Plasma Human Immunodeficiency Virus 1 Soluble Glycoprotein 120 Association With Correlates of Immune Dysfunction and Inflammation in Antiretroviral Therapy-Treated Individuals With Undetectable Viremia.

BACKGROUND: Chronic inflammation persists in some people living with human immunodeficiency virus (HIV) during antiretroviral therapy and is associated with premature aging. The glycoprotein 120 (gp120) subunit of HIV-1 envelope sheds and can be detected in plasma, showing immunomodulatory properties even in the absence of detectable viremia. We evaluated whether plasma soluble gp120 (sgp120) and a family of gp120-specific anti-cluster A antibodies, linked to CD4 depletion in vitro, contribute to chronic inflammation, immune dysfunction, and subclinical cardiovascular disease in participants of the Canadian HIV and Aging Cohort Study with undetectable viremia. METHODS: Cross-sectional assessment of sgp120 and anti-cluster A antibodies was performed in 386 individuals from the cohort. Their association with proinflammatory cytokines and subclinical coronary artery disease was assessed using linear regression models. RESULTS: High levels of sgp120 and anti-cluster A antibodies were inversely correlated with CD4+ T cell count and CD4/CD8 ratio. The presence of sgp120 was associated with increased levels of interleukin 6. In participants with detectable atherosclerotic plaque and detectable sgp120, anti-cluster A antibodies and their combination with sgp120 levels correlated positively with the total volume of atherosclerotic plaques. CONCLUSIONS: This study showed that sgp120 may act as a pan toxin causing immune dysfunction and sustained inflammation in a subset of people living with HIV, contributing to the development of premature comorbid conditions.

Plasmatic HIV-1 soluble gp120 is associated with immune dysfunction and inflammation in ART-treated individuals with undetectable viremia.

Background: Chronic inflammation persists in some people living with HIV (PLWH), even during antiretroviral therapy (ART) and is associated with premature aging. The gp120 subunit of the HIV-1 envelope glycoprotein can shed from viral and cellular membranes and can be detected in plasma and tissues, showing immunomodulatory properties even in the absence of detectable viremia. We evaluated whether plasmatic soluble gp120 (sgp120) and a family of gp120-specific anti-cluster A antibodies, which were previously linked to CD4 depletion in vitro , could contribute to chronic inflammation, immune dysfunction, and sub-clinical cardiovascular disease in participants of the Canadian HIV and Aging cohort (CHACS) with undetectable viremia. Methods: Cross-sectional assessment of plasmatic sgp120 and anti-cluster A antibodies was performed in 386 individuals from CHACS. Their association with pro-inflammatory cytokines, as well as subclinical coronary artery disease measured by computed tomography coronary angiography was assessed using linear regression models. Results: In individuals with high levels of sgp120, anti-cluster A antibodies inversely correlated with CD4 count (p=0.042) and CD4:CD8 ratio (p=0.004). The presence of sgp120 was associated with increased plasma levels of IL-6. In participants with detectable atherosclerotic plaque and detectable sgp120, sgp120 levels, anti-cluster A antibodies and their combination correlated positively with the total volume of atherosclerotic plaques (p=0.01, 0.018 and 0.006, respectively). Conclusion: Soluble gp120 may act as a pan toxin causing immune dysfunction and sustained inflammation in a subset of PLWH, contributing to the development of premature comorbidities. Whether drugs targeting sgp120 could mitigate HIV-associated comorbidities in PLWH with suppressed viremia warrants further studies. Key points: Soluble gp120 is detected in the plasma of people living with HIV-1 with undetectable viremia. The presence of soluble gp120 and anti-cluster A antibodies is associated with immune dysfunction, chronic inflammation, and sub-clinical cardiovascular disease.

The Frequency and Function of NKG2C+CD57+ Adaptive NK Cells in Cytomagalovirus Co-Infected People Living with HIV Decline with Duration of Antiretroviral Therapy.

Human cytomegalovirus (CMV) infection drives the expansion and differentiation of natural killer (NK) cells with adaptive-like features. We investigated whether age and time on antiretroviral therapy (ART) influenced adaptive NK cell frequency and functionality. Flow cytometry was used to evaluate the frequency of adaptive and conventional NK cells in 229 CMV+ individuals of whom 170 were people living with HIV (PLWH). The frequency of these NK cell populations producing CD107a, CCL4, IFN-γ or TNF-α was determined following a 6-h antibody dependent (AD) stimulation. Though ART duration and age were correlated, longer time on ART was associated with a reduced frequency of adaptive NK cells. In general, the frequency and functionality of NK cells following AD stimulation did not differ significantly between treated CMV+PLWH and CMV+HIV- persons, suggesting that HIV infection, per se, did not compromise AD NK cell function. AD activation of adaptive NK cells from CMV+PLWH induced lower frequencies of IFN-γ or TNF-α secreting cells in older persons, when compared with younger persons.

Integrated immunovirological profiling validates plasma SARS-CoV-2 RNA as an early predictor of COVID-19 mortality.

Despite advances in COVID-19 management, identifying patients evolving toward death remains challenging. To identify early predictors of mortality within 60 days of symptom onset (DSO), we performed immunovirological assessments on plasma from 279 individuals. On samples collected at DSO11 in a discovery cohort, high severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA (vRNA), low receptor binding domain­specific immunoglobulin G and antibody-dependent cellular cytotoxicity, and elevated cytokines and tissue injury markers were strongly associated with mortality, including in patients on mechanical ventilation. A three-variable model of vRNA, with predefined adjustment by age and sex, robustly identified patients with fatal outcome (adjusted hazard ratio for log-transformed vRNA = 3.5). This model remained robust in independent validation and confirmation cohorts. Since plasma vRNA's predictive accuracy was maintained at earlier time points, its quantitation can help us understand disease heterogeneity and identify patients who may benefit from new therapies.

Use of HIV pre-exposure prophylaxis among urban Canadian gay, bisexual and other men who have sex with men: a cross-sectional analysis of the Engage cohort study.

BACKGROUND: In Canada, gay, bisexual and other men who have sex with men (GBM) are disproportionately affected by HIV. Our objective was to describe access to HIV pre-exposure prophylaxis (PrEP) and identify factors associated with not using PrEP among self-reported HIV-negative or HIV-unknown GBM. METHODS: This was a cross-sectional analysis of the Engage study cohort. Between 2017 and 2019, sexually active GBM aged 16 years or more in Montréal, Toronto and Vancouver were recruited via respondent-driven sampling (RDS). Participation included testing for HIV and sexually transmitted and blood-borne infections, and completion of a questionnaire. We examined PrEP access using a health care services model and fit RDS-adjusted logistic regressions to determine correlates of not using PrEP among those for whom PrEP was clinically recommended and who were aware of the intervention. RESULTS: A total of 2449 GBM were recruited, of whom 2008 were HIV-negative or HIV-unknown; 1159 (511 in Montréal, 247 in Toronto and 401 in Vancouver) met clinical recommendations for PrEP. Of the 1159, 1100 were aware of PrEP (RDS-adjusted proportion: Montréal 84.6%, Toronto 94.2%, Vancouver 92.7%), 678 had felt the need for PrEP in the previous 6 months (RDS-adjusted proportion: Montréal 39.2%, Toronto 56.1%, Vancouver 49.0%), 406 had tried to access PrEP in the previous 6 months (RDS-adjusted proportion: Montréal 20.6%, Toronto 33.2%, Vancouver 29.6%) and 319 had used PrEP in the previous 6 months (RDS-adjusted proportion: Montréal 14.5%, Toronto 21.6%, Vancouver 21.8%). Not using PrEP was associated with several factors, including not feeling at high enough risk, viewing PrEP as not completely effective, not having a primary care provider and lacking medication insurance. INTERPRETATION: Although half of GBM met clinical recommendations for PrEP, less than a quarter of them reported use. Despite high levels of awareness, a programmatic response that addresses PrEP-related perceptions and health care system barriers is needed to scale up PrEP access among GBM in Canada.

Community-Based Prevalence Estimates of Chlamydia trachomatis and Neisseria gonorrhoeae Infections Among Gay, Bisexual, and Other Men Who Have Sex With Men in Montréal, Canada.

BACKGROUND: Reported cases of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections are increasing among Canadian men. Estimates of community-based CT/NG prevalence are lacking among gay, bisexual, and other men who have sex with men (GBM). METHODS: Respondent driven sampling was used to recruit GBM in Montréal, Canada between February 2017 and June 2018. Specimens provided from urogenital, rectal, and pharyngeal sites were analyzed using nucleic acid amplification test to detect CT/NG. Prevalence estimates of CT/NG, overall and by anatomical site were calculated. All estimates are respondent-driven sampling-adjusted. RESULTS: Among 1177 GBM, the prevalence of rectal, urogenital, pharyngeal and overall were respectively 2.4%, 0.4%, 0.4%, and 2.8% for CT infections, and 3.1%, 0.4%, 3.5%, and 5.6% for NG infections. If testing had been limited to the urogenital site, 80% and 94% of CT and NG infections, respectively, would have been missed. CONCLUSIONS: This community-based study among GBM shows that the CT prevalence was about half of that observed for NG. A large part of CT/NG infections involves only the extragenital sites, highlighting the need for systematic multisite screening regardless of symptoms. In the mist of the COVID-19 pandemic and the limited CT/NG screening capacity due to test kits shortage, it might be considered to prioritize rectal and pharyngeal CT/NG testing over urogenital testing in asymptomatic GBM.

Combination HIV Prevention Strategies Among Montreal Gay, Bisexual, and Other Men Who Have Sex with Men in the PrEP Era: A Latent Class Analysis.

Pre-exposure prophylaxis (PrEP) became publicly available in Quebec for gay, bisexual and other men who have sex with men (GBM) in 2013. We used baseline data from Engage, a cohort of GBM recruited by respondent-driven sampling, to examine patterns of combination HIV prevention use among Montreal GBM since PrEP became available. Latent class analysis, stratified by HIV status, was used to categorize GBM by self-reported use of biomedical and behavioural prevention strategies. Correlates of resulting classes were identified using multinomial logistic regression. Among HIV-negative/unknown GBM (n = 968), we identified four classes: low use of prevention (32%), condoms (40%), seroadaptive behaviour (21%), and biomedical (including PrEP; 7%). Those using prevention (condoms, seroadaptive behaviour, and biomedical) had a higher number of anal sex partners and were more likely to report a recent sexually transmitted infection diagnosis. GBM using biomedical prevention also had a higher level of formal education. Among GBM living with HIV (n = 200), we identified three classes: mainly antiretroviral treatment (ART) with viral suppression (53%), ART with viral suppression and condoms (19%), and ART with viral suppression and seroadaptive behaviour (18%). Again, the number of anal sex partners was higher among those using condoms and seroadaptive behaviours. Our findings show antiretroviral-based prevention, either alone or in combination with other strategies, is clearly a component of the HIV prevention landscape for GBM in Montreal. Nevertheless, PrEP uptake remains low, and there is a need to promote its availability more widely.

Population-Level Sexual Mixing According to HIV Status and Preexposure Prophylaxis Use Among Men Who Have Sex With Men in Montreal, Canada: Implications for HIV Prevention.

Using cross-sectional survey data (Engage, 2017-2018) from 1,137 men who have sex with men, ≥16 years old, in Montreal, we compared observed human immunodeficiency virus (HIV) seroconcordance in previous-6-months' sexual partnerships with what would have been observed by chance if zero individuals serosorted. Of 5 recent partnerships where both individuals were HIV-negative, we compared observed concordance in preexposure prophylaxis (PrEP) use with the counterfactual if zero individuals selected partners based on PrEP use. We estimated the concordance by chance using a balancing-partnerships approach assuming proportionate mixing. HIV-positive respondents had a higher proportion of HIV-positive partners (66.4%, 95% confidence interval (CI): 64.0, 68.6) than by chance (23.9%, 95% CI: 23.1, 24.7). HIV-negative respondents (both on and not on PrEP) had higher proportions of HIV-negative partners (82.9% (95% CI: 81.1, 84.7) and 90.7% (95% CI: 89.6, 91.7), respectively) compared with by chance (76.1%, 95% CI: 75.3, 76.9); however, those on PrEP had a higher proportion of HIV-positive partners than those not on PrEP (17.1% (95% CI: 15.3, 18.9) vs. 9.3% (95% CI: 8.3, 10.4). Those on PrEP also had a higher proportion of partners on PrEP among their HIV-negative partners (50.6%, 95% CI: 42.5, 58.8) than by chance (28.5%, 95% CI: 27.5, 29.4). The relationship between PrEP and sexual-mixing patterns demonstrated by less population-level serosorting among those on PrEP and PrEP-matching warrants consideration during PrEP roll-out.