Deciphering Factors Linked With Reduced Severe Acute Respiratory Syndrome Coronavirus 2 Susceptibility in the Swiss HIV Cohort Study.

BACKGROUND: Factors influencing susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain to be resolved. Using data from the Swiss HIV Cohort Study on 6270 people with human immunodeficiency virus (HIV) and serologic assessment for SARS-CoV-2 and circulating human coronavirus (HCoV) antibodies, we investigated the association of HIV-related and general parameters with SARS-CoV-2 infection. METHODS: We analyzed SARS-CoV-2 polymerase chain reaction test results, COVID-19-related hospitalizations, and deaths reported to the Swiss HIV Cohort Study between 1 January 2020 and 31 December 2021. Antibodies to SARS-CoV-2 and HCoVs were determined in prepandemic (2019) and pandemic (2020) biobanked plasma samples and compared with findings in HIV-negative individuals. We applied logistic regression, conditional logistic regression, and bayesian multivariate regression to identify determinants of SARS-CoV-2 infection and antibody responses to SARS-CoV-2 in people with HIV. RESULTS: No HIV-1-related factors were associated with SARS-CoV-2 acquisition. High prepandemic HCoV antibodies were associated with a lower risk of subsequent SARS-CoV-2 infection and with higher SARS-CoV-2 antibody responses on infection. We observed a robust protective effect of smoking on SARS-CoV-2 infection risk (adjusted odds ratio, 0.46 [95% confidence interval, .38-.56]; P < .001), which occurred even in previous smokers and was highest for heavy smokers. CONCLUSIONS: Our findings of 2 independent protective factors, smoking and HCoV antibodies, both affecting the respiratory environment, underscore the importance of the local immune milieu in regulating susceptibility to SARS-CoV-2.

HLA-B locus products resist degradation by the human cytomegalovirus immunoevasin US11.

To escape CD8+ T-cell immunity, human cytomegalovirus (HCMV) US11 redirects MHC-I for rapid ER-associated proteolytic degradation (ERAD). In humans, classical MHC-I molecules are encoded by the highly polymorphic HLA-A, -B and -C gene loci. While HLA-C resists US11 degradation, the specificity for HLA-A and HLA-B products has not been systematically studied. In this study we analyzed the MHC-I peptide ligands in HCMV-infected cells. A US11-dependent loss of HLA-A ligands was observed, but not of HLA-B. We revealed a general ability of HLA-B to assemble with ß2m and exit from the ER in the presence of US11. Surprisingly, a low-complexity region between the signal peptide sequence and the Ig-like domain of US11, was necessary to form a stable interaction with assembled MHC-I and, moreover, this region was also responsible for changing the pool of HLA-B ligands. Our data suggest a two-pronged strategy by US11 to escape CD8+ T-cell immunity, firstly, by degrading HLA-A molecules, and secondly, by manipulating the HLA-B ligandome.

ART-DEX: A novel strategy to monitor broadly neutralizing antibody activity during antiretroviral therapy of HIV-1.

Therapeutic use of HIV-1 broadly neutralizing antibodies (bnAbs), passively administered or induced by therapeutic vaccines, is a focus of advanced treatment strategies under development. To enable monitoring of bnAb activity during concurrent antiretroviral therapy (ART), we developed ART-DEX, an analytic strategy that allows high-throughput detection of pure antibody-based neutralizing activity. ART-DEX combines pH-dependent dissociation of antiretrovirals (ARVs) from plasma proteins and size exclusion to effectively remove ARVs from plasma samples, reducing the confounding effects of ARVs on neutralization assays. For complete details on the use and execution of this protocol, please refer to Schwarzmüller et al.1.

Decoupling HIV-1 antiretroviral drug inhibition from plasma antibody activity to evaluate broadly neutralizing antibody therapeutics and vaccines.

The development of broadly neutralizing antibody (bnAb)-based therapeutic HIV-1 vaccines and cure concepts depends on monitoring bnAb plasma activity in people with HIV (PWH) on suppressive antiretroviral therapy (ART). To enable this, analytical strategies must be defined to reliably distinguish antibody-based neutralization from drug inhibition. Here, we explore strategies that either utilize drug-resistant viruses or remove drugs from plasma. We develop ART-DEX (ART dissociation and size exclusion), an approach which quantitatively separates drugs from plasma proteins following pH-triggered release allowing accurate definition of antibody-based neutralization. We demonstrate that ART-DEX, alone or combined with ART-resistant viruses, provides a highly effective and scalable means of assessing antibody neutralization during ART. Implementation of ART-DEX in standard neutralization protocols should be considered to enhance the analytical capabilities of studies evaluating bnAb therapeutics and therapeutic vaccines, furthering the development of advanced ART and HIV-1 cure strategies.

Cross-protective HCoV immunity reduces symptom development during SARS-CoV-2 infection.

Numerous clinical parameters link to severe coronavirus disease 2019, but factors that prevent symptomatic disease remain unknown. We investigated the impact of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and endemic human coronavirus (HCoV) antibody responses on symptoms in a longitudinal children cohort (n = 2,917) and a cross-sectional cohort including children and adults (n = 882), all first exposed to SARS-CoV-2 (March 2020 to March 2021) in Switzerland. Saliva (n = 4,993) and plasma (n = 7,486) antibody reactivity to the four HCoVs (subunit S1 [S1]) and SARS-CoV-2 (S1, receptor binding domain, subunit S2 [S2], nucleocapsid protein) was determined along with neutralizing activity against SARS-CoV-2 Wuhan, Alpha, Delta, and Omicron (BA.2) in a subset of individuals. Inferred recent SARS-CoV-2 infection was associated with a strong correlation between mucosal and systemic SARS-CoV-2 anti-spike responses. Individuals with pre-existing HCoV-S1 reactivity exhibited significantly higher antibody responses to SARS-CoV-2 in both plasma (IgG regression coefficients = 0.20, 95% CI = [0.09, 0.32], P < 0.001) and saliva (IgG regression coefficient = 0.60, 95% CI = [0.088, 1.11], P = 0.025). Saliva neutralization activity was modest but surprisingly broad, retaining activity against Wuhan (median NT50 = 32.0, 1Q-3Q = [16.4, 50.2]), Alpha (median NT50 = 34.9, 1Q-3Q = [26.0, 46.6]), and Delta (median NT50 = 28.0, 1Q-3Q = [19.9, 41.7]). In line with a rapid mucosal defense triggered by cross-reactive HCoV immunity, asymptomatic individuals presented with higher pre-existing HCoV-S1 activity in plasma (IgG HKU1, odds ratio [OR] = 0.53, 95% CI = [0.29,0.97], P = 0.038) and saliva (total HCoV, OR = 0.55, 95% CI = [0.33, 0.91], P = 0.019) and higher SARS-CoV-2 reactivity in saliva (IgG S2 fold change = 1.26, 95% CI = [1.03, 1.54], P = 0.030). By investigating the systemic and mucosal immune responses to SARS-CoV-2 and HCoVs in a population without prior exposure to SARS-CoV-2 or vaccination, we identified specific antibody reactivities associated with lack of symptom development.IMPORTANCEKnowledge of the interplay between human coronavirus (HCoV) immunity and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection is critical to understanding the coexistence of current endemic coronaviruses and to building knowledge potential future zoonotic coronavirus transmissions. This study, which retrospectively analyzed a large cohort of individuals first exposed to SARS-CoV-2 in Switzerland in 2020-2021, revealed several key findings. Pre-existing HCoV immunity, particularly mucosal antibody responses, played a significant role in improving SARS-CoV-2 immune response upon infection and reducing symptoms development. Mucosal neutralizing activity against SARS-CoV-2, although low in magnitude, retained activity against SARS-CoV-2 variants underlining the importance of maintaining local mucosal immunity to SARS-CoV-2. While the cross-protective effect of HCoV immunity was not sufficient to block infection by SARS-CoV-2, the present study revealed a remarkable impact on limiting symptomatic disease. These findings support the feasibility of generating pan-protective coronavirus vaccines by inducing potent mucosal immune responses.

Antibodies from convalescent plasma promote SARS-CoV-2 clearance in individuals with and without endogenous antibody response.

BACKGROUNDNeutralizing antibodies are considered a key correlate of protection by current SARS-CoV-2 vaccines. The manner in which human infections respond to therapeutic SARS-CoV-2 antibodies, including convalescent plasma therapy, remains to be fully elucidated.METHODSWe conducted a proof-of-principle study of convalescent plasma therapy based on a phase I trial in 30 hospitalized COVID-19 patients with a median interval between onset of symptoms and first transfusion of 9 days (IQR, 7-11.8 days). Comprehensive longitudinal monitoring of the virological, serological, and disease status of recipients allowed deciphering of parameters on which plasma therapy efficacy depends.RESULTSIn this trial, convalescent plasma therapy was safe as evidenced by the absence of transfusion-related adverse events and low mortality (3.3%). Treatment with highly neutralizing plasma was significantly associated with faster virus clearance, as demonstrated by Kaplan-Meier analysis (P = 0.034) and confirmed in a parametric survival model including viral load and comorbidity (adjusted hazard ratio, 3.0; 95% CI, 1.1-8.1; P = 0.026). The onset of endogenous neutralization affected viral clearance, but even after adjustment for their pretransfusion endogenous neutralization status, recipients benefitted from plasma therapy with high neutralizing antibodies (hazard ratio, 3.5; 95% CI, 1.1-11; P = 0.034).CONCLUSIONOur data demonstrate a clear impact of exogenous antibody therapy on the rapid clearance of viremia before and after onset of the endogenous neutralizing response, and point beyond antibody-based interventions to critical laboratory parameters for improved evaluation of current and future SARS-CoV-2 therapies.TRIAL REGISTRATIONClinicalTrials.gov NCT04869072.FUNDINGThis study was funded via an Innovation Pool project by the University Hospital Zurich; the Swiss Red Cross Glückskette Corona Funding; Pandemiefonds of the UZH Foundation; and the Clinical Research Priority Program "Comprehensive Genomic Pathogen Detection" of the University of Zurich.

Multifactorial seroprofiling dissects the contribution of pre-existing human coronaviruses responses to SARS-CoV-2 immunity.

Determination of SARS-CoV-2 antibody responses in the context of pre-existing immunity to circulating human coronavirus (HCoV) is critical for understanding protective immunity. Here we perform a multifactorial analysis of SARS-CoV-2 and HCoV antibody responses in pre-pandemic (N = 825) and SARS-CoV-2-infected donors (N = 389) using a custom-designed multiplex ABCORA assay. ABCORA seroprofiling, when combined with computational modeling, enables accurate definition of SARS-CoV-2 seroconversion and prediction of neutralization activity, and reveals intriguing interrelations with HCoV immunity. Specifically, higher HCoV antibody levels in SARS-CoV-2-negative donors suggest that pre-existing HCoV immunity may provide protection against SARS-CoV-2 acquisition. In those infected, higher HCoV activity is associated with elevated SARS-CoV-2 responses, indicating cross-stimulation. Most importantly, HCoV immunity may impact disease severity, as patients with high HCoV reactivity are less likely to require hospitalization. Collectively, our results suggest that HCoV immunity may promote rapid development of SARS-CoV-2-specific immunity, thereby underscoring the importance of exploring cross-protective responses for comprehensive coronavirus prevention.