Susan Moir

A subset of people living with HIV (PLWH) can produce broadly neutralizing antibodies (bNAbs) against HIV, but the lymph node (LN) dynamics that promote the generation of these Abs are poorly understood. Here, we explored LN-associated histological, immunological, and virological determinants of bNAb generation in a cohort of antiretroviral therapy–naive PLWH. We found that participants who produce bNAbs, termed “neutralizers” (Ns), have a better-preserved LN-associated B cell follicle architecture than do PLWH who do not. The former was associated with a substantially higher in situ prevalence of B-cell lymphoma 6 (Bcl-6 ^hi ) follicular helper CD4 ⁺ T cells (Tfh), expressing a molecular program that favors their differentiation and stemness, and substantially reduced IL-10 follicular suppressor CD4 ⁺ T cells. Furthermore, our data reveal possible molecular targets mediating Tfh–B cell interactions in Ns. Together, we identify germinal center cellular and molecular signatures that could contribute to the development of bNAbs in PLWH.

Mucosal immunity is an important correlate of protection against respiratory infections such as SARS-CoV-2. Comparing B cell responses to vaccines and infection at relevant mucosal sites may provide unique and important insights into tissue immunity. Here, we characterize antigen-specific B cells in the tonsils, adenoids, and peripheral blood of children who had been infected with SARS-CoV-2 or vaccinated with SARS-CoV-2 mRNA vaccines. SARS-CoV-2-specific switched memory B cells (B _SM ) are found in the pharyngeal lymphoid tissues and blood after vaccination or infection. However, infection generates a higher proportion of IgA ⁺ B _SM and CXCR3 ⁺ CD21 ⁺ B _SM . CXCR3 ⁺ CD21 ⁺ B _SM show distinct spatial localization, greater clonal expansion and increased propensity for plasma cell differentiation compared to their CXCR3 ^- counterparts, accompanied by persistent activation of innate and T follicular helper cells in the tissues. Our data provide evidence for tissue-specific B cell memory after either SARS-CoV-2 vaccination or infection, but with distinct characteristics that can influence the quality, durability, and localization of immunity.

Short-term boosting of the currently licensed rVSV∆G-ZEBOV-GP vaccine does not generate lasting antibody respones to Ebola virus (EBOV), prompting interest in strategies that elicit more durable immunity. Here, we elucidated the longitudinal humoral immune repertoire over 3 years following prime and boost rVSV∆G-ZEBOV-GP vaccinations administered 18 months apart in healthy adults compared to participants randomized to no boost. This delayed booster vaccination induced long-lasting EBOV-neutralizing antibodies that persisted up to 36 month at levels similar to peak titers after a single dose. Phage display libraries, expressing linear and conformational epitopes of EBOV glycoprotein (GP), demonstrated a highly diverse and durable antibody epitope repertoire following prime boost vaccination. Delayed booster vaccination recalled memory B cells, promoted anti-GP IgG class switching and induced antibodies specific to GP with Fcγ receptor interaction and functional antibody-dependent cellular cytotoxicity and phagocytosis. The 18-month interval led to 13-fold higher antibody affinity maturation than a single dose, maintained up to 36 months. Overall, delayed rVSV∆G-ZEBOV-GP booster vaccination promoted a diverse, stronger, durable, predominant IgG, highly affinity-matured antibody response to GP.

Some people with HIV control the virus without medication. This study identified a rare group lacking detectable HIV reservoirs, offering important clues for developing future cures.

The strength of the repressive histone H3K27me3 signal varies across silencers. Focusing on regions with unusually strong signals—super-silencers—we show that B-cell super-silencers are initially linked to gene upregulation in development, with target genes highly expressed in stem cells. About 13% of B-cell super-silencers convert to super-enhancers in B-cell lymphoma; 22% of these recur in over half of patients. Genes like BCL6 and BACH2 tied to these conversions are downregulated faster by JQ1, a super-enhancer-disrupting anti-cancer agent. Super-silencers are enriched for B-cell cancer-associated variants—both somatic and germline—and translocation breakpoints, exceeding levels in other regulatory elements like CTCF binding sites. Over 80% of B-cell lymphoma t(3;14)(q27;q32) translocations fuse BCL6 super-silencers with enhancer-rich regions. Super-silencer repression depends on CpG content: CpG-rich elements block promoter–enhancer contacts; CpG-poor — inhibit looping. These findings highlight super-silencers’ key role in B-cell regulation and suggest their alteration may be a primary factor of B-cell carcinogenesis.

Mucosal immunity is an important correlate of protection against respiratory infections such as SARS-CoV-2. Comparing B cell responses in the upper respiratory tract following vaccination and infection may offer unique insights into mucosal immunity. Here, we characterized antigen-specific B cells in the tonsils, adenoids, and peripheral blood of children who had been infected with SARS-CoV-2 or vaccinated with SARS-CoV-2 mRNA vaccines. SARS-CoV-2-specific switched memory B cells (B_SM) and germinal center B cells were found in the blood and pharyngeal lymphoid tissues after vaccination or infection. However, infection generated a higher proportion of IgA⁺ B_SM and CXCR3⁺CD21⁺ B_SM, which showed distinct spatial localization, greater clonal expansion and increased propensity for plasma cell differentiation compared to their CXCR3⁻ counterparts, accompanied by persistent activation of innate and T follicular helper cells in the tissues. Our data provide evidence for tissue-specific B cell memory after either SARS-CoV-2 vaccination or infection, but with distinct characteristics that can influence the quality, durability, and localization of immunity.

The clinical management of people with multidrug-resistant (MDR) human immunodeficiency virus (HIV) remains challenging despite continued development of antiretroviral agents. A 58-year-old male individual with MDR HIV and Kaposi sarcoma (KS) was treated with a new antiretroviral regimen consisting of anti-CD4 domain 1 antibody UB-421 and capsid inhibitor lenacapavir. The individual experienced delayed but sustained suppression of plasma viremia and a substantial increase in the CD4⁺ T cell count. A longitudinal examination of plasma HIV and infectious isolates showed no evidence of viral evolution or the emergence of UB-421- or lenacapavir-resistant viruses. The individual received three cycles of liposomal doxorubicin and five doses of anti-programmed cell death protein 1 (PD-1) monoclonal antibody pembrolizumab that resulted in improvement in KS with flattening of lesions. Our data demonstrate that combination therapy with UB-421 could provide sustained virologic suppression in people harboring MDR HIV with limited therapeutic alternatives.

Immunological health has been challenging to characterize but could be defined as the absence of immune pathology. While shared features of some immune diseases and the concept of immunologic resilience based on age-independent adaptation to antigenic stimulation have been developed, general metrics of immune health and its utility for assessing clinically healthy individuals remain ill defined. Here we integrated transcriptomics, serum protein, peripheral immune cell frequency and clinical data from 228 patients with 22 monogenic conditions impacting key immunological pathways together with 42 age- and sex-matched healthy controls. Despite the high penetrance of monogenic lesions, differences between individuals in diverse immune parameters tended to dominate over those attributable to disease conditions or medication use. Unsupervised or supervised machine learning independently identified a score that distinguished healthy participants from patients with monogenic diseases, thus suggesting a quantitative immune health metric (IHM). In ten independent datasets, the IHM discriminated healthy from polygenic autoimmune and inflammatory disease states, marked aging in clinically healthy individuals, tracked disease activities and treatment responses in both immunological and nonimmunological diseases, and predicted age-dependent antibody responses to immunizations with different vaccines. This discriminatory power goes beyond that of the classical inflammatory biomarkers C-reactive protein and interleukin-6. Thus, deviations from health in diverse conditions, including aging, have shared systemic immune consequences, and we provide a web platform for calculating the IHM for other datasets, which could empower precision medicine.