cure ([2]). The primary obstacle to HIV eradication is the establishment of latent viral reservoirs, predominantly within resting memory CD4+ T cells, where integrated proviral DNA persists in a transcriptionally silent state ([3]). The latent reservoir is established early during acute infection, even before ART initiation, and exhibits remarkable stability with an estimated half-life of 44 months or longer ([4]). Upon treatment interruption, latent proviruses can reactivate, leading to viral rebound within weeks. This necessitates continuous ART administration, which is associated with long-term toxicities, drug resistance, cost burden, and challenges in resource-limited settings ([5]). Two major strategies have emerged to address the latent reservoir: "Shock and Kill" and "Block and Lock." The Shock and Kill approach aims to reactivate latent virus using latency-reversing agents (LRAs) while maintaining ART, with the expectation that reactivated infected cells will be eliminated by cytotoxic immune responses or viral cytopathic effects ([6]). However, clinical trials have demonstrated that current LRAs fail to significantly reduce the reservoir size, raising concerns about incomplete reactivation, immune escape, and potential systemic inflammation ([7]). In contrast, the Block and Lock strategy seeks to permanently silence HIV transcription by promoting deep latency through epigenetic modifications and inhibition of viral transactivation ([8]). This approach offers several theoretical advantages: it avoids the risks associated with viral reactivation, does not require immune-mediated clearance, and may allow for ART discontinuation if silencing is sufficiently robust and durable ([9]). This review provides a comprehensive analysis of the molecular basis of HIV latency, examines emerging Block and Lock therapeutic candidates, and discusses the challenges and opportunities in translating these strategies to clinical application.

2. Molecular Mechanisms of HIV Latency

2.1 Establishment of Latency

HIV latency is established through multiple interconnected mechanisms operating at transcriptional, post-transcriptional, and epigenetic levels ([10]). Following integration of viral DNA into the host genome, the fate of infected cells depends on their activation state, the integration site, and the local chromatin environment. Latency occurs predominantly when HIV integrates into transcriptionally inactive regions of the genome or when activated CD4+ T cells transition to a resting memory phenotype before completing the viral replication cycle ([11]).