CROI 2024 Abstract eBook

Abstract eBook

Oral Abstracts

subvariants and evaluated whether this property is associated with viral transmission. Methods: We first tested the capacity of plasma from 18 individuals who received a fifth dose of bivalent (BA.1 or BA.4/5) mRNA vaccine to recognize and neutralize Spikes from 13 recent Omicron subvariants. We also tested the susceptibility of Spikes to cold inactivation and measured their processing. We also measured how temperature affects the interaction between Spike and ACE2 by using biolayer interferometry, flow cytometry and virus capture assay. The associations between these parameters and the viral growth rate of each Omicron subvariants in the population between October 2022 and August 2023 was determined. Results: Compared to the early D614G strain, most Omicron subvariants Spike glycoproteins possess improved ACE2 binding, enhanced immune escape and are more susceptible to cold inactivation. Their Spikes bound ACE2 in a temperature-dependent manner, enhancing Spike binding and protomer cooperativity to ACE2. We also found that Omicron subvariants Spike processing is associated with their susceptibility to cold inactivation (r = -0.6124, p=0.0199) and with ACE2 interaction at low temperatures at the surface of pseudoviral particles (r = -0.6271, p=0.0164). Intriguingly, we found that Spike ACE2 binding at low temperatures is significantly associated with growth rates of Omicron subvariants in the human population (r = 0.9842, p<0.0001). Conclusion: Our findings indicate that Omicron subvariants acquired mutations enhancing resistance to neutralization by plasma, improving Spike processing, and increasing affinity for ACE2 at both low and high temperatures. Importantly, we found that Spike-ACE2 interaction at the surface of viral particles at low temperatures is strongly associated with Omicron subvariants growth rates. Our study underscores the necessity for ongoing surveillance of emerging subvariants and underscores the importance of measuring Spike-ACE2 interaction at low temperatures, since this parameter is highly associated with viral transmission. IFNα2 Autoantibodies Post-SARS-CoV-2 Wave 1 in India Are Associated With Lower Omicron Symptomology Enrico Bravo 1 , Marianne Perera 1 , Vasista Adiga 2 , Nirutha Chetan 2 , Asma Ahmed 2 , Hima Bindu 2 , Katie Doores 1 , Adrian Hayday 1 , Annapurna Vyakarnam 2 , Stuart J. Neil 1 1 King's College London, London, UK, 2 St John's Research Institute, Bangalore, India Background: Neutralizing autoantibodies against type I IFNs have been associated with life-threatening SARS-CoV-2 infection in the first wave of the pandemic. As part of a wider immunophenotyping study aimed at comparing susceptibility and immunopathogenesis of COVID-19 between the UK and India, we examined the levels of anti-IFNα2 neutralization in sera collected. Methods: We used sera from these cohorts to measure anti-Spike (S) and anti-Nucleocapsid (N) responses, screen for IFNα2 autoantibodies that neutralized both activation of JAK-STAT signalling in a HEK-Blue IFN alpha/ beta reporter cell line, and to attenuate the antiviral state in IFNα2-treated U87-MG cells when challenged with VSV-G pseudotyped HIV-1 vectors. As controls we used autoimmune polyendocrine syndrome type 1 (APS-1) patients with a deleterious variant of AIRE, a mediator of immune tolerance leading to excessive production of type I interferon autoantibodies that ameliorate autoinflammation. Results: Most pre-pandemic individuals in both the UK and India had no detectable neutralising IFNα2 autoantibodies. In line with previous studies, a small number of UK patients (2) hospitalized during wave 1 of the pandemic had detectable IFNα2 neutralizing activity. By contrast, the majority of Anti-S/ Anti-N+ healthy donors in India had low-level neutralizing activity compared the UK cohort. Intriguingly, amongst those hospitalized during the Omicron BA.2 wave in Bangalore, circulating anti-IFNα2 activity was significantly reduced in severe vs moderate disease. This correlated with a global increase in inflammatory phenotype in circulating leukocyte subsets in these. Notably, autoantibody levels did not correlate with age and gender across the various groups. In India, the sex distribution is closely balanced, while the UK cohorts are predominately male. Conclusion: In the first wave of the pandemic, while high levels of autoantibodies against IFNs were associated with severe disease in previously non-exposed individuals, our results suggest the interplay between such antibodies and SARS-CoV-2 pathogenesis may be more complex in different populations. We do not understand what biological and environmental factors underlie the presence of low-level autoantibodies to IFNα2 in healthy SARS-

levels of IL-6 (p=0.0015). In participants with detectable atherosclerotic plaque, levels of sgp120, anti-cluster A Abs, and their combination were associated with increased volume of atherosclerotic plaques (p=0.01, 0.018, and 0.006, respectively). Conclusion: sgp120 could act as a pan toxin, causing immune dysfunction and sustained inflammation in a subset of PLWH, contributing to the development of premature comorbidities. Rapid Emergence and Adaptive Evolution of SARS-CoV-2 Variants in Advanced HIV Infection Sung Hee Ko 1 , Pierce Radecki 1 , Frida Belinky 1 , Jinal Bhiman 2 , Susan Meiring 2 , Jackie Kleynhans 2 , Daniel Amoako 2 , Margaret Lucas 1 , Vanessa Guerra 1 , Tatsiana Bylund 1 , Nicole Wolter 2 , Stefano Tempia 2 , Anne von Gottberg 2 , Cheryl Cohen 2 , Eli Boritz 1 1 National Institutes of Health, Bethesda, MD, USA, 2 National Institute for Communicable Diseases, Johannesburg, South Africa Background: Prolonged SARS-CoV-2 RNA shedding and intra-host evolution in people with HIV (PWH) suggested that SARS-CoV-2 variants, including variants of concern (VOCs), may preferentially arise in PWH. Nonetheless, the evolutionary processes remain incompletely understood due to consensus based genetic characterization of intra-host virus from short-read whole genome sequencing. Alternatively, high-throughput single-genome amplification and sequencing (HT-SGS), which enables detection of unique linked groupings of mutations (i.e. haplotypes) at the level of single genomes, is more suitable for estimates of intra-host population diversity and allows a better understanding of evolutionary relationship among viruses. Methods: We sequenced SARS-CoV-2 spike genes in nasal swabs of longitudinal sample sets from 25 people without HIV (PWOH) and 22 PWH, who were subgrouped on the basis of CD4 T cell counts (CD4 counts). We developed HT-SGS, which used Pacific Biosciences single molecule, real-time technology (SMRT) coupled with unique molecular identifiers (UMIs) of virus genome sequences, to generate up to ~ 1000 single-copy sequences per sample with high accuracy. Results: Intra-host spike gene diversity was significantly higher in PWH with CD4 counts <200 cells/μL than in the other subgroups. These individuals had a median of 3.5 secondary Pango lineages/person, while PWOH had showed no secondary lineages. Through longitudinal analysis, remarkable features of SARS-CoV-2 dynamics were observed in PWH with CD4 counts <200 cells/μL, including 1) high early diversity, beginning shortly after COVID-19 symptom onset, 2) rapid changes in frequency of the most abundant haplotypes, and 3) large changes in population haplotype composition over time. Intra-host polymorphisms in PWH with CD4 counts <200 cells/μL included greater numbers of synonymous (reflecting more virus replicative cycles) and nonsynonymous mutations (often overlapping with defining mutations of VOCs) than other subgroups, indicating a high mutational burden. In addition, we found that patterns of gene evolution in PWH with CD4 counts <200 cells/ μL resulted from adaptation of the virus to the host by selective forces (positive selection). Conclusion: These reveal unique virus genetic aspects of SARS-CoV-2 infections in people with advanced HIV infection that markedly increase the risk for generation of new variants. Our results suggest that HIV treatment with antiretroviral therapy can help limit intra-host SARS-CoV-2 persistence and evolution. Temperature-Dependent SARS-CoV-2 Spike-ACE2 Interaction Is Associated With Viral Transmission Mehdi Benlarbi 1 , Shilei Ding 2 , Étienne Bélanger 1 , Alexandra Tauzin 1 , Halima Medjahed 2 , Raphaël Poujol 3 , Omar El-Ferri 4 , Yuxia Bo 4 , Julie Hussin 3 , Judith Fafard 5 , Marzena Pazgier 6 , Inès Levade 5 , Cameron Abrams 7 , Marceline Côté 4 , Andrés Finzi 1 1 Université de Montréal, Montreal, Canada, 2 Centre de Recherche du CHUM, Montreal, Canada, 3 Institut de Cardiologie de Montréal, Montreal, Canada, 4 University of Ottawa, Ottawa, Canada, 5 Laboratoire de Santé Publique du Québec, Sainte-Anne-de-Bellevue, Canada, 6 Uniformed Services University of the Health Sciences, Bethesda, MD, USA, 7 Drexel University, Philadelphia, PA, USA Background: The persistent evolution of SARS-CoV-2 gave rise to a wide range of variants harboring new mutations in their Spike glycoprotein. We previously demonstrated that temperature modulates the interaction between SARS-CoV-2 Spike and its host receptor ACE2, with low temperature increasing ACE2 binding affinity and viral entry. Here we characterized the latest Omicron

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CROI 2024