HIV: Current Research
Open Access

Targeting HIV Reservoirs through Innovative Cure Strategies

Sipho Ndlovu^{* *}Correspondence: Sipho Ndlovu, Department of Virology and Immunotherapy, University of Johannesburg, South Africa, Email:

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Description

HIV remains one of the most formidable infectious diseases of our time, primarily due to the virus's ability to establish latent reservoirs in the body. These reservoirs, composed mainly of resting memory CD4⁺ T-cells, harbor transcriptionally silent yet replication-competent proviruses that evade detection and elimination by both the immune system and antiretroviral therapy (ART). Despite significant progress in suppressing viremia through lifelong ART, the existence of these hidden viral sanctuaries poses a major obstacle to achieving a complete cure. As a result, scientific efforts have increasingly shifted from managing HIV to eradicating it by targeting these latent reservoirs through a range of innovative strategies.

One of the most widely explored approaches is the “shock and kill” strategy, which involves reactivating latent HIV using latency-reversing agents (LRAs), thereby rendering infected cells visible to the immune system or cytotoxic therapies. Histone deacetylase inhibitors (HDACis), bromodomain inhibitors, and protein kinase C (PKC) agonists have shown promise in vitro and in early-phase clinical trials, though their in vivo efficacy and safety profiles remain areas of active research. While these compounds can induce viral transcription, effective clearance of reactivated cells has proven challenging, likely due to immune exhaustion and insufficient cytolytic response. To address this, researchers are combining LRAs with immune-enhancing strategies such as therapeutic vaccines or broadly neutralizing antibodies (bNAbs) to improve viral clearance.

Another cutting-edge method involves gene editing tools like CRISPR-Cas9, which have demonstrated the ability to excise or disrupt HIV proviral DNA from host genomes. This technique, while still in its infancy, has generated tremendous excitement in preclinical models. Researchers are exploring the feasibility of delivering CRISPR constructs via viral vectors or nanoparticles to reach reservoir sites such as lymphoid tissues and the central nervous system. However, concerns over off-target effects, immune reactions, and efficient delivery mechanisms must be addressed before clinical applications can be realized.

An alternative approach, “block and lock,” seeks to push HIV into a deeper state of latency, making the provirus permanently silent and unable to reactivate. Agents like Tat inhibitors, which interfere with viral transcriptional machinery, are being studied as a means of achieving durable suppression without the need for continuous ART. This strategy holds promise, particularly in combination with other agents that promote epigenetic silencing of the HIV genome. Though not a sterilizing cure, “block and lock” could allow individuals to live drug-free without risk of viral rebound.

Recent advancements in immunotherapeutics are also showing promise. Chimeric Antigen Receptor (CAR) T-cell therapy, originally developed for cancer, has been adapted to target HIV-infected cells. Early studies have demonstrated that engineered T-cells can recognize and destroy HIV-infected cells, including those in latent reservoirs. Additionally, bispecific antibodies capable of binding both HIV-infected cells and immune effectors are being investigated to enhance the precision of immune clearance. The use of these biologics represents a significant leap in personalized and targeted HIV treatment.

South Africa, as one of the countries with the highest HIV burden, has become a key hub for reservoir-targeted research, often participating in multinational trials and leading in community-based strategies. Researchers and clinicians alike are increasingly aware of the need to integrate biomedical advances with sociocultural considerations, ensuring that cure research is both ethical and accessible. The country’s participation in trials like CAPRISA and the HIV Vaccine Trials Network (HVTN) underscores the growing emphasis on cure-oriented solutions tailored for high-prevalence regions.

Despite these promising developments, a functional or sterilizing cure for HIV remains elusive. Each strategy has its strengths and limitations, and no single approach is likely to suffice on its own. Most experts now advocate for a combination approach—much like ART itself—that integrates latency reversal, immune enhancement, gene editing, and epigenetic silencing. The heterogeneity of the reservoir, patient variability, and anatomical challenges such as the blood-brain barrier all necessitate multipronged and patient-specific interventions. Continued investment in basic science, translational research, and clinical trials is crucial to refine these techniques and bring them to broader populations.

In conclusion, targeting HIV reservoirs through innovative cure strategies represents the next frontier in the global fight against HIV/AIDS. While the road to a cure is fraught with scientific and logistical hurdles, the convergence of molecular biology, immunotherapy, and gene editing is ushering in a new era of hope. For regions like South Africa, which shoulder a disproportionate burden of the epidemic, the successful translation of these innovations into clinical practice could dramatically alter the course of public health. The dream of an HIV cure may no longer be a distant vision but a tangible goal on the horizon.