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Immune response dynamics in coronavirus disease 2019 (COVID-19) and their severe manifestations have largely been studied in circulation. Here, we examined the relationship between immune processes in the respiratory tract and circulation through longitudinal phenotypic, transcriptomic, and cytokine profiling of paired airway and blood samples from patients with severe COVID-19 relative to heathy controls. In COVID-19 airways, T cells exhibited activated, tissue-resident, and protective profiles; higher T cell frequencies correlated with survival and younger age. Myeloid cells in COVID-19 airways featured hyperinflammatory signatures, and higher frequencies of these cells correlated with mortality and older age. In COVID-19 blood, aberrant CD163+ monocytes predominated over conventional monocytes, and were found in corresponding airway samples and in damaged alveoli. High levels of myeloid chemoattractants in airways suggest recruitment of these cells through a CCL2-CCR2 chemokine axis. Our findings provide insights into immune processes driving COVID-19 lung pathology with therapeutic implications for targeting inflammation in the respiratory tract.
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COVID-19/inmunología , Pulmón/inmunología , Células Mieloides/inmunología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , COVID-19/sangre , COVID-19/mortalidad , COVID-19/patología , Citocinas/inmunología , Citocinas/metabolismo , Humanos , Inflamación , Estudios Longitudinales , Pulmón/patología , Macrófagos/inmunología , Macrófagos/patología , Persona de Mediana Edad , Monocitos/inmunología , Monocitos/patología , Células Mieloides/patología , SARS-CoV-2 , Linfocitos T/inmunología , Linfocitos T/patología , Transcriptoma , Adulto JovenRESUMEN
The pathogenesis of HIV-1 infection is governed by a highly dynamic, time-dependent interaction between the host and the viral genome. In this study, we developed a novel systematic approach to assess the host-virus interaction, using average pairwise viral diversity as a proxy for time since infection, and applied this method to nearly whole viral genome sequences (n = 4,464), human leukocyte antigen (HLA) genotyping data (n = 1,044), and viral RNA load (VL) measurements during the untreated chronic phase (n = 829) of Swiss HIV Cohort Study participants. Our systematic genome-wide screen revealed for 98 HLA/viral-variant pairs a signature of immune-driven selection in the form of an HLA-dependent effect of infection time on the presence of HIV amino acid variants. Of these pairs, 12 were found to have an effect on VL. Furthermore, 28/58 pairs were validated by time-to-event analyses and 48/92 by computational HLA-epitope predictions. Our diversity-based approach allows a powerful and systematic investigation of the interaction between the virus and cellular immunity, revealing a notable subset of such interaction effects. From an evolutionary perspective, these observations underscore the complexity of HLA-mediated selection pressures on the virus that shape viral evolution and pathogenesis.
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BACKGROUND: Factors influencing susceptibility to SARS-CoV-2 remain to be resolved. Using data of the Swiss HIV Cohort Study (SHCS) on 6,270 people with HIV (PWH) 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 PCR-tests, COVID-19 related hospitalizations, and deaths reported to the SHCS between January 1, 2020 and December 31, 2021. Antibodies to SARS-CoV-2 and HCoVs were determined in pre-pandemic (2019) and pandemic (2020) bio-banked plasma and compared to HIV-negative individuals. We applied logistic regression, conditional logistic regression, and Bayesian multivariate regression to identify determinants of SARS-CoV-2 infection and Ab responses to SARS-CoV-2 in PWH. RESULTS: No HIV-1-related factors were associated with SARS-CoV-2 acquisition. High pre-pandemic HCoV antibodies were associated with a lower risk of subsequent SARS-CoV-2 infection and with higher SARS-CoV-2 antibody responses upon infection. We observed a robust protective effect of smoking on SARS-CoV-2-infection risk (aOR= 0.46 [0.38,0.56], p=2.6*10-14), which occurred even in previous smokers, and was highest for heavy smokers. CONCLUSIONS: Our findings of two 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.
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Allogeneic haematopoietic cell transplantation (allo-HCT) recipients exhibit an increased risk of COVID-19, particularly in the early post-transplant phase, due to insufficient vaccine responses. This retrospective study investigated the incidence of SARS-CoV-2 infection in allo-HCT recipients who received tixagevimab/cilgavimab pre-exposure prophylaxis (T/C PrEP) compared to those who did not. Logistic regression, adjusted for sex, age, SARS-CoV-2 vaccination status and immunosuppressive treatment, revealed a significant reduction in the likelihood of SARS-CoV-2 infection risk with T/C PrEP (adjusted odds ratio aOR = 0.26 [0.07, 0.91]). These findings suggest the potential efficacy of monoclonal antibody PrEP in protecting this vulnerable patient population from COVID-19.
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Anticuerpos Monoclonales Humanizados , COVID-19 , Trasplante de Células Madre Hematopoyéticas , SARS-CoV-2 , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Masculino , COVID-19/prevención & control , Femenino , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anciano , Trasplante Homólogo , Profilaxis Pre-Exposición/métodos , AloinjertosRESUMEN
BACKGROUND: Although sex hormones are recognized to induce immune variations, the effect of hormonal therapy use on immunity is only poorly understood. Here, we quantified how hormonal therapy use affects HIV-1 immune markers in cis women (CW) and trans women and non-binary people (TNBP) with HIV. METHODS: We considered CD4, CD8 and lymphocyte measurements from cis men (CM), CW and TNBP in the Swiss HIV Cohort Study. We modelled HIV-1 markers using linear mixed-effects models with an interaction between 'gender' (CW, TNBP) and 'hormonal therapy use' (yes/no). Models were adjusted on age, ethnicity, education level, time since start of antiretroviral therapy and use of intravenous drugs. We assessed the inflammatory effect of hormonal therapy use in 31 TNBP using serum proteomics measurements of 92 inflammation markers. RESULTS: We included 54 083 measurements from 3092 CW and 83 TNBP, and 147 230 measurements from 8611 CM. Hormonal therapy use increased CD4 count and CD4:CD8 ratio in TNBP more than in CW (pinteraction = 0.02 and 0.007, respectively). TNBP with hormonal therapy use had significantly higher CD4 counts [median = 772 cells/µL, interquartile range (IQR): 520-1006] than without (617 cells/µL, 426-892). This was similar to the effect of CW versus CM on CD4 T cells. Hormonal therapy use did not affect serum protein concentrations in TNBP. CONCLUSION: This study highlights the potential role of hormonal therapy use in modulating the immune system among other biological and social factors, especially in TNBP with HIV.
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BACKGROUND: Serological data on endemic human coronaviruses (HCoVs) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in southern Africa are scarce. Here, we report on (1) endemic HCoV seasonality, (2) SARS-CoV-2 seroprevalence, and (3) correlates of SARS-CoV-2 seropositivity and strength of SARS-CoV-2 and endemic HCoV serological responses among adults living with human immunodeficiency virus (HIV). METHODS: Plasma samples were collected from February 2020 to July 2021 within an HIV cohort in Lesotho. We used the AntiBody CORonavirus Assay (ABCORA) multiplex immunoassay to measure antibody responses to endemic HCoV (OC43, HKU1, NL63, and 229E) and SARS-CoV-2 antigens. RESULTS: Results for 3173 samples from 1403 adults were included. Serological responses against endemic HCoVs increased over time and peaked in winter and spring. SARS-CoV-2 seropositivity reached >35% among samples collected in early 2021 and was associated with female sex, obesity, working outside the home, and recent tiredness or fever. Positive correlations were observed between the strength of response to endemic HCoVs and to SARS-CoV-2 and between older age or obesity and the immunoglobulin G response to SARS-CoV-2. CONCLUSIONS: These results add to our understanding of the impact of biological, clinical, and social/behavioral factors on serological responses to coronaviruses in southern Africa.
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COVID-19 , Coronavirus Humano 229E , Coronavirus Humano OC43 , Infecciones por VIH , Adulto , Humanos , Femenino , SARS-CoV-2 , Lesotho , Estudios Seroepidemiológicos , Formación de Anticuerpos , COVID-19/epidemiología , Obesidad , Infecciones por VIH/epidemiologíaRESUMEN
BACKGROUND: Despite effective prevention approaches, ongoing human immunodeficiency virus 1 (HIV-1) transmission remains a public health concern indicating a need for identifying its drivers. METHODS: We combined a network-based clustering method using evolutionary distances between viral sequences with statistical learning approaches to investigate the dynamics of HIV transmission in the Swiss HIV Cohort Study and to predict the drivers of ongoing transmission. RESULTS: We found that only a minority of clusters and patients acquired links to new infections between 2007 and 2020. While the growth of clusters and the probability of individual patients acquiring new links in the transmission network was associated with epidemiological, behavioral, and virological predictors, the strength of these associations decreased substantially when adjusting for network characteristics. Thus, these network characteristics can capture major heterogeneities beyond classical epidemiological parameters. When modeling the probability of a newly diagnosed patient being linked with future infections, we found that the best predictive performance (median area under the curve receiver operating characteristic AUCROC = 0.77) was achieved by models including characteristics of the network as predictors and that models excluding them performed substantially worse (median AUCROC = 0.54). CONCLUSIONS: These results highlight the utility of molecular epidemiology-based network approaches for analyzing and predicting ongoing HIV transmission dynamics. This approach may serve for real-time prospective assessment of HIV transmission.
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Infecciones por VIH , VIH-1 , Humanos , VIH-1/genética , Suiza/epidemiología , Estudios de Cohortes , Estudios Prospectivos , Filogenia , Análisis por ConglomeradosRESUMEN
Allogeneic haematopoietic cell transplantation (allo-HCT) recipients show impaired antibody (Ab) response to a standard two-dose vaccination against severe acute respiratory syndrome coronavirus-2 and currently a third dose is recommended as part of the primary vaccination regimen. By assessing Ab titres 1 month after a third mRNA vaccine dose in 74 allo-HCT recipients we show sufficient neutralisation activity in 77% of the patients. Discontinuation of immunosuppression before the third vaccine led to serological responses in 50% of low responders to two vaccinations. Identifying factors that might contribute to better vaccine responses in allo-HCT recipients is critical to optimise current vaccination strategies.
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COVID-19 , Trasplante de Células Madre Hematopoyéticas , Humanos , Vacunas contra la COVID-19 , Formación de Anticuerpos , COVID-19/prevención & control , SARS-CoV-2 , Receptores de Trasplantes , Vacunación , Anticuerpos AntiviralesRESUMEN
The Ebola vaccine based on Ad26.ZEBOV/MVA-BN-Filo prime-boost regimens is being evaluated in multiple clinical trials. The long-term immune response to the vaccine is unknown, including factors associated with the response and variability around the response. We analyzed data from three phase 1 trials performed by the EBOVAC1 Consortium in four countries: the United Kingdom, Kenya, Tanzania, and Uganda. Participants were randomized into four groups based on the interval between prime and boost immunizations (28 or 56 days) and the sequence in which Ad26.ZEBOV and MVA-BN-Filo were administered. Consecutive enzyme-linked immunosorbent assay (ELISA) measurements of the IgG binding antibody concentrations against the Kikwit glycoprotein (GP) were available for 177 participants to assess the humoral immune response up to 1 year postprime. Using a mathematical model for the dynamics of the humoral response, from 7 days after the boost immunization up to 1 year after the prime immunization, we estimated the durability of the antibody response and the influence of different factors on the dynamics of the humoral response. Ordinary differential equations (ODEs) described the dynamics of antibody response and two populations of antibody-secreting cells (ASCs), short-lived (SL) and long-lived (LL). Parameters of the ODEs were estimated using a population approach. We estimated that half of the LL ASCs could persist for at least 5 years. The vaccine regimen significantly affected the SL ASCs and the antibody peak but not the long-term response. The LL ASC compartment dynamics differed significantly by geographic regions analyzed, with a higher long-term antibody persistence in European subjects. These differences could not be explained by the observed differences in cellular immune response.IMPORTANCE With no available licensed vaccines or therapies, the West African Ebola virus disease epidemic of 2014 to 2016 caused 11,310 deaths. Following this outbreak, the development of vaccines has been accelerated. Combining different vector-based vaccines as heterologous regimens could induce a durable immune response, assessed through antibody concentrations. Based on data from phase 1 trials in East Africa and Europe, the dynamics of the humoral immune response from 7 days after the boost immunization onwards were modeled to estimate the durability of the response and understand its variability. Antibody production is maintained by a population of long-lived cells. Estimation suggests that half of these cells can persist for at least 5 years in humans. Differences in prime-boost vaccine regimens affect only the short-term immune response. Geographical differences in long-lived cell dynamics were inferred, with higher long-term antibody concentrations induced in European participants.
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Vacunas contra el Virus del Ébola/inmunología , Inmunidad Humoral/efectos de los fármacos , Anticuerpos Antivirales/inmunología , Formación de Anticuerpos/inmunología , Ensayos Clínicos Fase I como Asunto/métodos , Vacunas contra el Virus del Ébola/farmacología , Ebolavirus/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Fiebre Hemorrágica Ebola/metabolismo , Fiebre Hemorrágica Ebola/virología , Humanos , Inmunidad Celular/efectos de los fármacos , Inmunización Secundaria/métodos , Kenia , Masculino , Modelos Teóricos , Tanzanía , Uganda , Reino Unido , VacunaciónRESUMEN
The 2014-2016 Ebola outbreak in West Africa has triggered accelerated development of several preventive vaccines against Ebola virus. Under the EBOVAC1 consortium, three phase I studies were carried out to assess safety and immunogenicity of a two-dose heterologous vaccination regimen developed by Janssen Vaccines and Prevention in collaboration with Bavarian Nordic. To describe the immune response induced by the two-dose heterologous vaccine regimen, we propose a mechanistic ODE based model, which takes into account the role of immunological memory. We perform identifiability and sensitivity analysis of the proposed model to establish which kind of biological data are ideally needed in order to accurately estimate parameters, and additionally, which of those are non-identifiable based on the available data. Antibody concentrations data from phase I studies have been used to calibrate the model and show its ability in reproducing the observed antibody dynamics. Together with other factors, the establishment of an effective and reactive immunological memory is of pivotal importance for several prophylactic vaccines. We show that introducing a memory compartment in our calibrated model allows to evaluate the magnitude of the immune response induced by a booster dose and its long-term persistence afterwards.
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Vacunas contra el Virus del Ébola , Ebolavirus , Inmunidad , Modelos Biológicos , África Occidental , Vacunas contra el Virus del Ébola/inmunología , Ebolavirus/inmunología , Fiebre Hemorrágica Ebola/inmunología , Fiebre Hemorrágica Ebola/prevención & control , Humanos , Inmunidad/inmunología , VacunaciónRESUMEN
In human immunodeficiency virus-infected patients, antiretroviral therapy suppresses the viral replication, which is followed in most patients by a restoration of CD4+ T cells pool. For patients who fail to do so, repeated injections of exogenous interleukin 7 (IL7) are experimented. The IL7 is a cytokine that is involved in the T cell homeostasis and the INSPIRE study has shown that injections of IL7 induced a proliferation of CD4+ T cells. Phase I/II INSPIRE 2 and 3 studies have evaluated a protocol in which a first cycle of three IL7 injections is followed by a new cycle at each visit when the patient has less than 550 CD4 cells/µL. Restoration of the CD4 concentration has been demonstrated, but the long-term best adaptive protocol is yet to be determined. A mechanistic model of the evolution of CD4 after IL7 injections has been developed, which is based on a system of ordinary differential equations and includes random effects. Based on the estimation of this model, we use a Bayesian approach to forecast the dynamics of CD4 in new patients. We propose four prediction-based adaptive protocols of injections to minimize the time spent under 500 CD4 cells/µL for each patient, without increasing the number of injections received too much. We show that our protocols significantly reduce the time spent under 500 CD4 over a period of two years, without increasing the number of injections. These protocols have the potential to increase the efficiency of this therapy.
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Recuento de Linfocito CD4/estadística & datos numéricos , Infecciones por VIH/tratamiento farmacológico , Interleucina-7/uso terapéutico , Modelos Estadísticos , Adulto , Protocolos Clínicos , Interpretación Estadística de Datos , Humanos , Resultado del TratamientoRESUMEN
Immune interventions consisting in repeated injections are broadly used as they are thought to improve the quantity and the quality of the immune response. However, they also raise several questions that remain unanswered, in particular the number of injections to make or the delay to respect between different injections to achieve this goal. Practical and financial considerations add constraints to these questions, especially in the framework of human studies. We specifically focus here on the use of interleukin-7 (IL-7) injections in HIV-infected patients under antiretroviral treatment, but still unable to restore normal levels of [Formula: see text] T lymphocytes. Clinical trials have already shown that repeated cycles of injections of IL-7 could help maintaining [Formula: see text] T lymphocytes levels over the limit of 500 cells/[Formula: see text]L, by affecting proliferation and survival of [Formula: see text] T cells. We then aim at answering the question: how to maintain a patients level of [Formula: see text] T lymphocytes by using a minimum number of injections (i.e., optimizing the strategy of injections)? Based on mechanistic models that were previously developed for the dynamics of [Formula: see text] T lymphocytes in this context, we model the process by a piecewise deterministic Markov model. We then address the question by using some recently established theory on impulse control problem in order to develop a numerical tool determining the optimal strategy. Results are obtained on a reduced model, as a proof of concept: the method allows to define an optimal strategy for a given patient. This method could be applied to optimize injections schedules in clinical trials.
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Infecciones por VIH/inmunología , Infecciones por VIH/terapia , Interleucina-7/administración & dosificación , Algoritmos , Fármacos Anti-VIH/uso terapéutico , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Terapia Combinada , Simulación por Computador , Relación Dosis-Respuesta Inmunológica , Esquema de Medicación , Infecciones por VIH/tratamiento farmacológico , Humanos , Inmunoterapia/métodos , Inmunoterapia/estadística & datos numéricos , Interleucina-7/uso terapéutico , Cadenas de Markov , Conceptos Matemáticos , Modelos Inmunológicos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéuticoRESUMEN
OBJECTIVE: We developed a robust characterization of immune recovery trajectories in people living with HIV on antiretroviral treatment (ART) and relate our findings to epidemiological risk factors and bacterial pneumonia. METHODS: Using data from the Swiss HIV Cohort Study and the Zurich Primary HIV Infection Cohort Study (n = 5907), we analyzed the long-term trajectories of CD4 cell and CD8 cell counts and their ratio in people living with HIV on ART for at least 8 years by fitting nonlinear mixed-effects models. The determinants of long-term immune recovery were investigated using generalized additive models. In addition, prediction accuracy of the modeled trajectories and their impact on the fit of a model for bacterial pneumonia was assessed. RESULTS: Overall, our population showed good immune recovery (median plateau [interquartile range]-CD4: 718 [555-900] cells/µL, CD8: 709 [547-893] cells/µL, CD4/CD8: 1.01 [0.76-1.37]). The following factors were predictive of recovery: age, sex, nadir/zenith value, pre-ART HIV-1 viral load, hepatitis C, ethnicity, acquisition risk, and timing of ART initiation. The fitted models proved to be an accurate and efficient way of predicting future CD4 and CD8 cell recovery dynamics: Compared with carrying forward the last observation, mean squared errors of the fitted values were lower by 1.3%-18.3% across outcomes. When modeling future episodes of bacterial pneumonia, using predictors derived from the recovery dynamics improved most model fits. CONCLUSION: We described and validated a method to characterize individual immune recovery trajectories of people living with HIV on suppressive ART. These trajectories accurately predict long-term immune recovery and the occurrence of bacterial pneumonia.
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Fármacos Anti-VIH , Infecciones por VIH , Neumonía Bacteriana , Humanos , Estudios de Cohortes , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos , Antirretrovirales/uso terapéutico , Neumonía Bacteriana/tratamiento farmacológico , Neumonía Bacteriana/etiología , Carga Viral , Terapia Antirretroviral Altamente Activa/métodos , Fármacos Anti-VIH/uso terapéuticoRESUMEN
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.
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COVID-19 , Adulto , Niño , Humanos , SARS-CoV-2 , Estudios Transversales , Estudios Retrospectivos , Inmunoglobulina G , Anticuerpos Antivirales , Glicoproteína de la Espiga del CoronavirusRESUMEN
People with HIV may report neurocognitive complaints, with or without associated neurocognitive impairment, varying between individuals and populations. While the HIV genome could play a major role, large systematic viral genome-wide screens to date are lacking. The Swiss HIV Cohort Study biannually enquires neurocognitive complaints. We quantified broad-sense heritability estimates using partial 'pol' sequences from the Swiss HIV Cohort Study resistance database and performed a viral near full-length genome-wide association study for the longitudinal area under the curve of neurocognitive complaints. We performed all analysis (i) restricted to HIV Subtype B and (ii) including all HIV subtypes. From 8547 people with HIV with neurocognitive complaints, we obtained 6966 partial 'pol' sequences and 2334 near full-length HIV sequences. Broad-sense heritability estimates for presence of memory loss complaints ranged between 1% and 17% (Subtype B restricted 1-22%) and increased with the stringency of the phylogenetic distance thresholds. The genome-wide association study revealed one amino acid (Env L641E), after adjusting for multiple testing, positively associated with memory loss complaints (P = 4.3 * 10-6). Other identified mutations, while insignificant after adjusting for multiple testing, were reported in other smaller studies (Tat T64N, Env *291S). We present the first HIV genome-wide association study analysis of neurocognitive complaints and report a first estimate for the heritability of neurocognitive complaints through HIV. Moreover, we could identify one mutation significantly associated with the presence of memory loss complaints. Our findings indicate that neurocognitive complaints are polygenetic and highlight advantages of a whole genome approach for pathogenicity determination.
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Although sex and gender are recognized as major determinants of health and immunity, their role is rarely considered in clinical practice and public health. We identified six bottlenecks preventing the inclusion of sex and gender considerations from basic science to clinical practice, precision medicine and public health policies. (i) A terminology-related bottleneck, linked to the definitions of sex and gender themselves, and the lack of consensus on how to evaluate gender. (ii) A data-related bottleneck, due to gaps in sex-disaggregated data, data on trans/non-binary people and gender identity. (iii) A translational bottleneck, limited by animal models and the underrepresentation of gender minorities in biomedical studies. (iv) A statistical bottleneck, with inappropriate statistical analyses and results interpretation. (v) An ethical bottleneck posed by the underrepresentation of pregnant people and gender minorities in clinical studies. (vi) A structural bottleneck, as systemic bias and discriminations affect not only academic research but also decision makers. We specify guidelines for researchers, scientific journals, funding agencies and academic institutions to address these bottlenecks. Following such guidelines will support the development of more efficient and equitable care strategies for all.
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Understanding the balance between epitope shielding and accessibility on HIV-1 envelope (Env) trimers is essential to guide immunogen selection for broadly neutralizing antibody (bnAb) based vaccines. To investigate the antigenic space of Env immunogens, we created a strategy based on synthetic, high diversity, Designed Ankyrin Repeat Protein (DARPin) libraries. We show that DARPin Antigenicity Analysis (DANA), a purely in vitro screening tool, has the capability to extrapolate relevant information of antigenic properties of Env immunogens. DANA screens of stabilized, soluble Env trimers revealed that stronger trimer stabilization led to the selection of highly mutated DARPins with length variations and framework mutations mirroring observations made for bnAbs. By mimicking heterotypic prime-boost immunization regimens, DANA may be used to select immunogen combinations that favor the selection of trimer-reactive binders. This positions DANA as a versatile strategy for distilling fundamental antigenic features of immunogens, complementary to preclinical immunogenicity testing.
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Vitamin D promotes a shift from a proinflammatory to a more tolerogenic immune state in allogeneic hematopoietic cell transplant (HCT) recipients. The dominant mechanism responsible for this shift has not been elucidated. We took a multifaceted approach to evaluating the clinical and immunologic impact of low vitamin D levels in 53 HCT recipients. We used 28-plex flow cytometry for immunophenotyping, serum cytokine levels, T-cell cytokine production, and T-cell whole genome transcription. The median day-30 vitamin D level was 20 ng/mL, and deficiency was common in younger patients undergoing myeloablative transplantation. Low vitamin D levels were associated with a high CD8/Treg ratio, increased serum levels and T-cell production of proinflammatory cytokines, and a gene expression signature of unrestrained T-cell proliferation and epigenetic modulation through the PRC2/EZH2 complex. Immunophenotyping confirmed a strong association between high levels of vitamin D and an activated EZH2 signature, characterized by overexpression of ID3, which has a role in effector T-cell differentiation. Our findings demonstrate the critical role of vitamin D in modulating T-cell function in human GVHD and identify a previously undescribed interaction with EZH2 and ID3, which may impact effector differentiation and has implications to cell therapies and other forms of cancer immunotherapy. © 20XX American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Deficiencia de Vitamina D , Proteína Potenciadora del Homólogo Zeste 2/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Proteínas Inhibidoras de la Diferenciación , Proteínas de Neoplasias , Acondicionamiento Pretrasplante , Trasplante HomólogoRESUMEN
We identified determinants of SARS-CoV-2 mRNA vaccine antibody response in people with HIV (PWH). Antibody response was higher among PWH less than 60âyears, with CD4+ cell count superior to 350âcells/µl and vaccinated with mRNA-1273 by Moderna compared with BNT162b2 by Pfizer-BioNTech. Preinfection with SARS-CoV-2 boosted the antibody response and smokers had an overall lower antibody response. Elderly PWH and those with low CD4+ cell count should be prioritized for booster vaccinations.
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COVID-19 , Infecciones por VIH , Anciano , Anticuerpos Antivirales , Formación de Anticuerpos , Vacuna BNT162 , COVID-19/prevención & control , Vacunas contra la COVID-19 , Infecciones por VIH/complicaciones , Humanos , ARN Mensajero , SARS-CoV-2 , Vacunas Sintéticas , Vacunas de ARNmRESUMEN
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.