People with HIV (PWH) are 2-4x more likely to develop long COVID than people without HIV (PWOH), potentially due to the heightened immune activation and inflammation typical of chronic HIV despite effective antiretroviral therapy. We evaluated how long COVID symptoms in PWH compare to PWOH, and whether the shifts in monocyte and T cell populations seen in PWH are exacerbated in long COVID.Cohort DemographicsLC, long COVID; INSTI, integrase strand transfer inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. Mann-Whitney U test or Fisher exact test performed for statistical analysis.Long COVID symptom clusters are impacted by HIV and Obesity statusObesity defined as a BMI ≥ 30. Symptom clusters were determined via hierarchical clustering methods in R. Correlation values only shown if p ≤ 0.0001. We captured demographic and medical data who enrolled in our local prospective COVID-19 cohort. Participants completed a symptom survey (average 890 days [range 606-1174] after their first reported COVID-19 infection). Participants were grouped by HIV diagnosis prior to a COVID-19 infection as PWH (n=75) or PWOH (n=198). We performed flow cytometric analyses on peripheral blood mononuclear cells from PWH with (n=19) and without (n=23) long COVID and PWOH with (n=55) and without (n=66) long COVID. Cells were stained for surface markers of activation/exhaustion and monocyte subsets.Peripheral immune responses are driven by HIV, not long COVID.R - Recovered from acute COVID-19. LC - severe long COVID (> 5 symptoms). HIV(-) - People without HIV. HIV(+) - people with HIV. Differences in T cell marker expression and monocyte subset frequencies were analyzed via Kruskal-Wallis with post-hoc Dunn's. PWH reported higher frequencies of ENT symptoms as compared to PWOH (50% vs 34%). PWOH with obesity (BMI ≥ 30) reported higher frequencies of post-exertional malaise (78% vs 22%) and cardiovascular symptoms (68% vs 47%) compared to non-obese PWOH. Further, PWOH with obesity were more likely to have severe long COVID ( > 5 symptoms) (72% vs 38%). Notably, this BMI effect was not observed in PWH. Heatmaps were generated to further evaluate the impact of HIV and obesity status on symptom clustering. Correlative data among those with obesity suggests less heterogeneity in long COVID clinical presentations in PWH than PWOH (10 vs 33 highly correlated symptoms). Despite observing HIV- and obesity-related shifts in symptoms, peripheral immune responses differed by HIV-status alone. Our findings demonstrate that although peripheral immune response differences were HIV-specific, long COVID clinical manifestations differed by both HIV and obesity status. These insights suggest potential differences in the underlying pathogenesis of long COVID, which should be taken into the account when considering potential treatments for patients with inflammatory phenotypes of long COVID and other post-viral syndromes. All Authors: No reported disclosures

BACKGROUND:Post-acute sequelae of SARS-CoV-2 infection, more commonly known as long COVID, has emerged as a major health problem. The pathogenesis of long COVID is unknown, but among the leading hypotheses is viral persistence. We aimed to investigate whether the use of the SARS-CoV-2 antiviral nirmatrelvir-ritonavir improved long COVID symptoms. METHODS:We conducted a double-blind, placebo-controlled, randomised trial involving adults who had developed persistent symptoms (≥12 weeks) associated with three major symptom phenotypes (cognitive, autonomic, or exercise) after acute SARS-CoV-2 infection at 69 US sites. Participants were eligible if they were 18 years or older and had a previous suspected, probable, or confirmed SARS-CoV-2 infection, as defined by the Pan American Health Organization. Eligible participants were also required to have either at least two moderate symptoms from the same phenotype or one severe phenotype-associated symptom, as identified with the Cluster Targeted COVID-19 Symptom Questions. Participants were randomly allocated in a double-blind manner in a 1:1:1 ratio using permuted blocks of size 30 to receive either 15 days of active intervention followed by 10 days of placebo (300 mg nirmatrelvir-100 mg ritonavir twice daily, then 100 mg ritonavir-placebo); 25 days of active intervention (300 mg nirmatrelvir-100 mg ritonavir twice daily); or 25 days of placebo-ritonavir (100 mg ritonavir-placebo). A clinically significant change in patient-reported outcomes at day 90 comprised the primary endpoint: Patient-Reported Outcomes Measurement Information System Cognitive Function Short Form 8a, Orthostatic Hypotension Questionnaire question 1, and a modified version of the DePaul Symptom Questionnaire Post-Exertional Malaise short form. Secondary outcomes were phenotype-specific performance measures. The study was registered at ClinicalTrials.gov (NCT05595369) and is complete. FINDINGS:Between July 27, 2023, and Sept 6, 2024, 1207 individuals were screened. Of these, 964 were randomly allocated and 959 participants, excluding four participants who were later found ineligible and one who did not initiate treatment, were enrolled in the three phenotypes: 332 to cognitive, 334 to autonomic, and 332 to exercise. In the 959 participants in the mITT population, 643 (67%) self-reported as female, 314 (33%) were male, and two participants had a sex of unknown or undifferentiated; 750 (78%) were White; and 108 (11%) were Hispanic, Latino, or Spanish. The median age was 49 years (IQR 38-59). No statistically significant benefits were observed for any phenotype for primary endpoints. For the cognitive phenotype, adjusted differences compared to placebo were 3·2% (95% CI -10·4 to 16·8, p=0·65) for the 25-day regimen and -2·2% (-15·5 to 11·1, p=0·74) for the 15-day regimen. For the autonomic phenotype, adjusted differences were -6·4% (-18·5 to 5·7, p=0·30) for the 25-day regimen compared to placebo and -0·1% (-12·5 to 12·3, p=0·99) for the 15-day regimen compared to placebo. For exercise, adjusted differences were -7·8% (-19·5 to 3·8, p=0·19) for the 25-day regimen compared to placebo and 0·9% (-11·4 to 13·2, p=0·88) for the 15-day regimen compared to placebo. There were no differences in secondary endpoints, and no safety signals were observed; there were no deaths, and 52 serious adverse events occurred in 42 (4%) of 963 participants over the course of the study. INTERPRETATION:Nirmatrelvir-ritonavir for 15 days or 25 days showed no evidence of benefit in long COVID in any of the three phenotypes studied. These findings suggest additional approaches to measuring the symptom burden and treating Long COVID are needed. FUNDING:National Institutes of Health.

We aimed to test associations of participant-reported Long COVID symptom interference with life activities with Long COVID symptoms, presence of U09.9 Long COVID diagnosis code, demographics, and clinical factors. In a subgroup, we documented coding related to Long COVID and post-exertional malaise in the electronic medical record (EMR). Using a cross-sectional analysis (n = 205) of participant data from a Long COVID survey, we tested associations with Chi-square, Fisher’s exact, or Fisher-Freeman-Halton exact statistical tests and Independent Samples T-tests. Participants were predominately female (67

OBJECTIVE:To evaluate whether there is an association between a maternal classification of Long COVID and adverse pregnancy outcomes. METHODS:RECOVER (Researching COVID to Enhance Recovery)-Adult is a multicenter prospective longitudinal cohort study of adults with and without prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection enrolled from October 2021 to January 2024. This analysis included participants with a SARS-CoV-2 infection and at least one symptom survey for classification of Long COVID status recorded before or during pregnancy. Participants were classified as either likely having Long COVID (LCRI [Long COVID Research Index] score of 11 or higher) or as having Long COVID-indeterminate (LCRI score 0-10), with comparisons made between groups. The primary outcome was preterm birth before 37 weeks of gestation. Secondary outcomes included hypertensive disorders of pregnancy, cesarean delivery, neonatal intensive care admission, and small-for-gestational-age birth weight (below the 10th percentile). Propensity score methods with full matching were used to balance differences in baseline characteristics in estimating an average treatment effect, with a sensitivity analysis estimating the average treatment effect among the treated. RESULTS:Among 603 participants, 118 (19.6%) were classified as likely having Long COVID before or during pregnancy. Participants classified as likely having Long COVID were more likely to have specific adverse social determinants of health (difficulty covering expenses and paying bills, food insecurity, missed care because of cost, medical discrimination) and had higher prepregnancy body mass index (BMI) than those who were classified as having Long COVID-indeterminate. In the primary average treatment effect analysis, there was no association between likely Long COVID and preterm delivery (adjusted outcome rate 8.1% exposed vs 9.6% unexposed, absolute risk reduction [ARR] 0.82, 95% CI, 0.36-1.90) or secondary outcomes. In average treatment effect among the treated sensitivity analyses, likely Long COVID was similarly not associated with preterm delivery (ARR 1.11, 95% CI, 0.60-2.06) but was associated with an increased risk of hypertensive disorders of pregnancy (adjusted outcome rate 39.0% exposed vs 25.9% unexposed, ARR 1.51, 95% CI, 1.12-2.03) but not with other secondary outcomes. CONCLUSION:A classification of likely Long COVID was not significantly associated with preterm birth or several other adverse pregnancy outcomes. However, the association with hypertensive disorders of pregnancy in the average treatment effect among the treated analysis highlights the need for further research.

Abstract Introduction Long COVID is a chronic disease with potentially debilitating symptoms that affects millions of patients worldwide. Affected individuals often suffer from chronic inflammation and metabolic dysfunction, which may drive the chronic fatigue and brain fog characteristic of long COVID. Given the severity of symptoms and the high number of affected patients, understanding the causes and risk factors of this condition is crucial. Obesity is a known comorbidity for long COVID and drives immune and metabolic dysregulation. Thus, we hypothesized that obesity would exacerbate the underlying processes that contribute to long COVID. Methods To address this hypothesis, we performed multi-omic analyses on a cohort of patients with and without long COVID (LC+/-. These patients were then analyzed across BMI ranges (20-62). We performed serum proteomics and metabolomics. scRNAseq was also performed to determine the transcriptional profile of PBMCs and immune cells derived from subcutaneous adipose tissue in these patients. Results Our analysis revealed elevated levels of pro-inflammatory molecules in the serum of LC+ individuals. Furthermore, we observed enrichment of inflammatory gene signatures in a subset of PBMCs in LC+ patients and evidence of metabolic dysfunction. We next examined the adipose-residing immune cells where we observed widespread enrichment of inflammatory and anti-viral signatures in the LC+ individuals. Of note, the enrichment and breadth of these signatures correlated with patient BMI, as LC+ patients with higher BMIs appeared to have more widespread anti-viral signatures and metabolic dysfunction. Conclusion Taken together our data indicate that obesity exacerbates the immune and metabolic dysfunction that are hallmarks of long COVID. Given that patients with obesity have greater adiposity these data suggest that targeting adiposity may be an effective strategy in treatment of long COVID. Indeed, preliminary data suggests that GLP-1 agonists can provide relief for long COVID patients. Funding Source NIH RECOVER initiative Topic Categories Computational and Systems Immunology (COMP)

Broadly neutralizing antibodies (bnAbs) that target the HIV gp41 membrane-proximal external region (MPER) have some of the highest neutralization breadth. An MPER peptide-liposome vaccine has been found to expand MPER bnAb precursors in monkeys. The HVTN133 phase 1 clinical trial (NCT03934541) studied the MPER peptide-liposome immunogen in 24 HIV-1 seronegative individuals. Participants were randomized in a dose-escalation design to either 500 mcg or 2000 mcg of the MPER-peptide liposome or placebo. Four intramuscular injections were planned at months 0, 2, 6, and 12. The trial was stopped prematurely due to an anaphylaxis reaction in one participant attributed to vaccine-associated polyethylene glycol. The immunogen induced MPER-specific serum antibodies and CD4+ T-cell responses in 95% and 85% of vaccinees, respectively, and 35% of vaccine recipients had circulating IgG+ memory B cells with an MPER-bnAb binding phenotype. Affinity purification of plasma MPER-specific IgG demonstrated tier 2 HIV-1 neutralizing activity in two of five participants after 3 immunizations and tier 2 HIV-1 neutralizing B cell clonal lineages were isolated from MPER-reactive B cells. These results demonstrate that the HIV gp41 MPER region is a promising target for induction of heterologous neutralizing antibodies by a candidate HIV vaccine. Trial Registration:http://www.clinicaltrials.gov/ Identifier: NCT03934541.

Streptococcus pneumoniae (Spn) is the leading cause of community-acquired pneumonia (CAP). A quarter of hospitalized patients with CAP experience a major adverse cardiac event (MACE), raising their mortality by four to five times compared with pneumonia alone. Patients with CAP continue to face a significantly greater risk of MACE and cardiovascular-associated death during convalescence. However, the reasons responsible for this remain unclear. To elucidate the molecular mechanism(s) of Spn-induced MACE in convalescence, a mouse model of Spn infection and antibiotic rescue was employed. A marked decline in ejection fraction persisting at least 3 weeks after bacterial eradication with antibiotics was observed. Evidence of enduring cardiac injury was observed at the molecular, biochemical and histology levels. Blood analysis from patients with invasive pneumococcal disease confirmed unresolved inflammation in these individuals. Here we mechanistically identified that S100A8/A9-TLR4-NLRP3-mediated unresolved inflammation drives cardiac pathologies in Spn convalescent mice. This inflammation was central to the cardiac pathology because interventions with broad-spectrum immunosuppressive hydrocortisone or specific inhibitors of S100A9 (paquinimod) essentially rescued the Spn-induced cardiac pathologies. These results provide critical preclinical data and rationale for a clinical investigation into immunosuppressive interventions for managing Spn-mediated cardiac pathologies in convalescence. Hospitalization for community-acquired pneumonia (CAP) can lead to serious heart problems, even after recovery. Researchers explored why this happens. They studied both humans and mice to understand the link between pneumonia and heart problems. The study involved 10 healthy adults and 7 pneumonia patients. Researchers collected blood samples to analyze immune responses. They also used mice to study heart changes after pneumonia. The focus was on inflammation and its role in heart damage. Findings showed that inflammation persists even after the infection clears, leading to heart issues. The study identified a specific inflammatory pathway (S100A8/A9-TLR4-NLRP3) as a key player in this process. The researchers concluded that targeting this inflammation could help prevent heart problems after pneumonia. Future treatments might focus on reducing inflammation to protect the heart in pneumonia survivors.

BACKGROUND:This study evaluated the impact of aging on the frequency and prevalent symptoms of Long COVID, also termed post-acute sequelae of SARS-CoV-2, using a previously developed Long COVID research index (LCRI) of 41 self-reported symptoms in which those with 12 or more points were classified as likely to have Long COVID. METHODS:We analyzed community-dwelling participants ≥ 60 years old (2662 with prior infection, 461 controls) compared to participants 18-59 years (7549 infected, 728 controls) in the Researching COVID to Enhance Recovery adult (RECOVER-Adult) cohort ≥ 135 days post-onset. RESULTS:Compared to the Age 18-39 group, the adjusted odds of LCRI ≥ 12 were higher for the Age 40-49 group (odds ratio [OR] = 1.40, 95% confidence intervals [CI] = 1.21-1.61, p < 0.001) and 50-59 group (OR = 1.31, CI = 1.14-1.51, p < 0.001), similar for the Age 60-69 group (OR = 1.09, CI = 0.93-1.27, p = 0.299), and lower for the ≥ 70 group (OR = 0.68, CI = 0.54-0.85, p < 0.001). Participants ≥ 70 years had smaller adjusted differences between infected and uninfected symptom prevalence rates than those aged 18-39 for the following symptoms: hearing loss, fatigue, pain (including joint, back, chest pain and headache), post-exertional malaise, sleep disturbance, hair loss, palpitations, and sexual desire/capacity, making these symptoms less discriminating for Long COVID in older adults than in younger. Symptom clustering, as described in Thaweethai et al. (JAMA 2023) also exhibited age-related shifts: clusters 1 (anosmia and ageusia) and 2 (gastrointestinal, chronic cough and palpitations, without anosmia, ageusia or brain fog) were more likely, and clusters 3 (brain fog, but no loss of smell or taste) and 4 (a mix of symptoms) less likely to be found in older adults (relative risk ratios for clusters 3-4 ranging from 0.10-0.34, p < 0.001 vs. 18-39 year-olds). CONCLUSIONS:Within the limits of this observational study, we conclude that in community-dwelling older adults, aging alters the prevalence and pattern of reported Long COVID.

Host metabolic dysregulation, especially in tryptophan metabolism, is intricately linked to coronavirus disease 2019 (COVID-19) severity and its postacute sequelae (long COVID). People living with human immunodeficiency virus (HIV; PLWH) experience similar metabolic dysregulation and face an increased risk of developing long COVID. However, whether preexisting HIV-associated metabolic dysregulations contribute in predisposing PLWH to severe COVID-19 outcomes remains underexplored. Analyzing prepandemic samples from PLWH with documented postinfection outcomes, we found specific metabolic alterations, including increased tryptophan catabolism, predicting an elevated risk of severe COVID-19 and the incidence of long COVID. These alterations warrant further investigation for their potential prognostic and mechanistic significance in determining COVID-19 complications. Prepandemic metabolic dysregulation, particularly in tryptophan metabolism, in people living with HIV (PLWH) predicts postpandemic coronavirus disease 2019 (COVID-19) severity and long COVID incidence. These metabolic alterations warrant further investigation for their prognostic and mechanistic significance in determining COVID-19 complications.

BACKGROUND:There are currently no validated clinical biomarkers of postacute sequelae of SARS-CoV-2 infection (PASC). OBJECTIVE:To investigate clinical laboratory markers of SARS-CoV-2 and PASC. DESIGN:Propensity score-weighted linear regression models were fitted to evaluate differences in mean laboratory measures by prior infection and PASC index (≥12 vs. 0). (ClinicalTrials.gov: NCT05172024). SETTING:83 enrolling sites. PARTICIPANTS:RECOVER-Adult cohort participants with or without SARS-CoV-2 infection with a study visit and laboratory measures 6 months after the index date (or at enrollment if >6 months after the index date). Participants were excluded if the 6-month visit occurred within 30 days of reinfection. MEASUREMENTS:Participants completed questionnaires and standard clinical laboratory tests. RESULTS:Among 10 094 participants, 8746 had prior SARS-CoV-2 infection, 1348 were uninfected, 1880 had a PASC index of 12 or higher, and 3351 had a PASC index of zero. After propensity score adjustment, participants with prior infection had a lower mean platelet count (265.9 × 109 cells/L [95% CI, 264.5 to 267.4 × 109 cells/L]) than participants without known prior infection (275.2 × 109 cells/L [CI, 268.5 to 282.0 × 109 cells/L]), as well as higher mean hemoglobin A1c (HbA1c) level (5.58% [CI, 5.56% to 5.60%] vs. 5.46% [CI, 5.40% to 5.51%]) and urinary albumin-creatinine ratio (81.9 mg/g [CI, 67.5 to 96.2 mg/g] vs. 43.0 mg/g [CI, 25.4 to 60.6 mg/g]), although differences were of modest clinical significance. The difference in HbA1c levels was attenuated after participants with preexisting diabetes were excluded. Among participants with prior infection, no meaningful differences in mean laboratory values were found between those with a PASC index of 12 or higher and those with a PASC index of zero. LIMITATION:Whether differences in laboratory markers represent consequences of or risk factors for SARS-CoV-2 infection could not be determined. CONCLUSION:Overall, no evidence was found that any of the 25 routine clinical laboratory values assessed in this study could serve as a clinically useful biomarker of PASC. PRIMARY FUNDING SOURCE:National Institutes of Health.

We performed a secondary analysis of the National Institutes of Health-sponsored Adaptive COVID-19 Treatment Trial (ACTT-2) randomized controlled trial and found that baricitinib was associated with a 50% reduction in secondary infections after controlling for baseline and postrandomization patient characteristics. This finding provides a novel mechanism of benefit for baricitinib and supports the safety profile of this immunomodulator for the treatment of coronavirus disease 2019.

In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered the global coronavirus disease 2019 (COVID-19) pandemic. Although most infections cause a self-limited syndrome comparable to other upper respiratory viral pathogens, a portion of individuals develop severe illness leading to substantial morbidity and mortality. Furthermore, an estimated 10%–20% of SARS-CoV-2 infections are followed by post-acute sequelae of COVID-19 (PASC), or long COVID. Long COVID is associated with a wide variety of clinical manifestations including cardiopulmonary complications, persistent fatigue, and neurocognitive dysfunction. Severe acute COVID-19 is associated with hyperactivation and increased inflammation, which may be an underlying cause of long COVID in a subset of individuals. However, the immunologic mechanisms driving long COVID development are still under investigation. Early in the pandemic, our group and others observed immune dysregulation persisted into convalescence after acute COVID-19. We subsequently observed persistent immune dysregulation in a cohort of individuals experiencing long COVID. We demonstrated increased SARS-CoV-2-specific CD4 + and CD8 + T-cell responses and antibody affinity in patients experiencing long COVID symptoms. These data suggest a portion of long COVID symptoms may be due to chronic immune activation and the presence of persistent SARS-CoV-2 antigen. This review summarizes the COVID-19 literature to date detailing acute COVID-19 and convalescence and how these observations relate to the development of long COVID. In addition, we discuss recent findings in support of persistent antigen and the evidence that this phenomenon contributes to local and systemic inflammation and the heterogeneous nature of clinical manifestations seen in long COVID.

OBJECTIVES/GOALS: Despite highly effective antiretroviral therapy, people living with HIV (PLWH) experience chronic immune activation and inflammation which may influence the progression of infections such as SARS-CoV-2. Here, we explore the immune response and clinical outcomes in HIV(+) and HIV(-) individuals experiencing acute COVID-19 and long COVID (LC). METHODS/STUDY POPULATION: We performed flow cytometric analyses on peripheral blood mononuclear cells from the following: 1) HIV(-) individuals experiencing acute COVID-19, 2) PLWH experiencing acute COVID-19, and 3) pre-COVID-19 pandemic PLWH. Additionally, we will perform similar analyses for the following: 1) PLWH experiencing LC, 2) PLWH previously infected with SARS-CoV-2 who recovered, 3) pre-COVID-19 pandemic PLWH, and 4) HIV(-) individuals experiencing LC. Flow cytometry panels include surface markers for immune cell populations, activation and exhaustion surface markers (with and without SARS-CoV-2-specific antigen stimulation), and intracellular cytokine staining. We will also analyze how chronic HIV infection and other clinical and demographic factors (e.g., age, CD4 %) impact persistent symptomatic burden. RESULTS/ANTICIPATED RESULTS: Acute COVID-19 results–Overall, PLWH had higher baseline expression of activation markers OX40 and CD137 on CD4+ and CD8+ T cells, along with increased levels of TNFa producing CD8+ T cells. Interestingly, PLWH had increased expression of exhaustion markers PD1 and TIGIT but decreased expression of TIM3 on CD4+ and CD8+ T cells. Additionally, PLWH had decreased levels of IL-2 and IFNg producing CD4+ T cells which suggests functional exhaustion. Long COVID-19 expected results–we hypothesize that the activation and inflammation seen in chronic HIV infection will lead to more immune dysregulation and subsequently worsened symptomatic burden. Additionally, we hypothesize that PLWH may have different frequencies of certain LC manifestations, such as increased rates of neurocognitive impairment. DISCUSSION/SIGNIFICANCE: Our findings suggest that chronic HIV infection influences acute immune response during SARS-CoV-2 infection, and that PLWH have variable expression of exhaustion markers which warrants further study. Additionally, our findings in the LC cohort will aid in characterizing clinical manifestations and immunologic mechanisms of LC in PLWH.

Background:Post-COVID conditions are characterised by persistent symptoms that negatively impact quality of life after SARS-CoV-2 diagnosis. While post-COVID risk factors and symptoms have been extensively described in localised regions, especially in the global north, post-COVID conditions remain poorly understood globally. The global, observational cohort study HVTN 405/HPTN 1901 characterises the convalescent course of SARS-CoV-2 infection among adults in North and South America and Africa.Methods:We categorised the cohort by infection severity (asymptomatic, symptomatic, no oxygen requirement (NOR), non-invasive oxygen requirement (NIOR), invasive oxygen requirement (IOR)). We applied a regression model to assess correlations of demographics, co-morbidities, disease severity, and concomitant medications with COVID-19 symptom persistence and duration across global regions.Results:We enrolled 759 participants from Botswana, Malawi, South Africa, Zambia, Zimbabwe, Peru, and the USA a median of 51 (interquartile range (IQR) = 35-66) days post-diagnosis, from May 2020 to March 2021. 53.8% were female, 69.8% were 18-55 years old (median (md) = 44 years old, IQR = 33-58). Comorbidities included obesity (42.8%), hypertension (24%), diabetes (14%), human immunodeficiency virus (HIV) infection (11.6%) and lung disease (7.5%). 76.2% were symptomatic (NOR = 47.4%; NIOR = 22.9%; IOR = 5.8%). Median COVID-19 duration among symptomatic participants was 20 days (IQR = 11-35); 43.4% reported symptoms after COVID-19 resolution, 33.6% reported symptoms ≥30 days, 9.9% reported symptoms ≥60 days. Symptom duration correlated with disease severity (P < 0.001, NIOR vs NOR; P = 0.003, IOR vs NOR), lung disease (P = 0.001), race (P < 0.05, non-Hispanic Black vs White), and global region (P < 0.001). Prolonged viral shedding correlated with persistent abdominal pain (odds ratio (OR) = 5.51, P < 0.05) and persistent diarrhoea (OR = 6.64, P < 0.01).Conclusions:Post-COVID duration varied with infection severity, race, lung disease, and region. Better understanding post-COVID conditions, including regionally-diverse symptom profiles, may improve clinical assessment and management globally.Registration:Clinicaltrials.gov (#NCT04403880).

We recently reported that in humans the tetraspanin CD151 marks phenotypically distinct T cell subsets. The frequency of CD151+ T cells differs between T cell lineages and in between memory T cell populations. CD151+ T cells are hyper-proliferative and hyper-activated, as shown by phospho-proteomic analysis. We found that CD151 is an activation marker that is upregulated following TCR/CD3 activation, but at baseline, the presence of CD151 was associated with the loss of CD28 expression, a sign of T cell senescence. We hypothesized that the presence of CD151+ T cells is associated with immune hyperactivation and in extension, impaired immune surveillance. Unfortunately, we found that not even basic human CD151 T cell biology is reproduced in mouse models and thus had to resort to the study of pathological human conditions to elucidate the role(s) of CD151+ T cells. As cancer development requires immune escape, cancer diagnosis could be used as an indicator of impaired immune surveillance. Benefitting from the availability of longitudinal patient sample and data collections from people living with HIV (PLWH) we found that PLWH that developed cancer all had CD8+CD151+ T cell frequencies outside a normal reference range. CD8+CD151+ T cell frequency increase was not cancer-specific and could be detected years before the cancer diagnosis (0.5–12 years), indicating that the increase was not part of an anti-tumor response. Other established immune markers showed no correlation with the development of cancer. The findings associate elevated CD8+CD151+ T cell frequencies with impaired immune surveillance and suggest that elevated CD8+CD151+ T cell frequencies, at least in PLWH can be used as prognostic marker for cancer development. Supported by grants from NIH R01-AI122842, NIH R33-AI116188, NIH R33-AI133679

The chr12q24.13 locus encoding OAS1–OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European ( n = 2,249) and African ( n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454 -A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.

Despite decades of research, an effective HIV-1 vaccine remains elusive. Vaccine strategies leading to the generation of broadly neutralizing antibodies are likely needed to provide the best opportunity of generating a protective immune response against HIV-1.

A subset of COVID-19 patients exhibit post-acute sequelae of COVID-19 (PASC), but little is known about the immune signatures associated with these syndromes. We investigated longitudinal peripheral blood samples in 50 individuals with previously confirmed SARS-CoV-2 infection, including 20 who experienced prolonged duration of COVID-19 symptoms (lasting more than 30 days; median = 74 days) compared with 30 who had symptom resolution within 20 days. Individuals with prolonged symptom duration maintained antigen-specific T cell response magnitudes to SARS-CoV-2 spike protein in CD4(+) and circulating T follicular helper cell populations during late convalescence, while those without persistent symptoms demonstrated an expected decline. The prolonged group also displayed increased IgG avidity to SARS-CoV-2 spike protein. Significant correlations between symptom duration and both SARS-CoV-2-specific T cells and antibodies were observed. Activation and exhaustion markers were evaluated in multiple immune cell types, revealing few phenotypic differences between prolonged and recovered groups, suggesting that prolonged symptom duration is not due to persistent systemic inflammation. These findings demonstrate that SARS-CoV-2-specific immune responses are maintained in patients suffering from prolonged post-COVID-19 symptom duration in contrast to those with resolved symptoms and may suggest the persistence of viral antigens as an underlying etiology.

ABSTRACTGenomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76OAS1variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay ofOAS1. We suggest that genetically-regulated loss ofOAS1expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of theOAS1risk haplotypes.