The mechanisms of postacute medical conditions and unexplained symptoms after SARS-CoV-2 infection [Long Covid (LC)] are incompletely understood. There is growing evidence that viral persistence, immune dysregulation, and T cell dysfunction may play major roles. We performed whole-body positron emission tomography imaging in a well-characterized cohort of 24 participants at time points ranging from 27 to 910 days after acute SARS-CoV-2 infection using the radiopharmaceutical agent [ ¹⁸ F]F-AraG, a selective tracer that allows for anatomical quantitation of activated T lymphocytes. Tracer uptake in the postacute COVID-19 group, which included those with and without continuing symptoms, was higher compared with prepandemic controls in many regions, including the brain stem, spinal cord, bone marrow, nasopharyngeal and hilar lymphoid tissue, cardiopulmonary tissues, and gut wall. T cell activation in the spinal cord and gut wall was associated with the presence of LC symptoms. In addition, tracer uptake in lung tissue was higher in those with persistent pulmonary symptoms specifically. Increased T cell activation in these tissues was also observed in many individuals without LC. Given the high [ ¹⁸ F]F-AraG uptake detected in the gut, we obtained colorectal tissue for in situ hybridization of SARS-CoV-2 RNA and immunohistochemical studies in a subset of five participants with LC symptoms. We identified intracellular SARS-CoV-2 single-stranded spike protein–encoding RNA in rectosigmoid lamina propria tissue in all five participants and double-stranded spike protein–encoding RNA in three participants up to 676 days after initial COVID-19, suggesting that tissue viral persistence could be associated with long-term immunologic perturbations.

Characterizing microorganisms and enzymes involved in lignin biodegradation in thermal ecosystems can identify thermostable biocatalysts. We integrated stable isotope probing (SIP), genome-resolved metagenomics, and enzyme characterization to investigate the degradation of high-molecular weight, ¹³C-ring-labeled synthetic lignin by microbial communities from moderately thermophilic hot spring sediment (52 °C) and a woody “hog fuel” pile (53 and 62 °C zones). ¹³C-Lignin degradation was monitored using IR-GCMS of ¹³CO₂, and isotopic enrichment of DNA was measured with UHLPC-MS/MS. Assembly of 42 metagenomic libraries (72 Gb) yielded 344 contig bins, from which 125 draft genomes were produced. Fourteen genomes were significantly enriched with ¹³C from lignin, including genomes of Actinomycetes (Thermoleophilaceae, Solirubrobacteraceae, Rubrobacter sp.), Firmicutes (Kyrpidia sp., Alicyclobacillus sp.) and Gammaproteobacteria (Steroidobacteraceae). We employed multiple approaches to screen genomes for genes encoding putative ligninases and pathways for aromatic compound degradation. Our analysis identified several novel laccase-like multi-copper oxidase (LMCO) genes in ¹³C-enriched genomes. One of these LMCOs was heterologously expressed and shown to oxidize lignin model compounds and minimally transformed lignin. This study elucidated bacterial lignin depolymerization and mineralization in thermal ecosystems, establishing new possibilities for the efficient valorization of lignin at elevated temperature.

The identification of therapeutic strategies to induce sustained antiretroviral therapy (ART)-free control of HIV infection is a major priority ¹ . Combination immunotherapy including HIV vaccination, immune stimulation, latency reversal and passive transfer of broadly neutralizing antibodies (bNAbs) has shown promise in non-human primate models ^2–6 , but few studies have translated such approaches into people. Here we performed a single-arm, proof-of-concept study in ten people living with HIV on ART, combining the following three approaches: (1) therapeutic vaccination with an HIV Gag conserved element-targeted DNA + IL-12 prime/modified vaccinia Ankara (MVA) boost regimen followed by (2) administration of two bNAbs (10-1074, VRC07-523LS) and a toll-like receptor 9 agonist (lefitolimod) during ART suppression, followed by (3) repeat bNAb administration at the time of ART interruption (Clinicaltrials.gov: NCT04357821 ). Seven out of the ten participants exhibited post-intervention control after pausing ART, independent of residual bNAb plasma levels. Robust expansion of activated CD8 ⁺ T cells early in response to rebounding virus correlated with a lower median viral load after peak viraemia off ART. These data suggest that combination immunotherapy approaches might prove effective in inducing sustained control of HIV by slowing rebound and improving CD8 ⁺ T cell responses, and that these approaches should continue to be optimized.

The identification of therapeutic strategies to induce sustained antiretroviral therapy (ART)-free control of HIV infection is a major priority. Combination immunotherapy including HIV vaccination, immune stimulation/latency reversal, and passive transfer of broadly neutralizing antibodies (bNAbs) has shown promise in non-human primate models, but few studies have translated such approaches into people. Here, we performed a single-arm, proof-of-concept combination study of these three approaches in ten people with HIV on ART that included (1) therapeutic vaccination with an HIV/Gag conserved element (CE)-targeted DNA+IL-12 prime/MVA boost regimen followed by (2) administration of two bNAbs (10-1074 and VRC07-523LS) and a toll-like receptor 9 (TLR9) agonist (lefitolimod) during ART suppression, followed by (3) repeat bNAb administration at the time of ART interruption. Seven of the ten participants exhibited partial (low viral load set point) or complete (aviremic) post-intervention control after stopping ART, independent of residual bNAb plasma levels. Robust expansion of activated CD8+ T cells early in response to rebounding virus correlated with lower viral load set points. These data suggest that combination immunotherapy approaches might prove effective to induce sustained control of HIV by slowing rebound and improving CD8+ T cell responses, and that these approaches should continue to be optimized.

Autoantibodies (autoAbs) neutralizing type I interferons (IFN-I) markedly increase the risk of severe manifestations of some viral diseases. The prevalence of autoAbs neutralizing at least one IFN-I, specifically IFN-α2, IFN-β, and IFN-ω, in individuals from the Swiss human immunodeficiency virus 1 (HIV-1) cohort is largely similar to French age-matched healthy controls, with around 1% in adults by age 65 having neutralizing IFN-I autoAbs and rising thereafter. We analyzed samples from Danish individuals with HIV, including antiretroviral therapy (ART) treated (n = 260) and ART-naive (n = 58) individuals, aged 18–79 (mean age 46.6 years, SD ± 11.1 years), and American individuals with HIV, all of whom were ART-naive (n = 292) aged 20–76 (mean age 41.7 years, SD ± 10.1 years). In the Danish cohort, a total of 2/318 (0.63%) individuals had autoAbs neutralizing 1 ng/ml IFN-ω, whereas 1/318 (0.31%) had autoAbs neutralizing 200 pg/ml IFN-ω. In the American cohort, 2/292 (0.68%) individuals had autoAbs neutralizing IFN-ω at 1 ng/ml. Combining both cohorts, the overall prevalence of autoAbs neutralizing IFN-ω was 5/610 (0.82%). Longitudinal samples were available for two individuals with IFN-ω autoAbs: One displayed persistently detectable autoAbs over time, whereas the other showed a decline in neutralizing activity after 2 years. Two out of five individuals with IFN-I neutralizing autoAbs had a history of IFN-α treatment for chronic hepatitis C virus (HCV) infection. Individuals with IFN-I neutralizing autoAbs shared a history of viral infections, including mucocutaneous herpesvirus infections, zoster, and human papillomavirus disease. Collectively, the prevalence of IFN-I neutralizing autoAbs in people with HIV, whether ART-treated or ART-naive, did not significantly differ from that in the general population. Whereas hepatitis C and IFN therapy may contribute to the development of autoAbs to IFN-I, these autoAbs in turn seem to predispose to mucocutaneous herpesvirus infections and HPV-related neoplasia.