Thumbi Ndung'U

Broadly neutralizing antibodies (bNAbs) are a promising strategy to target the HIV-1 reservoir, the main barrier to cure. HIV-1 variants may differ in Env sequence and neutralization sensitivity across anatomical compartments. We investigated genetic differences and differences in neutralization sensitivity between Env variants persisting in peripheral blood mononuclear cell (PBMC) and lymph node (LN) reservoirs, and pre-therapy plasma variants. The study included 11 individuals on antiretroviral therapy in Durban, South Africa. Env sequences derived from pre-therapy plasma and from PBMCs and LN reservoirs were assessed for reservoir-specific genetic differences. Recombinant viruses encoding Env variants were generated for six participants and tested for neutralization sensitivity using a panel of nine clinically relevant bNAbs. We observed genetic divergence between compartments, with a median of 6 and 19 amino acid differences between pre-therapy plasma and LN and PBMC reservoirs, respectively. Of these, 63% (LN) and 73% (PBMC) were confirmed by next-generation sequencing to be unique to the reservoir, with few occurring at sites previously associated with altered bNAb sensitivity. Phenotypic analysis revealed no consistent compartment-specific patterns in neutralization sensitivity. CD4-binding site (CD4bs) and gp120–gp41 interface bNAbs showed broad coverage across compartments, while sensitivity to V2 and V3 antibodies was more variable. Although reservoir-derived Env variants show genetic divergence from pre-therapy viruses, this variation is largely not at sites reported to alter bNAb sensitivity and does not translate into consistent compartment-specific differences in bNAb sensitivity. The broad activity of CD4bs and interface-targeting bNAbs across compartments supports their suitability in antibody-based HIV cure strategies. IMPORTANCE: HIV persists in reservoirs during antiretroviral therapy, preventing a cure. Broadly neutralizing antibodies (bNAbs) are a promising strategy to target these reservoirs, but it is unclear whether viruses in different tissues respond differently to these antibodies. Here, we show that although HIV variants in blood and lymph node reservoirs differ genetically from viruses present before treatment; they do not show consistent changes in antibody sensitivity. Importantly, antibodies targeting the CD4-binding site and the gp120–gp41 interface remained broadly effective across all compartments. These findings suggest that key bNAbs can target HIV reservoirs throughout different body compartments, supporting their use in cure strategies and highlighting the value of combining antibodies to overcome viral diversity.

Long-term exposure to malaria may shape baseline immune function, yet its effects in healthy adults remain unclear. Here we show that healthy Kenyan adults living in regions with higher malaria transmission and broader infectious exposure have distinct baseline immune profiles. Using blood-cell gene expression and circulating immune mediators from 60 adults across regions with differing malaria endemicity, we identify 658 differentially expressed genes. Higher exposure is associated with increased expression of pathways related to B-cell activation, antigen presentation, immune regulation, and post-transcriptional RNA processing, alongside reduced inflammatory, chemotactic, and vascular gene programmes. Circulating immune mediators are modestly elevated despite reduced inflammatory gene expression, indicating a partial dissociation between systemic mediator levels and cellular transcription. Our findings show that long-term malaria exposure in pathogen-endemic environments is associated with a distinct immune state characterised by adaptive immune activation and restrained inflammatory transcription, which may influence responses to subsequent infections and vaccination.

Background: Virus-specific CD8+ T cells play an important part in human immunodeficiency virus (HIV) cure/remission in adults, yet their role in pediatric immune control is limited by tolerogenic early-life immunity. Very-early antiretroviral therapy (ART) initiation, while effective in restricting viral reservoir size, also prevents antigenic exposure and, thereby, the induction of HIV-specific CD8+ T-cell responses. Analytical treatment interruption (ATI) is an established tool in cure/remission studies for assessing time to viral rebound and viral set point off ART, yet the impact of ATI on HIV-specific immune responses and plasma viral load (pVL) remains understudied in pediatric populations. Methods: We evaluated a historical randomized cohort of early ART-treated children in South Africa. Infants with HIV were randomized to either Arm-1, receiving an initial course of ART followed by 3 short, pVL-guided treatment interruptions, or Arm-2, receiving continuous ART. Both arms then underwent an extended ATI in the second year of life. Virological outcomes, viral sequencing, and HIV-specific T-cell responses were assessed longitudinally. Results: During the extended ATI, Arm-1 participants, following multiple treatment interruptions, demonstrated a lower peak and set point pVL compared to Arm-2, alongside an early induction of HIV-specific CD8+ T-cell responses. One Arm-1 participant achieved undetectable pVL for 1.5 months during the extended ATI, before losing immune control associated with viral escape within dominant Gag CD8+ T-cell epitopes. Conclusions: Short-term viral exposure from serial ATIs is associated with the induction and/or boosting of HIV-specific CD8+ T-cell responses and enhanced immune control of HIV in early ART-treated children.

Whether asymptomatic TB contributes to M. tuberculosis (Mtb) transmission is critical to global public health strategy. To address this, we evaluated microbiologic, radiographic, molecular and spatial data from a population-based TB study in South Africa. We found that 82% of microbiologically-confirmed pulmonary TB occurred in asymptomatic individuals. Microbiologic and radiologic correlates of infectiousness, including measures of bacterial burden and lung cavitation, were similar between asymptomatic and symptomatic TB detected in the community. Drug-resistant variants, ranging from mono-to multi-drug resistance, were detected in people with asymptomatic TB. Analysis of Mtb strains showed that half of genotypic transmission clusters involved exclusively asymptomatic people. Our results demonstrate that most prevalent pulmonary TB is asymptomatic and that asymptomatic TB, including that involving drug-resistant Mtb, is transmissible. Overall, these findings suggest that symptoms do not reliably identify people with transmissible TB and that screening strategies to detect asymptomatic disease will be required to end TB.

Understanding the selective forces acting upon HIV early in infection is crucial to design prevention strategies. By leveraging deep sequencing and the short diagnostic intervals of the FRESH and RV217 cohorts between the last-negative and first-positive RNA tests (median 4 days), we captured a precise and early snapshot of acute HIV infection. The frequency of multiple transmitted viruses of 37% in these as well as placebo recipients from the AMP trials (NCT02716675 and NCT02568215) was higher than previously published, with the true frequency likely to be higher. The relative abundance of lineages fluctuated substantially over time in two-thirds of the multilineage infections, generating uncertainty in identifying the specific viruses that were transmitted and founding the infection. At the population level, viral populations exhibited limited diversity and selection on the Gag and Env proteins at the earliest times examined, with sites inferred to be undergoing negative selection most evident. These data may help explain vaccination failures and provide new targets for prevention.

Introduction: International goals aim to eliminate Hepatitis B Virus (HBV) as a public health threat by 2030, but data representing African populations remain limited. We therefore investigated the population prevalence of HBV and treatment eligibility in a rural South African setting. Methods: We tested archived plasma samples from 2200 participants in a population-based study in KwaZuku Natal for HBV surface antigen (HBsAg), HBV core antibody (anti-HBc), and HBV surface antibody (anti-HBs). For samples testing HBsAg-positive, we quantified alanine transferase (ALT) and HBV DNA viral load. We evaluated demographic and clinical correlates of HBV biomarkers, explored the geographical distribution of HBsAg, and assessed HBV treatment eligibility. Results: Weighted HBV infection prevalence was 10.4% (95% CI: 9.0%-12.1%). Evidence of HBV exposure and clearance was found in 34.9% (95% CI: 32.4 - 37.5). Overall prevalence of vaccine-mediated HBV immunity was 8.9% (95% CI: 7.5%-10.4%) but for the sub-group born between 2000-2005 (after the HBV vaccine was implemented) this increased to 20.2% (95% CI 15.8-25.4). Infection prevalence was highest in the South of the region. Over 60% of individuals testing HBsAg-positive met treatment eligibility criteria. Conclusion: Prevalence of HBV infection and exposure in this setting is high, while vaccine-mediated immunity is low. These data highlight a pressing need for scale-up of interventions to support progress towards global elimination targets. Funding: The Francis Crick Institute (ref. CC2223), the Africa Oxford Initiative (Research Development Award) and Wellcome Strategic Core Award (227167/A/23/z). Ethics: University of KZN (UKZN) ref. 00004495/2022; University College London ref. 23221/001.

The human immunodeficiency virus (HIV) remains a global health crisis [1], disproportionately affecting regions in eastern and southern Africa, which bear the highest burden of the epidemic [2]. Su...