Long-Acting Injectables, Gene Editing, and bNAbs: The Non-Vaccine Arsenal Closing the Gap in HIV Prevention
核心洞察
A recent review in *Viruses* synthesizes the evolving landscape of non-vaccine biomedical HIV (搜索) interventions, highlighting long-acting injectables, gene-editing technologies, and broadly neutralizing antibodies (bNAbs).
Phase III trials of lenacapavir, a six-monthly capsid inhibitor, reported prevention efficacy of 100% (PURPOSE 1) and 96% (PURPOSE 2), while long-acting cabotegravir reduced HIV (搜索) acquisition by 66% to 89% versus daily oral PrEP.
Gene-editing approaches such as CRISPR-Cas9 targeting CCR5 (搜索) and Brec1-mediated proviral excision show preclinical promise but face challenges including off-target effects, delivery, and ethical concerns.
Despite more than four decades of intensive research, HIV (搜索) remains one of the most persistent global health crises, with approximately 39.9 million people living with the virus and 1.3 million new infections reported in 2023. While the search for an effective prophylactic vaccine continues, a recent review published in the journal Viruses argues that a growing arsenal of non-vaccine biomedical interventions—ranging from six-monthly injectables to gene-editing technologies and engineered antibodies—could substantially reduce transmission and help achieve the global 2030 target of ending the AIDS (搜索) epidemic.
The review, titled "Biomedical Interventions for HIV (搜索) Prevention and Control: Beyond Vaccination," synthesizes evidence from clinical trials, epidemiological models, and mechanistic studies, organizing interventions across pre-exposure, post-exposure, and post-infection stages.
Long-acting PrEP reshapes the prevention landscape
The authors highlight that newer long-acting formulations represent an important advance in HIV (搜索) prophylaxis, directly addressing the adherence challenges that have limited the real-world effectiveness of daily oral pre-exposure prophylaxis (PrEP). Lenacapavir, a long-acting HIV-1 capsid inhibitor administered via subcutaneous injection every six months, delivered striking results in Phase III clinical trials: the PURPOSE 1 and PURPOSE 2 studies reported prevention efficacy estimates of 100% and 96%, respectively, in the studied populations.
Similarly, long-acting injectable cabotegravir was associated with a 66% to 89% reduction in HIV (搜索) acquisition compared with daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). These findings support the potential of long-acting treatments to overcome barriers related to daily pill fatigue and inconsistent adherence.
Established interventions retain critical roles
Beyond pharmaceutical prophylaxis, the review reaffirms the central importance of antiretroviral therapy (ART)-mediated viral suppression under the Undetectable = Untransmittable (U=U) principle, which effectively eliminates the risk of sexual transmission when viral loads remain continuously suppressed. Comprehensive vertical transmission prevention strategies can reduce mother-to-child transmission rates to below 1%.
Voluntary medical male circumcision (VMMC) was also found to decrease heterosexual acquisition risk in men by approximately 60%, attributed to the removal of foreskin tissue enriched with CD4+ T-cell targets. However, the authors caution that VMMC does not eliminate acquisition risk, prevent transmission from men living with HIV (搜索) to their partners, or replace other prevention measures.
Emerging technologies: gene editing and bNAbs
The review evaluates two categories of investigational approaches that may broaden future prevention and treatment options. Gene-editing strategies, including CRISPR-Cas9-mediated editing of the CCR5 (搜索) co-receptor and Brec1 recombinase-mediated excision of integrated proviral DNA, have shown promise in laboratory and animal studies, with limited early clinical evidence available for some approaches.
Bispecific and trispecific broadly neutralizing antibodies (bNAbs) have demonstrated improved antiviral breadth primarily in preclinical models, while passively infused bNAbs have shown acceptable safety and tolerability in humans.
However, both approaches remain experimental. Gene editing faces significant hurdles including limited editing efficiency, delivery challenges, off-target effects, ethical concerns, and potential tumorigenesis. bNAbs are constrained by high production and storage costs, strain-specific activity, and the potential need for repeated administration.
Biological barriers and the vaccine horizon
The review underscores several core biological barriers that have complicated HIV (搜索) intervention development: high genetic variability across HIV strains, dense N-linked glycan shielding of the envelope glycoprotein gp120 (搜索) that enables "conformational masking," and the persistence of latent viral reservoirs that ART alone cannot eliminate.
The authors conclude that while a prophylactic HIV (搜索) vaccine remains the ultimate goal, it is unlikely to become clinically available soon due to continuing technical hurdles. In the interim, established non-vaccine biomedical interventions provide highly effective tools for reducing transmission, while investigational approaches may broaden the prevention and treatment toolkit and contribute meaningfully to the global 2030 goal of ending the AIDS (搜索) epidemic.