Beyond Viral Suppression: Next-Generation HIV Therapeutics Target Reservoirs, Broadly Neutralizing Antibodies, and Gene Editing

For decades, oral regimens of antiretroviral therapy (ART) have served as the bedrock of HIV prevention and treatment, transforming a once-fatal diagnosis into a chronic, manageable condition. The recent emergence of long-acting injectables represents a pivotal advancement in therapeutic delivery. Compared with daily oral ART regimens, generally offered in 90-day prescriptions, long-acting injectables reduce the number of required clinic visits for patients and eliminate the need for an at-home adherence regimen.¹ These advantages are particularly meaningful for populations in which daily pill taking is especially burdensome or logistically complex.

However, while long-acting injectables have the potential to revolutionize the logistics of HIV management, they have not overcome ART’s inherent mechanistic limitations. Like oral regimens, injectables merely suppress viral replication without eliminating latent reservoirs. Consequently, they do not offer a permanent cure or protective immunity. Because the antiviral mechanism remains contingent upon maintaining therapeutic drug levels at all times, both prevention and treatment still necessitate strict lifelong access and adherence to care. For high-risk populations in low-resource settings, this creates a persistent vulnerability: Any interruption in the clinical supply chain can trigger surges in new infections and the emergence of drug-resistant strains.²

Regardless of the delivery method, viral suppression alone cannot fully restore immune function, especially if ART is initiated later in disease progression. A complex interplay of chronic inflammation, suppressed immune function, therapy-related toxicities, and social determinants of health elevates the risk of comorbidities, including cancer, cardiometabolic disease, and neurocognitive disorder, in people who age with HIV.^3,4

From Viral Suppression to Immune-Mediated Protection

To move beyond indefinite disease management, therapeutic developers must look to alternative therapeutic mechanisms that help the immune system eliminate and recover from HIV infection.

A universally effective prophylactic vaccine has long been the focus of these efforts, because such a vaccine could offer broad, population-wide protection from HIV.⁵ However, attempts to develop such a vaccine have been thwarted by HIV’s exceptional immune-evasion tactics. Unlike other viruses for which vaccines exist, there are no cases of natural sterilizing immunity to HIV, in which the immune system eradicates an HIV infection. Instead, a successful HIV vaccine must engineer the immune system to do what it normally cannot achieve on its own.⁵

While a vaccine remains elusive, decades of investment in vaccine development have helped researchers better understand what an effective immune response could look like and how therapeutic strategies could help achieve it.

Supporting the Production of Broadly Effective Antibodies

One promising mechanism for the prevention and treatment of HIV is assisting the production of antibodies that are broadly effective against genetically diverse strains of HIV. Antibodies against HIV can target only one protein, which encapsulates the virus. But the exposed regions of this protein mutate very rapidly. Consequently, the virus can change to escape most antibodies produced by the immune system. ⁶

Meanwhile, conserved regions of this protein generally evade immune detection because they are cloaked in a thick layer of host-derived sugars, known as the glycan shield. Natural safeguards against autoimmunity frequently eliminate the B-cell lineages that could eventually mature to produce broadly neutralizing antibodies (bnAbs).⁶ Occasionally, functional bnAbs do develop in people with HIV, but only after years of chronic infection. These edge cases offer a potential path to prevention or even cure, if therapeutic developers can determine how to reliably guide the adaptive immune system to rapidly mature these rare lineages of bnAb-producing B cells.⁷

One such approach, which has demonstrated early proof of concept, involves stepwise vaccination. First, mRNA delivery platforms deliver "germline-targeting" immunogens, which activate specific, rare precursor B cells. After the first shot initiates the desired immune response, a booster guides the immune system toward bnAb production.⁸ Alternative methods of introducing bnAbs include direct infusion of long-acting bnAb therapy and gene-editing approaches to induce bnAb production.⁷

Eliminating Viral Reservoirs

Following infection, HIV establishes latent reservoirs of infected cells that are immunologically invisible. This raises the bar even higher for a prophylactic vaccine that prevents HIV acquisition, because such a vaccine must completely prevent HIV from infecting cells. However, therapeutic vaccines, in combination with therapies that “flush out” these reservoirs, offer a possible pathway towards treatment-free remission or cure.^9,10

Latency-reversing agents (LRAs) currently in development are designed to “shock” latent viruses into transcriptional activity, making infected cells susceptible to immune system targeting. One class of LRAs is chromatin remodelers. Chromatin structure helps suppress HIV gene expression in latently infected cells, and therapeutically altering chromatin-remodelling complexes can promote reactivation.¹⁰Following the initial shock, HIV can then be treated with traditional ART and emerging immune-mediated mechanisms, including therapeutic vaccines and direct infusion of bnAbs.Multiple clinical trials incorporating different combinations of vaccines, ART, LRAs, and bNAbs are in the pipeline, but as of this writing, the trials remain ongoing.

Advances in Pediatric HIV Prevention

Newborns at risk of acquiring HIV at childbirth or during breastfeeding may be especially good candidates for ART alternatives that offer sustained immune protection or remission, because the at-risk population is well defined and the value of avoiding life-long ART dependence is clear. Additionally, unique qualities of the pediatric immune system may make children better able to mount a durable HIV response.¹¹

Research in non-human primates suggests that inducing bnAb production may be most feasible in newborns, whose immune systems have unique qualities that may make them more tolerant of these B-cell lineages.¹² Additionally, in rare cases, ART, in combination with the pediatric immune system, is able to achieve long-term remission.¹¹

Therefore, many of the ongoing trials focused on inducing immunity against HIV are focused on children. One ongoing AbVax trial with an estimated study completion in 2028 is investigating three different ARMs of combination treatment, including vaccines and bNAB infusion interspersed with treatment interruption.¹³

Genetically Engineering Infection Resistance

An alternative to immune-mediated therapy is to achieve cellular resistance to infection. Documented cures using this method have involved stem cell transplants carrying a homozygous CCR5Δ32 genetic mutation. The genetic deletion renders cells resistant to some strains of HIV. When combined with immune reconstitution, a cell transplant carrying this mutation can result in the clearance of infected cells and the establishment of an HIV-resistant immune system. But the approach is limited to individuals with concurrent blood cancers and carries significant procedural risks.¹⁴

More scalable alternatives in the future would likely involve gene editing. CRISPR/Cas9 and other platforms are being explored to disrupt HIV co-receptors, such as CCR5 and CXCR4, or to excise integrated proviral DNA directly from host genomes.⁹ These interventions may be delivered ex vivo to autologous CD4+ T cells or hematopoietic stem cells, which are then reinfused into the patient. Multiplex editing strategies that target multiple viral and host loci simultaneously are under investigation to reduce the risk of viral escape.¹⁴ Despite promising preclinical data, significant challenges remain in achieving efficient delivery, minimizing off-target effects, and ensuring long-term engraftment and immune function.

Will Next-Generation Therapies Have a Real-World Impact?

In whatever form it takes, an HIV-1 vaccine will likely be the most complex vaccine ever designed, involving advanced modalities and multi-step vaccination. It may also require a combination with other therapies. This may limit the feasibility of population-wide vaccination for HIV control. Instead, a vaccine is more likely to provide an alternative to ART-based prevention and treatment for specific high-risk populations in need of other options.¹⁵

But what would be the point of an HIV vaccine that doesn’t deliver population-wide protection from HIV? This question highlights a central tension between developing biologically advanced therapies that address ART’s mechanistic limitations and investing in approaches that are feasible relative to existing standards of care.

First-generation therapies that achieve protective immunity or a cure may be ingenious but inaccessible, requiring further adaptation to become cost-effective, scalable, and deployable in low-resource settings. The recent success of long-acting injectables for prophylaxis and for treatment further raises the bar for therapeutic developers, who should carefully identify populations most underserved by ART-based interventions and determine whether a novel therapeutic approach could better attain improved outcomes for these populations.¹⁵

Even as therapeutic developers reckon with the real-world value of ART alternatives, it’s important to recognize what has been achieved by research that was initially unclear in value. More than 40 years ago, HIV was a near-certain death sentence. Now, it is a manageable and preventable chronic condition. Incremental but profound victories paved the way to this success. Some of these victories failed to produce an HIV vaccine but provided insight into the human immune system that advanced other fields of medicine. Today, therapeutic developers have made progress towards a future where HIV is curable, but the finish line remains an incalculable distance away. Continuing to make meaningful advances in HIV therapeutic development will require ongoing interrogation of novel alternatives to ART-based therapies that push the boundaries of what is possible.

References

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