Peter W. Hunt

Persistence of SARS-CoV-2 has been proposed as a biological driver of Long COVID, a disabling chronic illness with no proven treatments. We conducted an exploratory, placebo-controlled, double-blind, 2:1 randomized mechanistic trial (NCT05877508) of the SARS-CoV-2-specific monoclonal antibody AER002 in 36 participants who met the World Health Organization case definition of Long COVID. After baseline characterization, participants received a single infusion and were followed for 360 days. The primary endpoint was the PROMIS-29 Physical Health Summary Score (PHSS) at 90 days; secondary and exploratory endpoints included patient-reported and objective measures of physical and neurocognitive function as well as blood-, imaging-, and tissue-based biomarkers. While AER002 was safe and well tolerated, no significant differences in physical health, quality of life, objective measures of physical function or cognition, or blood-based biomarkers were demonstrated between the treatment and control arms. In a post-hoc analysis, participants with a lower baseline SARS-CoV-2 antibody level and higher drug exposure were more likely to perceive treatment benefit based on the Patient Global Impression of Change scale ( p < 0.05 for anti-S, S1, and RBD). Although AER002 was not efficacious in this proof-of-concept study, our findings could inform future trials using monoclonal antibodies to target viral persistence in Long COVID.

Objective: To evaluate the durability of SARS-CoV-2–specific humoral and cellular immune responses after booster vaccination in people living with HIV (PLWH) in a prospective longitudinal cohort study. Methods: We analyzed 46 PLWH with no prior history of SARS-CoV-2 infection who received a booster dose. Anti-receptor-binding domain (RBD) IgG concentrations, neutralization titers, and T cell responses were measured over time. The associations between CD4+ T cell count and CD4/CD8 ratio with antibody dynamics were assessed, adjusting for age, sex, and vaccine type. Results: Anti-RBD IgG and neutralization titers declined significantly over time. Participants with CD4+ T cell counts <500 cells/μL exhibited a 3-fold faster decline in anti-RBD IgG compared to those with ≥500 cells/μL. Neutralization capacity declined similarly across both groups, suggesting that CD4+ T cell count primarily influences antibody quantity rather than functional quality. A lower CD4/CD8 ratio was independently associated with reduced baseline IgG concentrations but did not influence the rate of antibody decay. In a subset of 30 participants, a lower CD4/CD8 ratio was also associated with altered follicular helper (Tfh) CD4+ T cell frequencies and faster decline of Spike-specific Tfh over time. Conclusions: CD4+ T cell count influences antibody persistence, while the CD4/CD8 ratio affects initial antibody magnitude and Tfh cell frequencies, highlighting complementary roles in shaping vaccine responses in PLWH.

BACKGROUND. Despite antiretroviral therapy (ART), people with HIV (PWH) are at heightened risk for insulin resistance (IR) and type 2 diabetes (T2D). Subcutaneous adipose tissue (SAT) fibrosis contributes to metabolic disease, but its role in IR among PWH is unknown. We investigated the relationship between SAT fibrosis and IR in PWH, along with transcriptional signatures to distinguish it from SAT fibrosis due to obesity. METHODS. We analyzed body composition and SAT fibrosis (hydroxyproline) in 46 PWH and 74 people without HIV (PWoH), excluding individuals with T2D. We examined fibrosis-related gene transcription in the SAT using a targeted panel and measured plasma endotrophin, a marker of extracellular matrix (ECM) remodeling. RESULTS. PWH had substantially more SAT fibrosis than PWoH, notably in non-obese individuals. Moreover, SAT fibrosis in these PWH was strongly associated with IR, independently of prior legacy ART or ongoing integrase strand inhibitor treatment. This SAT fibrosis was highlighted by a distinct transcriptional pattern marked by upregulation of COL14A1 , key immune-related genes (e.g., CCL4 , NLRP3 ), and pathways governing ECM remodeling and immune activation, as well as downregulation of thermogenic, lipid metabolic, and insulin signaling pathways. Plasma endotrophin levels were also elevated in PWH and correlated independently with SAT fibrosis. CONCLUSION. SAT fibrosis was associated with IR independent of obesity in PWH and was mirrored by circulating endotrophin levels, offering a plausible noninvasive biomarker for early intervention. The distinct transcriptional signature of HIV-associated SAT fibrosis highlights candidate mechanisms that may underlie metabolic risk and offer therapeutic avenues in this population.

People with HIV (PWH) are at an increased risk of venous thromboembolism (VTE), and cannabis use is common in this population. However, evidence of cannabis impact on VTE risk has been conflicting and not well evaluated in PWH. Using data from five Centers for AIDS Research Network of Integrated Clinical Systems sites (2009–2020), we assessed the association between cannabis use and VTE risk. Among 13,646 PWH, 30% reported current cannabis use. In adjusted Cox models, neither former (adjusted hazard ratio [aHR] 0.78, 95% confidence interval (CI) 0.57–1.07) nor current (aHR 0.74, 95% CI 0.51–1.06) cannabis use showed a significant increase in VTE incidence compared with never use. Additionally, no dose-dependent relationship was observed between cannabis use frequency and VTE. Among PWH, cannabis use does not appear to be associated with an elevated risk of VTE. Further research is needed to elucidate the relationship between cannabis and VTE risk in this population.

People with HIV (PWH) receiving suppressive antiretroviral therapy (ART) remain at increased risk of severe non-AIDS events (SNAEs) and premature death, but the biological mechanisms that precede these outcomes remain poorly defined. We performed a nested case-control study within CoRIS, a nationwide prospective cohort of 17,906 ART-naive PWH, to identify inflammatory and transcriptional signatures associated with subsequent SNAEs and mortality during suppressive ART. Plasma obtained two years after ART initiation from 187 participants (92 cases and 95 matched controls) underwent high-dimensional proteomic profiling of 326 inflammation-related proteins and RNA sequencing of paired peripheral blood mononuclear cells (PBMCs). Proteomic screening identified 33 differentially expressed proteins in participants who later developed SNAEs, with marked heterogeneity across clinical phenotypes. By contrast, transcriptomic analyses showed consistent enrichment of type I interferon-stimulated genes among individuals who subsequently developed SNAEs or died during follow-up. Among circulating proteins, galectin-9 (LGALS9) showed the most consistent association with adverse outcomes. Orthogonal measurement by ELISA confirmed the reproducibility of LGALS9, whereas other candidates showed weaker or context-dependent associations. We then sought external validation in CNICS using a case-cohort study of ART-suppressed PWH across eight US sites, in which 922 participants with available plasma were randomly sampled from 9,430 eligible individuals and followed longitudinally for non-accidental mortality; 103 deaths occurred over a median follow-up of 9 years. In this independent cohort, higher LGALS9 plasma levels showed a clear graded association with shorter time to death. These findings identify galectin-9 and interferon-linked immune activation as reproducible features of the inflammatory milieu that precedes major non-AIDS outcomes in treated HIV, and support LGALS9 as a prognostic biomarker for risk stratification and outcome-focused validation.

BACKGROUND: Among antiretroviral therapy–suppressed (ART-suppressed) people with HIV (PWH), women have higher levels of some inflammatory markers than men, but the effect of sex on the inflammatory proteome, and whether age modifies these differences, remain unclear. METHODS: Plasma inflammatory protein levels were assessed in ART-suppressed PWH from the Center for AIDS Research Network of Integrated Clinical Systems. The relationship between sex and plasma proteins — including 22 interferon-α response pathway proteins — was assessed, adjusting for confounders and assessing interactions by age. RESULTS: Of 922 participants, 162 (18%) were female. The median age was 47, above which the majority of women had undetectable plasma anti-Müllerian hormone levels, a biomarker of ovarian reserve. Age modified the influence of sex on the inflammatory proteome. Older age (>47) was associated with greater increases among women than men in 194 proteins. Interferon-α response proteins were higher in men in those ≤ 47 but higher in women in those > 47 (interaction P < 0.001). Among the 131 proteins associated with mortality risk ( q < 0.05), only 5 differed by sex among those ≤ 47, while 79 differed by sex in those > 47, with nearly all being higher in women. Women had decreased mortality than men ≤ 47 ( P < 0.001) but had similar mortality > 47 ( P = 0.84). CONCLUSION: The menopausal transition appears to increase systemic type I interferon responses and inflammation in women with HIV, which may contribute to a loss of female advantage in mortality. FUNDING: NIH National Heart, Lung, and Blood Institute; National Institute of Neurological Disorders and Stroke; National Institute of Allergy and Infectious Diseases.

Background: Neurocognitive impairment (NCI) among people living with human immunodeficiency virus (HIV; PWH) on antiretroviral therapy (ART) may result from residual viral replication. The A5324 trial found that ART intensification with dolutegravir (DTG) with or without maraviroc (MVC) did not affect NCI in PWH. We evaluated the impact of ART intensification on peripheral virological measures during the first 12 weeks of intensification. Methods: The A5324 study was a randomized, double-blind, placebo (PBO)–controlled, 96-week trial of ART intensification with either dual PBO, DTG + PBO, or DTG + MVC in PWH with NCI on ART who were naive to integrase strand transfer inhibitors and MVC. At baseline and weeks 2, 4, and 12, HIV-1 RNA was measured in plasma with a low-copy assay, while HIV-1 cell-associated DNA (caDNA), cell-associated unspliced RNA (caRNA), and cell-associated 2-long terminal repeat circles (ca2LTR) were quantified from peripheral blood mononuclear cells using droplet digital polymerase chain reaction. Results: Of the 171 participants, 59 were randomized to dual PBO, 57 to DTG + PBO, and 55 to DTG + MVC. Changes in caDNA and caRNA and detection of plasma RNA did not differ between treatment arms over 12 weeks (P > 0.05). Detection of ca2LTR was less frequent at weeks 2–4 in the DTG + MVC arm (40.4%) than in the dual-PBO (70.7%; P =0 .02) and DTG + PBO (68.4%; P = 0.03) arms. However, this difference diminished by week 12, and baseline ca2LTR detection in the DTG + MVC arm was lower than in the other groups. Conclusions: DTG intensification had no effect on peripheral markers of HIV-1 persistence. DTG + MVC intensification reduced ca2LTR detection at weeks 2–4, though this effect did not persist through week 12. These findings indicate the minimal impact of intensification on the HIV-1 peripheral reservoir, consistent with prior studies.

Introduction: Since its global reemergence in 2022, monkeypox (mpox) has demonstrated increased incidence and severity among people with human immunodeficiency virus (HIV [PWH]). Predictors of mpox diagnosis, vaccination, and outcomes among PWH are limited. Methods: We included PWH with primary care visits after 1 January 2022 at 9 US sites participating in the Centers for AIDS Research Network of Integrated Clinic Systems Network. We identified mpox diagnosed between 1 June 2022 and 31 May 2023, through a combination of polymerase chain reaction result, diagnosis code, and/or tecovirimat receipt. We examined validated clinical diagnoses, laboratory results, vaccine data, and patient reported outcomes. We evaluated relative risks (RR) of mpox diagnosis, hospitalization, tecovirimat treatment, and vaccine receipt. Findings: Among 19 777 PWH in care, 413 mpox cases (all male sex at birth) occurred (2.2 cases/100 person-years). Age <40 years, geographic region, Hispanic/Latine ethnicity, lack of antiretroviral therapy, detectable HIV viral load, and recent bacterial sexually transmitted infection predicted mpox diagnosis. PWH with CD4 200–349 cells/mm3 were most likely to be hospitalized (adjusted RR, 3.20; 95% confidence interval: 1.44–7.09) compared to CD4 ≥500, but half as likely as those with CD4 <200 to receive tecovirimat. Overall, smallpox/mpox vaccine effectiveness of ≥1 vaccine was 71% (adjusted RR, 0.29; 95% confidence interval: .14–.47) at preventing mpox, and 86% or better with CD4 ≥350 or HIV viral suppression. Non-Hispanic Black PWH were less likely to be vaccinated than other racial/ethnic identities. Interpretation: PWH not on antiretroviral therapy or with unsuppressed HIV were more likely to be diagnosed with, and hospitalized for, mpox. Mpox/smallpox vaccine effectiveness was high, inclusive of those with low CD4 count and HIV viremia.