A groundbreaking study from the University of the Witwatersrand (Wits) in Johannesburg has revealed a crucial link between early immune responses in people living with HIV and the rare development of protective broadly neutralizing antibodies, often abbreviated as bnAbs. These powerful antibodies can target and neutralize a wide range of HIV strains, offering hope for future vaccines and treatments. Led by prominent South African researcher Professor Penny L. Moore, the research highlights how specific patterns of immune activation during the initial stages of infection may predict who will go on to produce these elite antibodies.
The findings, published in PLOS Pathogens on April 9, 2026, stem from an international collaboration that analyzed blood samples from South African women in the CAPRISA cohort, a long-standing study tracking HIV infection since 2003. This work not only advances global HIV research but also underscores Wits University's pivotal role in addressing South Africa's HIV epidemic, where approximately 8 million people are living with the virus, representing about 12.8% of the adult population aged 15-49.
The Persistent Challenge of HIV in South Africa
South Africa bears the heaviest burden of HIV globally, with new infections continuing despite widespread access to antiretroviral therapy (ART). The country's high prevalence, particularly in KwaZulu-Natal where the CAPRISA cohort is based, makes it an epicenter for HIV research. Universities like Wits and the University of KwaZulu-Natal (UKZN) have been at the forefront, contributing to landmark trials such as the CAPRISA 004 tenofovir gel study and ongoing bnAb investigations.
Despite ART suppressing the virus in millions, a curative vaccine remains elusive. Traditional vaccines struggle against HIV's genetic diversity and ability to evade the immune system. bnAbs represent a beacon of hope, as they can block diverse HIV variants, but only 10-30% of untreated individuals naturally develop them after years of infection. Understanding their origins is critical for vaccine design.
What Are Broadly Neutralizing Antibodies?
Broadly neutralizing antibodies (bnAbs) are specialized immune proteins produced by B cells that bind to conserved regions on HIV's envelope glycoprotein, preventing the virus from entering host cells. Unlike strain-specific antibodies that appear early in infection, bnAbs require extensive maturation, often taking 2-3 years, involving high levels of somatic hypermutation.
In rare 'elite neutralizers,' bnAbs achieve potency against 50-90% of circulating HIV strains. South African researchers, including those at Wits, have extensively characterized these from local subtype C viruses, predominant in the region. Professor Moore's team has tracked bnAb evolution in CAPRISA participants for over two decades, providing invaluable longitudinal data.
Methodology of the Wits-Led Study
The study employed cutting-edge cell-free nucleic acid sequencing on plasma samples. Cell-free RNA (cfRNA) and DNA (cfDNA) from blood capture host transcripts, viral sequences, and microbiome signals non-invasively. Researchers analyzed 42 samples from 14 women: seven who developed bnAbs and seven matched controls without, collected shortly after infection.
Samples came from the CAPRISA acute infection cohort in Durban, where participants are monitored intensively from seroconversion. Advanced bioinformatics reconstructed HIV quasispecies, profiled immune gene expression, and assessed microbial correlates. This multi-omics approach revealed subtle early differences invisible to standard assays.
The full paper is available here.
Key Findings: Early Immune Activation Signature
Central to the discovery was a transcriptomic signature in bnAb developers: elevated expression of major histocompatibility complex (MHC) class I antigen presentation genes within weeks of infection. MHC class I molecules display viral peptides on infected cell surfaces, alerting cytotoxic T cells. This heightened vigilance persisted independently of viral load or CD4 T cell counts, fading as infection progressed.
- Increased interferon-stimulated genes, signaling innate immune detection.
- Upregulation of genes for natural killer cell activity and apoptosis in infected cells.
- The signature's timing aligns with B cell priming for bnAb lineages.
This suggests early viral control via CD8+ T cells fosters an environment for bnAb maturation.
Photo by Markus Winkler on Unsplash
Microbial and Co-Infection Influences
Intriguingly, bnAb producers showed enriched microbial taxa in plasma, including higher GB virus C (GBV-C), a non-pathogenic flavivirus common in HIV cohorts. GBV-C is associated with slower HIV progression, possibly by modulating immunity or competing for receptors.
Other bacteria and viruses differed, hinting at microbiome-immune crosstalk. In high-prevalence settings like South Africa, co-infections (e.g., TB, STIs) may shape HIV responses. These findings open avenues for microbiome-targeted interventions to boost bnAb induction.
Professor Penny Moore and Wits' Legacy in HIV Research
Professor Penny L. Moore, holder of the DST/NRF South African Research Chair in Virus-Host Dynamics at Wits, co-authored the study. Affiliated with Wits' Antibody Immunity Research Unit and CAPRISA, her 20+ years of work on bnAbs from subtype C infections has informed global vaccine strategies. "This international collaboration identified previously undescribed triggers of these rare broadly neutralizing antibodies. As these antibodies are essential for an HIV vaccine, understanding how they develop provides us with important clues for making future HIV vaccines," Moore stated.
South Africa's Central Role in Global HIV Vaccine Efforts
South Africa hosts numerous bnAb trials, including HPTN 108 (PAUSE) at Wits RHI evaluating bnAbs for prevention. The BRILLIANT consortium launched Africa's first HIV vaccine trial in 2026. With 7.5 million on ART, SA's infrastructure supports ambitious studies. Wits and UKZN contribute critical data from high-incidence cohorts.
Challenges persist: stigma, adherence, and inequality hinder progress. Yet, local expertise positions SA universities as leaders.
Implications for HIV Vaccine Development
This pilot identifies biomarkers for bnAb inducers, guiding vaccine design. Vaccines mimicking early MHC I activation could prime B cells. Microbiome modulation (e.g., GBV-C mimics) warrants exploration. Larger cohorts will validate findings, potentially accelerating trials like those targeting V2-apex or CD4-binding site epitopes.
Joan Camunas-Soler from Gothenburg noted: "By studying the immune responses that occur in people who naturally develop broadly protective antibodies against HIV, we can better understand the biological processes that vaccine researchers aim to reproduce."
Read the full Wits press release.Future Directions and Larger Studies
As a pilot with 14 participants, replication in expanded cohorts like CAPRISA or IAVI Protocol C is essential. Integrating cfRNA with single-cell sequencing could pinpoint B cell clones. Therapeutic bnAbs (e.g., VRC01, 3BNC117) are in trials; vaccine-induced versions remain the holy grail.
Wits plans to apply these insights to pediatric bnAb studies, vital in SA where mother-to-child transmission persists.
Photo by Robiul Islam on Unsplash
Stakeholder Perspectives and Broader Impact
- Government/Policy: SA's National Strategic Plan emphasizes vaccines; findings support funding for bnAb research.
- Communities: High-burden areas like KZN benefit from local trials fostering trust.
- Global Partners: Collaborations with Stanford, Gothenburg amplify SA capacity-building.
This research exemplifies how South African universities drive solutions to local crises with global relevance.
In summary, Wits' discovery illuminates the path to an HIV vaccine by decoding bnAb origins. With SA's research ecosystem, optimism grows for ending AIDS as a public health threat. Ongoing work at institutions like Wits promises actionable insights, blending cutting-edge tech with community-rooted cohorts.
