M. Peluso

Multiomic and Spatial Profiling of Colorectal Tissue Reveals Viral Persistence and Immune Dysregulation in Long COVID

CD4 Count and CD4/CD8 Ratio Impact Antibody Responses to COVID-19 mRNA Booster Vaccination in People with HIV on Suppressive ART.

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.

HIV DNA and transcription before and after ART in natural controllers compared to noncontrollers

ABSTRACT HIV-1 natural controllers can limit plasma HIV RNA levels in the absence of antiretroviral therapy (ART). Although controllers have less HIV DNA, it remains unclear how HIV transcription differs from noncontrollers, and whether ART further reduces HIV DNA or RNA in controllers. To address these questions, we quantified different HIV transcripts and HIV DNA regions/proviruses in longitudinal blood samples collected before ART and up to 3–5 years on suppressive ART from 10 controllers (5 “elite” and 5 viremic) and compared them to ART-suppressed noncontrollers. Compared to noncontrollers, controllers exhibited lower levels of most HIV DNA regions (but not intact proviruses) and lower total levels of initiated and completed HIV RNA, but paradoxically higher levels per provirus of initiated and 5′ elongated HIV transcripts. Controllers also showed a lower ratio of completed/elongated HIV RNA. After ART, controllers showed lower levels of multiply spliced HIV RNA and a lower ratio of multiply spliced/completed HIV RNA. These results suggest that natural controllers limit HIV infection frequency and selectively restrict HIV transcript completion and splicing. ART treatment of controllers led to further increases in CD4 counts and decreases in HIV DNA and some HIV transcripts, supporting the potential for clinical benefits in this population. IMPORTANCE Natural HIV controllers can suppress HIV-1 replication without antiretroviral therapy (ART) and serve as a model for an HIV functional cure, but the mechanisms are unclear. We found that natural control was associated with mechanisms that reduce levels of total HIV DNA and the HIV promoter regions to below the levels seen in ART-treated noncontrollers (NC), resulting in lower total levels of most HIV transcripts. When corrected for HIV DNA levels, natural controllers exhibited higher levels per provirus of short, prematurely terminated HIV transcripts but lower proportions of completed and spliced HIV transcripts. These findings suggest that the mechanisms of natural control do not only limit HIV infection frequency, but specifically limit production or increase clearance of infected cells making completed and spliced HIV transcripts. ART treatment of controllers led to further increases in CD4+ T-cell counts and decreases in HIV DNA and RNA, suggesting that ART should be offered to controllers. Natural HIV controllers can suppress HIV-1 replication without antiretroviral therapy (ART) and serve as a model for an HIV functional cure, but the mechanisms are unclear. We found that natural control was associated with mechanisms that reduce levels of total HIV DNA and the HIV promoter regions to below the levels seen in ART-treated noncontrollers (NC), resulting in lower total levels of most HIV transcripts. When corrected for HIV DNA levels, natural controllers exhibited higher levels per provirus of short, prematurely terminated HIV transcripts but lower proportions of completed and spliced HIV transcripts. These findings suggest that the mechanisms of natural control do not only limit HIV infection frequency, but specifically limit production or increase clearance of infected cells making completed and spliced HIV transcripts. ART treatment of controllers led to further increases in CD4+ T-cell counts and decreases in HIV DNA and RNA, suggesting that ART should be offered to controllers.

Nirmatrelvir-ritonavir targeting viral persistence in post-COVID-19 condition (long COVID) in the USA (RECOVER-VITAL): a randomised, double-blind, placebo-controlled, phase 2 trial.

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.