Ole Schmeltz Søgaard

RIO is an ongoing phase 2 double-blind randomized placebo-controlled human trial. Sixty-eight adult men living with human immunodeficiency virus (HIV), who were predominantly white and initiated antiretroviral therapy (ART) during primary or early-stage infection, underwent treatment interruption and were randomly assigned to a group receiving one or two doses of two long-acting broadly neutralizing antibodies (bNAbs) 3BNC117-LS and 10-1074-LS (arm A, n = 34) or saline (arm B, n = 34). The primary clinical study met its primary endpoint and was published elsewhere, demonstrating significantly delayed viral rebound and prolonged ART-free control in participants receiving bNAbs compared with placebo. The infusions were generally safe and well tolerated, with no study-related serious adverse events reported. The most common reported treatment-related adverse events were fatigue, lethargy and somnolence. Here we report on prespecified secondary analyses examining viral rebound, antibody sensitivity and reservoir dynamics, as well as prespecified exploratory analyses of rebound virus evolution and autologous antibody activity. Preinfusion reservoir measurements showed low levels of intact proviral HIV-1 DNA in circulating CD4 ⁺ T cells in both arms. The rebounding viruses in participants who received the antibodies showed significant selection for resistance to 10-1074-LS but not to 3BNC117-LS. Notably, there was a significant correlation between greater initial reservoir sensitivity to autologous antibodies and 10-1074 and time to rebound. Finally, comparison of preinfusion and prerebound HIV-1 proviral reservoir showed a decrease in intact but not defective proviruses in arm A but not in arm B. Together, these findings suggest that baseline humoral immunity and prolonged exposure to LS-bNAbs jointly shape post-treatment viral rebound dynamics in individuals who initiate ART during primary infection. ClinicalTrials.gov identifier: NCT04319367 .

Only few cases of human immunodeficiency virus (HIV) remission have been reported after allogeneic haematopoietic stem cell transplantation (HSCT), mostly involving stem cell donors with the homozygous CCR5Δ32 (CCR5Δ32/Δ32) mutation, which confers resistance to CCR5-tropic HIV-1. Here we report the case of a 63-year-old man in off-treatment HIV remission, 5 years after HSCT with a CCR5Δ32/Δ32 sibling donor for myelodysplastic syndrome. In-depth clinical characterization including virological and immunological analyses of peripheral blood, gut and bone marrow samples revealed that full donor chimerism was achieved. Antiretroviral therapy was discontinued after 24 months, and 48 months after HSCT, no intact HIV DNA was detected in blood or gut biopsies. Replication-competent virus and HIV-specific T cell responses were absent, and HIV antibody responses showed a gradual decline. Full donor chimerism in the gut, which is the primary viral reservoir, underscores the likelihood of a cure.

Antiretroviral therapy (ART) interruption typically leads to rapid HIV-1 viral rebound in people with HIV-1. To develop an HIV-1 cure, insight into immunological mechanisms capable of preventing HIV-1 viral rebound is urgently needed. Here, we describe three exceptional post-intervention controllers (PICs) who maintained ART-free virological control for >6.5 years (ongoing), >7.5 years (ongoing) and 2.5 years following administration of broadly neutralizing antibodies. PICs had quantifiable genetically intact/inducible infectious proviral reservoirs that were increasingly clonal and located in nongenic/centromeric chromosomal regions, indicating immune-mediated selection. Potent autologous neutralizing antibodies and polyfunctional HIV-1-specific CD4 ⁺ and CD8 ⁺ T cell responses, pre-programmed for antigen response, were present before, and persisted during, ART interruption. In one PIC, viral rebound following 2.5 years of ART-free control was associated with accumulated viral mutations that resulted in escape from neutralizing antibody and T cell responses. Collectively, our findings support developing HIV-1 curative strategies aimed at enhancing pre-existing adaptive immune responses.

Autoantibodies (autoAbs) neutralizing type I interferons (IFN-I) markedly increase the risk of severe manifestations of some viral diseases. The prevalence of autoAbs neutralizing at least one IFN-I, specifically IFN-α2, IFN-β, and IFN-ω, in individuals from the Swiss human immunodeficiency virus 1 (HIV-1) cohort is largely similar to French age-matched healthy controls, with around 1% in adults by age 65 having neutralizing IFN-I autoAbs and rising thereafter. We analyzed samples from Danish individuals with HIV, including antiretroviral therapy (ART) treated (n = 260) and ART-naive (n = 58) individuals, aged 18–79 (mean age 46.6 years, SD ± 11.1 years), and American individuals with HIV, all of whom were ART-naive (n = 292) aged 20–76 (mean age 41.7 years, SD ± 10.1 years). In the Danish cohort, a total of 2/318 (0.63%) individuals had autoAbs neutralizing 1 ng/ml IFN-ω, whereas 1/318 (0.31%) had autoAbs neutralizing 200 pg/ml IFN-ω. In the American cohort, 2/292 (0.68%) individuals had autoAbs neutralizing IFN-ω at 1 ng/ml. Combining both cohorts, the overall prevalence of autoAbs neutralizing IFN-ω was 5/610 (0.82%). Longitudinal samples were available for two individuals with IFN-ω autoAbs: One displayed persistently detectable autoAbs over time, whereas the other showed a decline in neutralizing activity after 2 years. Two out of five individuals with IFN-I neutralizing autoAbs had a history of IFN-α treatment for chronic hepatitis C virus (HCV) infection. Individuals with IFN-I neutralizing autoAbs shared a history of viral infections, including mucocutaneous herpesvirus infections, zoster, and human papillomavirus disease. Collectively, the prevalence of IFN-I neutralizing autoAbs in people with HIV, whether ART-treated or ART-naive, did not significantly differ from that in the general population. Whereas hepatitis C and IFN therapy may contribute to the development of autoAbs to IFN-I, these autoAbs in turn seem to predispose to mucocutaneous herpesvirus infections and HPV-related neoplasia.

Synergistic polyreactivity of antibodies—where distinct oligo- or polyreactive clones combine to enable broad-spectrum antigen binding—was recently demonstrated for human anti-galactose-α-1,3-galactose (αGal) antibodies. However, it remains unclear whether this phenomenon also occurs in other antigen-defined antibody populations. Here, we investigated synergistic polyreactivity in isohemagglutinins (naturally occurring antibodies against ABO blood group antigens) and its potential role in antimicrobial defense. Isohemagglutinins were affinity-purified from pooled plasma from groups of healthy donors sharing the same ABO blood group, then characterized by solid-phase immunoassays, SDS-PAGE, and Western blotting. Binding to formaldehyde-fixed Streptococcus pneumoniae representing 30 serotypes was assessed by flow cytometry. Specificity was further examined using inhibition assays with soluble pneumococcal polysaccharides. To evaluate clinical relevance, ABO blood group types (used as proxies for isohemagglutinin profiles) were linked to serotype-specific invasive pneumococcal disease (IPD) events using Danish nationwide registry data. The purified isohemagglutinins retained specificity for their cognate ABO antigens. Notably, they bound all tested pneumococcal strains, primarily through reactivity with the common cell wall polysaccharide. Adsorption studies further revealed serotype-specific capsule binding mediated by distinct isohemagglutinin clones, demonstrating synergistic polyreactivity. Despite this, population-level analyses showed only modest protection: most notably, individuals with blood types B or O (producers of anti-A and anti-A,B isohemagglutinins, respectively) had a 19% lower prevalence of serotype 9V IPD than blood type A or AB individuals. Although the overall protective effect of isohemagglutinins against IPD seems limited, the observed synergistic polyreactivity supports the concept that this is a general feature of antigen-defined antibodies, extending beyond anti-αGal antibodies.

Interventions to induce lasting human immunodeficiency virus (HIV) remission are needed to obviate the requirement for lifelong antiretroviral therapy. Durable post-intervention control (PIC) of viraemia has been achieved in a subset of people following administration of broadly neutralizing anti-HIV-1 antibodies (bNAb) and analytical interruption of treatment ^1–4 . Previous studies support a role for CD8 ⁺ T cells in PIC ^5–9 , but the precise features of CD8 ⁺ T cells involved remain unclear. Here we mapped and functionally profiled CD8 ⁺ T cell responses to autologous HIV epitopes using longitudinal samples from four analytical treatment interruption trials in bNAb recipients. PIC was associated with superior pre-intervention HIV-specific CD8 ⁺ T cell proliferative capacity, stem-cell-like memory phenotype and recall cytotoxicity against autologous HIV peptide-pulsed CD4 ⁺ T cells. CD8 ⁺ T cell stemness was increased further following bNAb administration without emergence of new clonotypes targeting defined HLA-optimal epitopes. Multi-modal single-cell analyses revealed molecular features associated with PIC and HIV-specific CD8 ⁺ T cell stemness, including signatures of metabolic fitness and reduced T cell exhaustion. These results identify immune features that precede subsequent PIC to inform the development of combination immunotherapies that will elicit durable HIV remission.

RIO is an ongoing double blind randomized placebo controlled human trial in which participants that started antiretroviral therapy (ART) during primary or early-stage infection underwent treatment interruption and were randomly assigned to a group receiving one or two doses of two long acting broadly neutralizing antibodies 3BNC117-LS and 10-1074-LS (Arm A), or saline (Arm B). The two arms differed significantly in time to viral rebound, ART restart and number of individuals that remained off therapy after 96 weeks (p=0.001) ¹. Here we report on the relationship between viremic control, the latent HIV-1 proviral reservoir, rebound viruses and their sensitivity to the infused and autologous antibodies. Pre-infusion reservoir measurements showed low levels of intact proviral HIV-1 DNA in circulating CD4+ T cells in both arms. The rebounding viruses in participants that received the antibodies, showed significant selection for resistance to 10-1074-LS but not to 3BNC117-LS. Notably, there was a significant correlation between initial reservoir sensitivity to autologous antibodies and to 10-1074 and time to rebound. Finally, comparison of pre-infusion and pre-rebound HIV-1 proviral reservoir in participants that received antibodies showed that the reservoir of intact proviruses decayed faster than earlier reports with a half-life of 0.65 years.

The only current strategy to test efficacy of novel interventions for sustained HIV control without antiretroviral therapy (ART) among people with HIV (PWH) is through an analytical treatment interruption (ATI). Inclusion of ‘placebo’ controls in ATIs poses ethical, logistical, and economic challenges. To understand viral dynamics and rates of post-treatment control (PTC) after ATI among PWH receiving either placebo or no intervention, we undertook an individual-participant data meta-analysis. In total, 24 eligible prospective studies with 382 individuals with ≥5 plasma HIV RNA viral loads (pVLs) within the first 84 days post-ATI were included. Early-ART was defined as ART initiation within 6 months of HIV acquisition; others were classified as late-ART or unknown. Median age was 42 years, 91% male, 75% white, 45% received early-ART. Median time to pVL >50, >400, and >10,000 copies/mL was 16 days (interquartile range [IQR]:13–25), 21 (IQR:15–28), and 32 (IQR:20–35), respectively. PTC defined as pVL n = 14) of participants (6% early-ART and 1% late-ART). Sustained PTC of pVL <50 copies/ml after 84 days is rare in PWH, especially in those starting ART late. Our findings inform future interventional HIV cure/remission trials on study size and design.