ABSTRACT
Background: Autophagy, a cytosolic-structure degradation pathway, allows production of IL21 by CD4 T-cells and efficient cytolytic responses by CD8 T-cells. Autophagy is in part regulated by acyl-CoA-binding protein (ACBP) which has two functions. Intracellular ACBP favors autophagy, whereas secreted extracellular ACBP inhibits autophagy. Herein, we assessed whether autophagy and the ACBP pathway were associated with COVID-19 severity. Method(s): Through the BQC-19 Quebec biobank, somalogic proteomic analysis was performed on 5200 proteins in plasma samples collected between March 2020 and December 2021. Plasma from 903 patients (all data available) during the acute phase of COVID-19 were assessed. COVID-19 severity was stratified using WHO criteria. In vitro, ACBP intracellular levels, autophagy levels (LC3II) and IL21 production were assessed by flow in PBMCs after a 24h stimulation with IL6, phorbol myristate acetate (PMA)+ionomycin or lipopolysaccharide (LPS). Plasma levels of anti-SARS-CoV-2 (full spike protein or RBD) IgG were assessed by ELISA. Result(s): Median age of the cohort was 62 yo, 48% were female, 55% had comorbidities (see table). Increasing plasma levels of ACBP were found with severity (mild, moderate, severe and fatal groups having 5.3, 7.3, 9.5 and 10.6 RFU/50muL of plasma, respectively, p< 0.001 for all comparisons). Patients with comorbidities had higher plasma ACBP levels (7.4 vs 6.4 RFU/50muL, p< 0.001). Plasma ACBP levels were higher during the delta and omicron-variant periods (8.4 vs 6.8 RFU/50muL;p< 0.001). Plasma ACBP levels correlated with LC3II levels (r=0.51, P< 0.001) and IL6 (r=0.41, p< 0.001), but neither with markers IL1beta nor IL8. ACBP levels negatively correlated with IL21 levels (r=-0.27, p< 0.001), independently of age, sex, and severity. ACBP levels were not associated with levels of anti-SARS-CoV-2 IgG levels. In vitro, IL6 stimulation of healthy control PBMC induced extracellular ACBP release. Moreover, adding recombinant ACBP: 1) reduced autophagy in lymphocytes and monocytes upon polyclonal stimulation with PMA/ionomycin or LPS;2) reduced intracellular production of IL21 in T-cells after PMA/ ionomycin stimulation. Conclusion(s): Plasma ACBP levels were inversely linked with IL21 levels, suggesting that autophagy and IL21 allow control of SARS-CoV-2 infection, independently of the level of SARS-CoV-2 antibody secretion. ACBP is a targetable autophagy checkpoint and its extracellular inhibition may improve SARS-CoV-2 immune control. (Table Presented).
ABSTRACT
Background: Ending the HIV Epidemic by 2030 initiative includes phylogenetics as a molecular framework to track patterns of HIV spread. In this study, phylogenetics was combined with available epidemiological data to elucidate track evolving trends in HIV-1 spread among Men having Sex with Men (MSM) and Heterosexual (HET) populations in Quebec. Methods: Phylogenetic linkage analysis was performed using MEGA-10 and HIV-TRACE/Microbe-TRACE methodologies. New infections genotyped between 2014-2020 were stratified into groups: i) Subtype B MSM (subtype B male singletons/male-male clusters, n=1812);ii) Subtype B Heterosexual (female singletons/female-male clusters, n=432), including migrants from the Caribbean and Americas;and iii) Non-B subtype (n=737) epidemics. Test requisition data and clinical data from Clinique Actuel (n=141 and 50, 2016-2018) monitored epidemiological features in a subset of newly diagnosed persons. Results: Among MSM, annual new infections declined by 20% and 40% over the 2015-2017 and 2018-2020 periods, respectively. Overall, 45% of new infections in MSM were associated with 20 active large clusters, adding 8-96 infections/clusters from 2014-2020. Clinical data showed 37% newly diagnosed MSM were born outside Canada, 28% of whom were linked to large cluster outbreaks. Among heterosexuals with subtype B infections, there was a 31% increase from 2015-2017 followed by a 36% decline from 2018-2020 post-COVID. Of note, large cluster HET outbreaks occurred in Quebec City, Richelieu, and Northern Quebec Overall, non-B subtype infections remained steady (median 100 annually) over the 2014 to 2020 period. Several non-B subtype clusters reflect the domestic introduction and spread of subtype CRF02- AG variants. Cluster membership and cluster size was associated with recent stage infection, viral sequence recency (based on % mixed base calls) and younger age of members within individual clusters. Conclusion: Annual numbers of new HIV-1 infections have steadily declined among MSM post-2008, concomitant to improved HIV prevention paradigms. Epidemic control among MSM and HET groups has been thwarted by large cluster outbreaks. Recent arrivals to Quebec accounted for a growing number of subtype B and non-B subtype infections. HIV prevention efforts must continue in the post-COVID era, tailored to avert transmission cascades in younger persons and recent migrant populations.
ABSTRACT
Background: Dolutegravir/Lamivudine (DTG/3TC) 2-drug regimen (2DR) was non-inferior to a tenofovir alafenamide (TAF)-based 3-/ 4-drug regimen (3/4DR) (TBR) through the Week 48 primary endpoint in TANGO. Here we present prespecified Week 96 secondary analyses from TANGO. Method: TANGO, a randomized, open-label, non-inferiority phase III study, evaluates efficacy and safety of switching to once-daily DTG/3TC in HIV-1- infected, virologically suppressed adults vs remaining on a TBR over 148 weeks. Week 96 analysis assessed non-inferiority with a 4% non-inferiority margin for Snapshot virologic failure (VF) and 8% for virologic success (VS;US Food and Drug Administration Snapshot algorithm, intention-to- treat- exposed [ITT-E] population). Results: 741 participants were randomized/exposed (DTG/3TC: 369;TBR: 372). For Snapshot VF, switching to DTG/3TC was non-inferior to continuing TBR at Week 96 in the ITT-E analysis: 0.3% vs 1.1%;adjusted difference: -0.8% (95% CI: -2.0, 0.4) and superior to TBR in the per-protocol analysis: 0% vs 1.1%;adjusted difference: -1.1% (95% CI: -2.3, -0.0);P = 0.044 (2-sided). Snapshot VS was high in both arms (DTG/3TC: 85.9%;TBR: 79.0%;adjusted difference: 6.8% [95% CI: 1.4-12.3]). Forty-four participants (5.9%) had missing data in the Week 96 window due to COVID-19. No participants on DTG/3TC and 3 (<1%) on TBR met confirmed virologic withdrawal (CVW) criteria, with no resistance observed at failure. Overall adverse event (AE) rates were similar between arms, with more drug-related AEs in the DTG/3TC arm. Total cholesterol (TC), low-density lipoprotein cholesterol, and triglycerides improved significantly with DTG/3TC, whereas high-density lipoprotein (HDL) cholesterol changes significantly favored TBR, with no difference in TC/HDL-cholesterol ratio between arms. Decreases in glomerular filtration rate by cystatin C were observed with significantly lower decreases in the DTG/3TC arm;proximal tubular function marker changes were small and similar across arms. Conclusion: At Week 96, switching to DTG/3TC FDC was non-inferior to continuing a TAF-based 3/4DR in maintaining virologic suppression in HIV-1- infected antiretroviral therapy-experienced adults. The safety profile of DTG/3TC FDC was consistent with the DTG and 3TC respective labels. DTG/3TC 2DR offers a robust switch option with durable efficacy, good safety and tolerability, and a high barrier to resistance with zero CVWs through 96 weeks.