Advances in the Management of Cardiovascular Disease in the Setting of Human Immunodeficiency Virus.

This state-of-the art review discusses the underlying mechanisms that contribute to atherosclerotic cardiovascular disease, heart failure and arrhythmias among people with human immunodeficiency virus (HIV), risk prediction and prevention, management, and outstanding research questions, including a discussion of how the Randomized Trial to Prevent Vascular Events in HIV may inform clinical practice.

HIV-Associated Heart Failure: Phenotypes and Clinical Outcomes in a Safety-Net Setting.

Background: Human immunodeficiency virus (HIV) is associated with increased risk of heart failure (HF) but data regarding phenotypes of heart failure and outcomes after HF diagnosis, especially within the safety-net which is where half of people with HIV in the United States receive care, are less clear. Methods: Using an electronic health record cohort of all individuals with HF within a municipal safety-net system from 2001-2019 linked to the National Death Index Plus, we compared HF phenotypes, all-cause mortality, HF hospitalization, and cause of death for individuals with and without HIV. Results: Among people with HF (n=14,829), 697 individuals had HIV (4.7%). Persons with HIV (PWH) were diagnosed with HF ten years younger on average. A higher proportion of PWH had a reduced ejection fraction at diagnosis (37.9% vs 32.7%). Adjusted for age, sex, and risk factors, coronary artery disease on angiography was similar by HIV status. HIV was associated with 55% higher risk of all-cause mortality (HR 1.55; 95% CI 1.37-1.76; P<0.001) and lower odds of HF hospitalization (OR 0.51; 95% CI 0.39-0.66; P<0.001). Among PWH with HF, cause of death was less often attributed to cardiovascular disease (22.5% vs 54.6% uninfected; P<0.001) and more to substance use (17.9% vs 9.3%; P<0.001), consistent with autopsy findings in a subset (n=81). Conclusions: Among people with HF who receive care within a municipal safety-net system, HIV infection is associated with higher mortality, despite lower odds of HF hospitalization, attributable to non-cardiovascular causes including substance-related and HIV-related mortality.

Association Between Coronary Assessment in Heart Failure and Clinical Outcomes Within a Safety-Net Setting Using a Target Trial Emulation Observational Design.

BACKGROUND: Ischemic cardiomyopathy is the leading cause of heart failure (HF). Most patients do not undergo coronary assessment after HF diagnosis. There are no randomized clinical trials of coronary assessment after HF diagnosis. METHODS: Using an electronic health record cohort of all individuals with HF within the San Francisco Health Network from 2001 to 2019, we identified factors associated with coronary assessment. Then, we studied the association of coronary assessment within 30 days of HF diagnosis with all-cause mortality and a composite of mortality and emergent angiography using a target trial emulation observational comparative-effectiveness approach. Target trial emulation is an approach to causal inference based on creating a hypothetical randomized clinical trial protocol and using observational data to emulate the protocol. We used propensity scores for covariate adjustment. We used national death records to improve the ascertainment of mortality and included falsification end points for the cause of death. RESULTS: Among 14 829 individuals with HF (median, 62 years old; 5855 [40%] women), 3987 (26.9%) ever completed coronary assessment, with 2467/13 301 (18.5%) with unknown coronary artery disease status at HF diagnosis assessed. Women, older individuals, and people without stable housing were less likely to complete coronary assessment. Among 5972 eligible persons of whom 627 underwent early elective coronary assessment, coronary assessment was associated with lower mortality (hazard ratio, 0.84 [95% CI, 0.72-0.97]; P=0.025), reduced risk of the composite outcome (hazard ratio, 0.86 [95% CI, 0.73-1.00]), higher rates of revascularization (odds ratio, 7.6 [95% CI, 5.4-10.6]), and higher use of medical therapy (odds ratio, 2.5 [95% CI, 1.7-3.6]), but not the falsification end points. CONCLUSIONS: In a safety-net population, disparities in coronary assessment after HF diagnosis are not fully explained by coronary artery disease risk factors. Early coronary assessment is associated with improved HF outcomes possibly related to higher rates of revascularization and guideline-directed medical therapy but with low certainty that this finding is not attributable to unmeasured confounding.

Association of nirmatrelvir for acute SARS-CoV-2 infection with subsequent Long COVID symptoms in an observational cohort study.

Oral nirmatrelvir/ritonavir is approved as treatment for acute COVID-19, but the effect of treatment during acute infection on risk of Long COVID is unknown. We hypothesized that nirmatrelvir treatment during acute SARS-CoV-2 infection reduces risk of developing Long COVID and rebound after treatment is associated with Long COVID. We conducted an observational cohort study within the Covid Citizen Science (CCS) study, an online cohort study with over 100 000 participants. We included vaccinated, nonhospitalized, nonpregnant individuals who reported their first SARS-CoV-2 positive test March-August 2022. Oral nirmatrelvir/ritonavir treatment was ascertained during acute SARS-CoV-2 infection. Patient-reported Long COVID symptoms, symptom rebound and test-positivity rebound were asked on subsequent surveys at least 3 months after SARS-CoV-2 infection. A total of 4684 individuals met the eligibility criteria, of whom 988 (21.1%) were treated and 3696 (78.9%) were untreated; 353/988 (35.7%) treated and 1258/3696 (34.0%) untreated responded to the Long COVID survey (n = 1611). Among 1611 participants, median age was 55 years and 66% were female. At 5.4 ± 1.3 months after infection, nirmatrelvir treatment was not associated with subsequent Long COVID symptoms (odds ratio [OR]: 1.15; 95% confidence interval [CI]: 0.80-1.64; p = 0.45). Among 666 treated who answered rebound questions, rebound symptoms or test positivity were not associated with Long COVID symptoms (OR: 1.34; 95% CI: 0.74-2.41; p = 0.33). Within this cohort of vaccinated, nonhospitalized individuals, oral nirmatrelvir treatment during acute SARS-CoV-2 infection and rebound after nirmatrelvir treatment were not associated with Long COVID symptoms more than 90 days after infection.

Brief Report: The Role of Substance Use in Structural Heart Disease Among Women Living With HIV.

BACKGROUND: People living with HIV have increased risk of cardiovascular disease, but few studies focus on women with HIV (WWH) and few account for the use of multiple substances. SETTING: We recruited WWH from San Francisco shelters, free meal programs, street encampments, and a safety net HIV clinic. METHODS: Between 2016 and 2019, participants completed 6 monthly interviews, specimen collection, and a transthoracic echocardiogram. We assessed associations between 3 echocardiographic indices of cardiac hypertrophy (concentric hypertrophy, concentric remodeling, and eccentric hypertrophy) and study factors, including cardiovascular risk factors, substance use, and HIV-specific factors (CD4 + count, viral load, HIV medication). RESULTS: Among 62 participants, the average age was 53 years and 70% were ethnic minority women. Just over 70% had elevated blood pressure. Toxicology-confirmed substance use included tobacco (63%), cannabis (52%), cocaine (51%), methamphetamine (29%), and alcohol (26%). Concentric hypertrophy was detected in 26% of participants. It was positively associated with cocaine use [adjusted relative risk (aRR) = 32.5, P < 0.01] and negatively associated with cannabis use (aRR = 0.07, P < 0.01). Concentric remodeling was detected in 40% of participants. It was positively associated with cocaine use (aRR = 11.2, P < 0.01) and negatively associated with cannabis use (aRR = 0.17, P = 0.02). Eccentric hypertrophy was not significantly associated with factors studied here. CONCLUSIONS: Routine evaluation of stimulant use as a contributing factor to cardiovascular risk may improve risk assessment in WWH. Whether cannabis use mitigates the impact of cocaine use on structural heart disease among WWH merits further investigation.

The breadth of the neutralizing antibody response to original SARS-CoV-2 infection is linked to the presence of Long COVID symptoms.

The associations between longitudinal dynamics and the breadth of SARS-CoV-2 neutralizing antibody (nAb) response with various Long COVID phenotypes before vaccination are not known. The capacity of antibodies to cross-neutralize a variety of viral variants may be associated with ongoing pathology and persistent symptoms. We measured longitudinal neutralizing and cross-neutralizing antibody responses to pre- and post-SARS-CoV-2 Omicron variants in participants infected early in the COVID-19 pandemic, before widespread rollout of SARS-CoV-2 vaccines. Cross-sectional regression models adjusted for clinical covariates and longitudinal mixed-effects models were used to determine the impact of the breadth and rate of decay of neutralizing responses on the development of Long COVID symptoms, as well as Long COVID phenotypes. We identified several novel relationships between SARS-CoV-2 antibody neutralization and the presence of Long COVID symptoms. Specifically, we show that, although nAb responses to the original, infecting strain of SARS-CoV-2 were not associated with Long COVID in cross-sectional analyses, cross-neutralization ID50 levels to the Omicron BA.5 variant approximately 4 months following acute infection was independently and significantly associated with greater odds of Long COVID and with persistent gastrointestinal and neurological symptoms. Longitudinal modeling demonstrated significant associations in the overall levels and rates of decay of neutralization capacity with Long COVID phenotypes. A higher proportion of participants had antibodies capable of neutralizing Omicron BA.5 compared with BA.1 or XBB.1.5 variants. Our findings suggest that relationships between various immune responses and Long COVID are likely complex but may involve the breadth of antibody neutralization responses.

Association of SARS-CoV-2 Infection and Cardiopulmonary Long COVID With Exercise Capacity and Chronotropic Incompetence Among People With HIV.

Background Postacute sequelae of COVID-19 (PASC) and HIV are both associated with reduced exercise capacity, but whether SARS-CoV-2 or PASC are associated with exercise capacity among people with HIV (PWH) is unknown. We hypothesized that PWH with PASC would have reduced exercise capacity from chronotropic incompetence. Methods and Results We conducted cross-sectional cardiopulmonary exercise testing within a COVID recovery cohort that included PWH with and without prior SARS-CoV-2 infection and people without HIV with prior SARS-CoV-2 infection (controls). We evaluated associations of HIV, SARS-CoV-2, and PASC with exercise capacity (peak oxygen consumption) and chronotropy (adjusted heart rate reserve). We included 83 participants (median age, 54 years; 35% women; 37 PWH): 23 out of 37 (62%) PWH and all 46 controls had prior SARS-CoV-2 infection, and 11 out of 23 (48%) PWH and 28 out of 46 (61%) without HIV had PASC. Peak oxygen consumption was reduced among PWH versus controls (80% predicted versus 99%, P=0.005), a difference of 5.5 mL/kg per minute (95% CI, 2.7-8.2; P<0.001). Chronotropic incompetence was more prevalent among PWH (38% versus 11%, P=0.002), with lower adjusted heart rate reserve (60% versus 83%, P<0.0001) versus controls. Among PWH, SARS-CoV-2 coinfection and PASC were not associated with exercise capacity. Chronotropic incompetence was more common among PWH with PASC: 7 out of 11 (64%) with PASC versus 7 out of 26 (27%) without PASC (P=0.04). Conclusions Exercise capacity and chronotropy are lower among PWH compared with individuals with SARS-CoV-2 infection without HIV. Among PWH, SARS-CoV-2 infection and PASC were not strongly associated with reduced exercise capacity. Chronotropic incompetence may be a common underrecognized mechanism of exercise intolerance among PWH, especially those with cardiopulmonary PASC.

Longitudinal outcomes following peripheral vascular intervention among older persons living with HIV.

BACKGROUND: Persons living with human immunodeficiency virus (HIV, PLWH) have an increased risk of peripheral artery disease (PAD) in comparison to the general population. However, a gap remains in understanding optimal management for this condition. This study assesses longitudinal outcomes associated with peripheral endovascular intervention (PVI) for PAD among PLWH. METHODS: All Medicare fee-for-service patients undergoing femoropopliteal artery PVI between April 1, 2015 and December 31, 2018 were identified and stratified by HIV serostatus. The primary outcome was major adverse limb events (MALE), defined as major amputation or arterial embolism/thrombosis following an index procedure. The subdistribution hazard was used to evaluate the association between HIV serostatus and MALE, accounting for the competing risk of death. Results were adjusted for sociodemographics and major comorbidities. RESULTS: Of 168,553 patients who underwent PVI, 357 (0.21%) were PLWH. The average age was 77.0 ± 7.6 years; 80.3% had hypertension, 70.3% had hyperlipidemia, and 24.6% had tobacco use disorder. Compared to those without HIV, PLWH were younger and had a higher burden of cardiovascular risk factors. MALE were substantially more frequent among PLWH, with a cumulative incidence of 24.6%, compared to 14.5% among those without HIV. The adjusted subdistribution hazard ratio was 1.26 (95% CI 1.00-1.58, p = 0.05). The use of guideline-directed statin therapy was low in both groups in the 90 days following revascularization (57.9% in PLWH vs 58.1% in those without HIV, p = 0.95). CONCLUSION: Among US Medicare beneficiaries, PLWH had poorer long-term outcomes following PVI. Greater attention to the management of symptomatic PAD is warranted for the HIV population, particularly following revascularization.

Multimodal Molecular Imaging Reveals Tissue-Based T Cell Activation and Viral RNA Persistence for Up to 2 Years Following COVID-19.

The etiologic mechanisms of post-acute medical morbidities and unexplained symptoms (Long COVID) following SARS-CoV-2 infection are incompletely understood. There is growing evidence that viral persistence and immune dysregulation may play a major role. We performed whole-body positron emission tomography (PET) imaging in a cohort of 24 participants at time points ranging from 27 to 910 days following acute SARS-CoV-2 infection using a novel radiopharmaceutical agent, [18F]F-AraG, a highly selective tracer that allows for anatomical quantitation of activated T lymphocytes. Tracer uptake in the post-acute COVID group, which included those with and without Long COVID symptoms, was significantly higher compared to pre-pandemic controls in many anatomical regions, including the brain stem, spinal cord, bone marrow, nasopharyngeal and hilar lymphoid tissue, cardiopulmonary tissues, and gut wall. Although T cell activation tended to be higher in participants imaged closer to the time of the acute illness, tracer uptake was increased in participants imaged up to 2.5 years following SARS-CoV-2 infection. We observed that T cell activation in spinal cord and gut wall was associated with the presence of Long COVID symptoms. In addition, tracer uptake in lung tissue was higher in those with persistent pulmonary symptoms. Notably, increased T cell activation in these tissues was also observed in many individuals without Long COVID. Given the high [18F]F-AraG uptake detected in the gut, we obtained colorectal tissue for in situ hybridization SARS-CoV-2 RNA and immunohistochemical studies in a subset of participants with Long COVID symptoms. We identified cellular SARS-CoV-2 RNA in rectosigmoid lamina propria tissue in all these participants, ranging from 158 to 676 days following initial COVID-19 illness, suggesting that tissue viral persistence could be associated with long-term immunological perturbations.

Coronary Assessment in Heart Failure within a Safety-Net Setting: Disparities and Outcomes.

Background: Though ischemic cardiomyopathy is the leading cause of heart failure (HF), most patients do not undergo coronary assessment after heart failure diagnosis. In a safety-net population, referral patterns have not been studied, and it is unknown whether coronary assessment is associated with improved HF outcomes. Methods: Using an electronic health record cohort of all individuals with HF within San Francisco Health Network from 2001-2019, we identified factors associated with completion of coronary assessment (invasive coronary angiography, nuclear stress, or coronary computed tomographic angiography). Then we emulated a randomized clinical trial of elective coronary assessment with outcomes of all-cause mortality and a composite outcome of mortality and emergent angiography. We used propensity scores to account for differences between groups. We used national death records to improve ascertainment of mortality. Results: Among 14,829 individuals with HF (median 62 years old, 5,855 [40%] women), 3,987 (26.9%) ever completed coronary assessment, with 2,467 (18.5%) assessed out of 13,301 with unknown CAD status at HF diagnosis. Women and older individuals were less likely to complete coronary assessment, with differences by race/ethnicity, medical history, substance use, housing, and echocardiographic findings. Among 5,972 eligible for inclusion in the "target trial," 627 underwent early elective coronary assessment and 5,345 did not. Coronary assessment was associated with lower mortality (HR 0.84; 95% CI 0.72-0.97; p=0.025), reduced risk of the composite outcome, higher rates of revascularization, and higher use of medical therapy. Conclusions: In a safety-net population, disparities in coronary assessment after HF diagnosis are not fully explained by CAD risk factors. Our target trial emulation suggests coronary assessment is associated with improved HF outcomes possibly related to higher rates of revascularization and GDMT use, but with low certainty that this is finding is not attributable to unmeasured confounding.

Cardiovascular health among persons with HIV without existing atherosclerotic cardiovascular disease.

OBJECTIVES: We sought to characterize atherosclerotic cardiovascular disease (ASCVD) risk and metrics of cardiovascular health in persons with HIV (PWH) eligible for primary prevention of ASCVD. DESIGN: A cross-sectional study of PWH 40 years and older without documented ASCVD who received care at three HIV clinics in San Francisco from 2019 to 2022. METHODS: We used ICD-10 codes and electronic health record data to assess ASCVD risk and cardiovascular health, as defined by the American Heart Association's Life's Essential 8 (LE8) metrics for nicotine exposure, BMI, lipids, glucose, and blood pressure (BP). RESULTS: Among 2567 PWH eligible for primary prevention of ASCVD, the median age was 55 years, 14% were women, and 95% were on antiretroviral therapy. Seventy-seven percent had undergone complete assessment of ASCVD risk factors, and 50% of these patients had intermediate-high ASCVD risk (≥7.5%). Of those with hypertension, 39% were prescribed an antihypertensive. Among those eligible, 43% were prescribed a statin. The mean LE8 cardiovascular health score [0--100 (best health)] was 55.1 for nicotine exposure, 71.3 for BMI, 70.4 for lipids, 81.2 for blood glucose, 56.0 for BP, with an average score of 66.2 across the five metrics. Patients with Medicare insurance, black patients, and those with sleep apnea and chronic kidney disease had on average lower cardiovascular health scores; patients with undetectable viral loads had higher cardiovascular health scores. CONCLUSION: We highlight opportunities for improving primary prevention of ASCVD among PWH, especially in the areas of guideline-based therapy, nicotine exposure, and BP control.

Autoantigen profiling reveals a shared post-COVID signature in fully recovered and long COVID patients.

Some individuals do not return to baseline health following SARS-CoV-2 infection, leading to a condition known as long COVID. The underlying pathophysiology of long COVID remains unknown. Given that autoantibodies have been found to play a role in severity of SARS-CoV-2 infection and certain other post-COVID sequelae, their potential role in long COVID is important to investigate. Here, we apply a well-established, unbiased, proteome-wide autoantibody detection technology (T7 phage-display assay with immunoprecipitation and next-generation sequencing, PhIP-Seq) to a robustly phenotyped cohort of 121 individuals with long COVID, 64 individuals with prior COVID-19 who reported full recovery, and 57 pre-COVID controls. While a distinct autoreactive signature was detected that separated individuals with prior SARS-CoV-2 infection from those never exposed to SARS-CoV-2, we did not detect patterns of autoreactivity that separated individuals with long COVID from individuals fully recovered from COVID-19. These data suggest that there are robust alterations in autoreactive antibody profiles due to infection; however, no association of autoreactive antibodies and long COVID was apparent by this assay.

Psychological stress is associated with arterial inflammation in people living with treated HIV infection.

Stress and depression are increasingly recognized as cerebrovascular risk factors, including among high stress populations such as people living with HIV infection (PLWH). Stress may contribute to stroke risk through activation of neural inflammatory pathways. In this cross-sectional study, we examined the relationships between stress, systemic and arterial inflammation, and metabolic activity in stress-related brain regions on 18F-fluorodeoxyglucose (FDG)-PET in PLWH. Participants were recruited from a parent trial evaluating the impact of alirocumab on radiologic markers of cardiovascular risk in people with treated HIV infection. We administered a stress battery to assess different forms of psychological stress, specifying the Perceived Stress Scale as the primary stress measure, and quantified plasma markers of inflammation and immune activation. Participants underwent FDG-PET of the brain, neck, and chest. Age- and sex-matched control participants without HIV infection were selected for brain FDG-PET comparisons. Among PLWH, we used nonparametric pairwise correlations, partial correlations, and linear regression to investigate the association between stress and 1) systemic inflammation; 2) atherosclerotic inflammation on FDG-PET; and metabolic activity in 3) brain regions in which glucose metabolism differed significantly by HIV serostatus; and 4) in a priori defined stress-responsive regions of interest (ROI) and stress-related neural network activity (i.e., ratio of amygdala to ventromedial prefrontal cortex or temporal lobe activity). We studied 37 PLWH (mean age 60 years, 97% men) and 29 control participants without HIV (mean age 62 years, 97% men). Among PLWH, stress was significantly correlated with systemic inflammation (r = 0.33, p = 0.041) and arterial inflammation in the carotid (r = 0.41, p = 0.023) independent of age, race/ethnicity, traditional vascular risk factors and health-related behaviors. In voxel-wise analyses, metabolic activity in a cluster corresponding to the anterior medial temporal lobes, including the bilateral amygdalae, was significantly lower in PLWH compared with controls. However, we did not find a significant positive relationship between stress and this cluster of decreased metabolic activity in PLWH, a priori defined stress-responsive ROI, or stress-related neural network activity. In conclusion, psychological stress was associated with systemic and carotid arterial inflammation in this group of PLWH with treated infection. These data provide preliminary evidence for a link between psychological stress, inflammation, and atherosclerosis as potential drivers of excess cerebrovascular risk among PLWH.

Association of SARS-CoV-2 Infection and Cardiopulmonary Long COVID with Exercise Capacity and Chronotropic Incompetence among People with HIV.

Background: Long COVID has been associated with reduced exercise capacity, but whether SARS-CoV-2 infection or Long COVID is associated with reduced exercise capacity among people with HIV (PWH) has not been reported. We hypothesized that PWH with cardiopulmonary post-acute symptoms of COVID-19 (PASC) would have reduced exercise capacity due to chronotropic incompetence. Methods: We conducted cross-sectional cardiopulmonary exercise testing within a COVID recovery cohort that included PWH. We evaluated associations of HIV, prior SARS-CoV-2 infection, and cardiopulmonary PASC with exercise capacity (peak oxygen consumption, VO 2 ) and adjusted heart rate reserve (AHRR, chronotropic measure) with adjustment for age, sex, and body mass index. Results: We included 83 participants (median age 54, 35% female). All 37 PWH were virally suppressed; 23 (62%) had prior SARS-CoV-2 infection, and 11 (30%) had PASC. Peak VO 2 was reduced among PWH (80% predicted vs 99%; p=0.005), a difference of 5.5 ml/kg/min (95%CI 2.7-8.2, p<0.001). Chronotropic incompetence more prevalent among PWH (38% vs 11%; p=0.002), and AHRR was reduced among PWH (60% vs 83%, p<0.0001). Among PWH, exercise capacity did not vary by SARS-CoV-2 coinfection, but chronotropic incompetence was more common among PWH with PASC: 3/14 (21%) without SARS-CoV-2, 4/12 (25%) with SARS-CoV-2 without PASC, and 7/11 (64%) with PASC (p=0.04 PASC vs no PASC). Conclusions: Exercise capacity and chronotropy are lower among PWH compared to SARS-CoV-2 infected individuals without HIV. Among PWH, SARS-CoV-2 infection and PASC were not strongly associated with reduced exercise capacity. Chronotropic incompetence may be a mechanism limiting exercise capacity among PWH.

Reduced Exercise Capacity, Chronotropic Incompetence, and Early Systemic Inflammation in Cardiopulmonary Phenotype Long Coronavirus Disease 2019.

BACKGROUND: Mechanisms underlying persistent cardiopulmonary symptoms after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (postacute sequelae of coronavirus disease 2019 [COVID-19; PASC] or "long COVID") remain unclear. This study sought to elucidate mechanisms of cardiopulmonary symptoms and reduced exercise capacity. METHODS: We conducted cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring among adults >1 year after SARS-CoV-2 infection, compared those with and those without symptoms, and correlated findings with previously measured biomarkers. RESULTS: Sixty participants (median age, 53 years; 42% female; 87% nonhospitalized; median 17.6 months after infection) were studied. At CPET, 18/37 (49%) with symptoms had reduced exercise capacity (<85% predicted), compared with 3/19 (16%) without symptoms (P = .02). The adjusted peak oxygen consumption (VO2) was 5.2 mL/kg/min lower (95% confidence interval, 2.1-8.3; P = .001) or 16.9% lower percent predicted (4.3%-29.6%; P = .02) among those with symptoms. Chronotropic incompetence was common. Inflammatory markers and antibody levels early in PASC were negatively correlated with peak VO2. Late-gadolinium enhancement on CMR and arrhythmias were absent. CONCLUSIONS: Cardiopulmonary symptoms >1 year after COVID-19 were associated with reduced exercise capacity, which was associated with earlier inflammatory markers. Chronotropic incompetence may explain exercise intolerance among some with "long COVID."

The Breadth of the Neutralizing Antibody Response to Original SARS-CoV-2 Infection is Linked to the Presence of Long COVID Symptoms.

Background: The associations between longitudinal dynamics and the breadth of SARS-CoV-2 neutralizing antibody response with various Long COVID (LC) phenotypes prior to vaccination are not known. The capacity of antibodies to cross neutralize a variety of viral variants may be associated with ongoing pathology and persistent symptoms. Methods: We measured longitudinal neutralizing and cross-neutralizing antibody responses to pre- and post-SARS-CoV-2 Omicron variants in participants infected during the early waves of the COVID-19 pandemic, prior to wide-spread rollout of SARS-CoV-2 vaccines. Cross sectional regression models adjusted for various clinical covariates and longitudinal mixed effects models were used to determine the impact of the breadth and rate of decay of neutralizing responses on the development of Long COVID symptoms in general, as well as LC phenotypes. Results: We identified several novel relationships between SARS-CoV-2 antibody neutralization and the presence of LC symptoms. Specifically, we show that, although neutralizing antibody responses to the original, infecting strain of SARS-CoV-2 were not associated with LC in cross-sectional analyses, cross-neutralization ID50 levels to the Omicron BA.5 variant approximately 4 months following acute infection was independently and significantly associated with greater odds of LC and with persistent gastrointestinal and neurological symptoms. Longitudinal modeling demonstrated significant associations in the overall levels and rates of decay of neutralization capacity with LC phenotypes. A higher proportion of participants had antibodies capable of neutralizing Omicron BA.5 compared with BA.1 or XBB.1.5 variants. Conclusions: Our findings suggest that relationships between various immune responses and LC are likely complex but may involve the breadth of antibody neutralization responses.

Effect of Immune-Modulatory Interventions on Asymptomatic Cytomegalovirus Shedding During Suppressive Antiretroviral Therapy.

Long-term consequences of human immunodeficiency virus (HIV) are likely the result of persistent inflammation and immune dysfunction of which cytomegalovirus (CMV) is a known contributor. We leveraged 2 AIDS Clinical Trials Group clinical trials exploring the effects of immune modulators (ruxolitinib and sirolimus) on inflammation in people with HIV on antiretroviral therapy to determine whether these interventions affected CMV shedding at various mucosal sites. Analyzing 635 mucosal samples collected, we found no significant difference in CMV levels across study arms or time points. Men had more CMV shedding than women. We did confirm an association between higher CMV DNA and immune markers associated with HIV persistence and HIV-associated mortality rates.

Autoantigen profiling reveals a shared post-COVID signature in fully recovered and Long COVID patients.

Some individuals do not return to baseline health following SARS-CoV-2 infection, leading to a condition known as Long COVID. The underlying pathophysiology of Long COVID remains unknown. Given that autoantibodies have been found to play a role in severity of COVID infection and certain other post-COVID sequelae, their potential role in Long COVID is important to investigate. Here we apply a well-established, unbiased, proteome-wide autoantibody detection technology (PhIP-Seq) to a robustly phenotyped cohort of 121 individuals with Long COVID, 64 individuals with prior COVID-19 who reported full recovery, and 57 pre-COVID controls. While a distinct autoreactive signature was detected which separates individuals with prior COVID infection from those never exposed to COVID, we did not detect patterns of autoreactivity that separate individuals with Long COVID relative to individuals fully recovered from SARS-CoV-2 infection. These data suggest that there are robust alterations in autoreactive antibody profiles due to infection; however, no association of autoreactive antibodies and Long COVID was apparent by this assay.