Correlates of Breakthrough SARS-CoV-2 Infections in People with HIV: Results from the CIHR CTN 328 Study.

COVID-19 breakthrough infection (BTI) can occur despite vaccination. Using a multi-centre, prospective, observational Canadian cohort of people with HIV (PWH) receiving ≥2 COVID-19 vaccines, we compared the SARS-CoV-2 spike (S) and receptor-binding domain (RBD)-specific IgG levels 3 and 6 months post second dose, as well as 1 month post third dose, in PWH with and without BTI. BTI was defined as positivity based on self-report measures (data up to last study visit) or IgG data (up to 1 month post dose 3). The self-report measures were based on their symptoms and either a positive PCR or rapid antigen test. The analysis was restricted to persons without previous COVID-19 infection. Persons without BTI remained COVID-19-naïve until ≥3 months following the third dose. Of 289 participants, 92 developed BTI (31.5 infections per 100 person-years). The median days between last vaccination and BTI was 128 (IQR 67, 176), with the most cases occurring between the third and fourth dose (n = 59), corresponding to the Omicron wave. In analyses adjusted for age, sex, race, multimorbidity, hypertension, chronic kidney disease, diabetes and obesity, a lower IgG S/RBD (log10 BAU/mL) at 1 month post dose 3 was significantly associated with BTI, suggesting that a lower IgG level at this time point may predict BTI in this cohort of PWH.

Efficient enzyme-free method to assess the development and maturation of the innate and adaptive immune systems in the mouse colon.

Researchers who aim to globally analyze the gastrointestinal immune system via flow cytometry have many protocol options to choose from, with specifics generally tied to gut wall layers of interest. To get a clearer idea of the approach we should use on full-thickness colon samples from mice, we first undertook a systematic comparison of three tissue dissociation techniques: two based on enzymatic cocktails and the other one based on manual crushing. Using flow cytometry panels of general markers of lymphoid and myeloid cells, we found that the presence of cell-surface markers and relative cell population frequencies were more stable with the mechanical method. Both enzymatic approaches were associated with a marked decrease of several cell-surface markers. Using mechanical dissociation, we then developed two minimally overlapping panels, consisting of a total of 26 antibodies, for serial profiling of lymphoid and myeloid lineages from the mouse colon in greater detail. Here, we highlight how we accurately delineate these populations by manual gating, as well as the reproducibility of our panels on mouse spleen and whole blood. As a proof-of-principle of the usefulness of our general approach, we also report segment- and life stage-specific patterns of immune cell profiles in the colon. Overall, our data indicate that mechanical dissociation is more suitable and efficient than enzymatic methods for recovering immune cells from all colon layers at once. Additionally, our panels will provide researchers with a relatively simple tool for detailed immune cell profiling in the murine gastrointestinal tract, regardless of life stage or experimental conditions.

IL-32 Drives the Differentiation of Cardiotropic CD4+ T Cells Carrying HIV DNA in People With HIV.

Interleukin 32 (IL-32) is a potent multi-isoform proinflammatory cytokine, which is upregulated in people with HIV (PWH) and is associated with cardiovascular disease (CVD) risk. However, the impact of IL-32 isoforms on CD4 T-cell cardiotropism, a mechanism potentially contributing to heart inflammation, remains unknown. Here we show that IL-32 isoforms ß and γ induce the generation of CCR4+CXCR3+ double positive (DP) memory CD4 T-cell subpopulation expressing the tyrosine kinase receptor c-Met, a phenotype associated with heart-homing of T cells. Our ex vivo studies on PWH show that the frequency of DP CD4 T cells is significantly higher in individuals with, compared to individuals without, subclinical atherosclerosis and that DP cells from antiretroviral-naive and treated individuals are highly enriched with HIV DNA. Together, these data demonstrate that IL-32 isoforms have the potential to induce heart-homing of HIV-infected CD4 T cells, which may further aggravate heart inflammation and CVD in PWH.

Preventative behaviours and COVID-19 infection in a Canadian cohort of people living with HIV.

Few studies have examined preventative behaviour practices with respect to COVID-19 among people living with HIV (human immunodeficiency virus). Using a cross-sectional survey from a Canadian Institutes of Health Research Canadian HIV Trials Network study (CTN 328) of people living with HIV on vaccine immunogenicity, we examined the relationships between participant characteristics and behavioural practices intended to prevent COVID-19 infection. Participants living in four Canadian urban centers were enrolled between April 2021-January 2022, at which time they responded to a questionnaire on preventative behaviour practices. Questionnaire and clinical data were combined to explore relationships between preventive behaviours and (1) known COVID-19 infection pre-enrolment, (2) multimorbidity, (3) developing symptomatic COVID-19 infection, and (4) developing symptomatic COVID-19 infection during the Omicron wave. Among 375 participants, 49 had COVID-19 infection pre-enrolment and 88 post-enrolment. The proportion of participants reporting always engaging in preventative behaviours included 87% masking, 79% physical distancing, 70% limiting social gatherings, 65% limiting contact with at-risk individuals, 33% self-isolating due to symptoms, and 26% self-quarantining after possible exposure. Participants with known COVID-19 infection pre-enrolment were more likely to self-quarantine after possible exposure although asymptomatic (65.0% vs 23.4%, p < 0.001; Chi-square test). Participants with multiple comorbidities more likely endorsed physical distancing (85.7% vs 75.5%, p = 0.044; Chi-square test), although this was not significant in logistic regression analysis adjusted for age, sex, race, number of household members, number of bedrooms/bathrooms in the household per person, influenza immunization, and working in close physical proximity to others. Overall, participants reported frequent practice of preventative behaviours.

Baseline characteristics of a prospective cohort study of aging and cardiovascular diseases among people living with HIV.

OBJECTIVES: Our objective was to report the baseline characteristics of participants in the Canadian HIV and Aging Cohort Study (CHACS) and present amendments to the initial protocol. METHODS: CHACS is a multi-centred prospective cohort study that was initially set from 2011 to 2016 and will now continue recruitment until 2024. Four additional years of follow-up have been added, and additional outcomes and covariates will be prospectively collected. Frailty will be assessed using a modified version of the Fried's frailty phenotype. The four interrelated aspects of gender-gender roles, gender identity, gender relationships, and institutionalized gender-will be measured using the GENESIS-PRAXY questionnaire. Diet will be assessed using a validated, web-based, self-administered food frequency questionnaire. RESULTS: A total of 1049 participants (77% people living with HIV) were recruited between September 2011 and September 2019. Median age at baseline was 54 years (interquartile range 50-61). Most participants were male (84%) and white (83%). Compared with participants without HIV, those with HIV were more likely to be male; to report lower education levels and incomes; to be more sedentary; to use tobacco, recreational, and prescription drugs; to report a personal history of cardiovascular diseases; and to be frail. CONCLUSIONS: The new assessments added to the CHACS protocol will allow for an even more detailed portrait of the pathways leading to accentuated aging for people living with HIV. Participants in the CHACS cohort display important differences in socio-economic and cardiovascular risk factors according to HIV serostatus. These imbalances must be taken into account for all further inferential analyses.

Knowledge of Cannabinoid Content Among People Living with HIV Who Use Cannabis: a Daily Diary Study.

BACKGROUND: Many people living with HIV (PLWH) use cannabis for medicinal reasons. Patients' knowledge of the tetrahydrocannabinol (THC) and cannabidiol (CBD) concentrations of the cannabis products they use may be important in helping patients achieve symptom relief while guarding against potential risks of cannabis use. However, no studies have examined cannabinoid concentration knowledge among PLWH. METHOD: PLWH (N = 29; 76% men, mean age 47 years) reporting cannabis use for both medicinal and nonmedicinal reasons completed daily surveys over 14 days assessing cannabis products used, knowledge of cannabinoid concentrations of cannabis products used, cannabis use motives (medicinal, nonmedicinal, both), and positive and negative cannabis-related consequences. Across the 361 cannabis use days captured on the daily surveys, at least some knowledge of cannabinoid concentrations was reported on an average of 43.1% (for THC) and 26.6% (for CBD) of the days. RESULTS: Generalized linear mixed models revealed that participants were more likely to report knowing THC and CBD concentrations on days when they used non-flower forms of cannabis relative to days when they used cannabis flower only. Participants who used cannabis for medicinal reasons on a greater proportion of days had greater knowledge of cannabinoid concentration overall across days. Further, greater overall knowledge of cannabinoid concentrations was associated with fewer reported negative cannabis-related consequences. CONCLUSIONS: Findings suggest that among PLWH, knowledge of cannabinoid concentrations may be higher when using non-flower cannabis products and among those reporting primarily medicinal cannabis use. Moreover, knowledge of cannabinoid concentration may protect against negative cannabis-related consequences in this population.

Donating One's Body to HIV Cure Research Through Canadian Medical Assistance in Dying: A Case Study.

BACKGROUND: Finding a cure for HIV is challenged by persisting reservoirs, the mapping of which necessitates invasive procedures. Inviting people with HIV (PWHIV) at the end of life to donate body specimens post-mortem through research autopsies is a novel approach, raising ethical concerns. OBJECTIVE: This case study aims to explore the motivations, barriers, and facilitators of a terminally-ill Canadian PWHIV who requested medical assistance in dying (MAID) and expressed interest in donating his body for HIV cure research. CASE PRESENTATION: An in-depth 3-hour and semi-structured interview was conducted with the participant. The interview transcription was thematically coded to identify motivations and perceived barriers and facilitators to participate in end-of-life HIV cure research. Our analysis identified six themes. Two themes expressed motivations: Collaboration in progress in health and science, seeing cure research as collaboration with professionals; and Opportunity to learn more, mostly about science and health. One theme expressed a barrier: Losing interest in or identification with long-term care research matters, especially those related to the management of long-term care. Three themes expressed by facilitators: Receiving information from professionals one trusts and knows, especially clinical and research teams; Perceiving research procedures as simple, useful, and embedded in care, perceiving clinical, educational, and interpersonal benefits that surpass costs of participation; and Perceiving research as one last way to contribute, that is, feeling useful or give back. CONCLUSION: Several circumstances facilitated the patient's participation: being a single man, having time to participate, having no strong religious belief, and valuing clear, direct communication. His motivations to participate in HIV cure research were altruistic, and also an experience of working with clinical and research teams. Finally, this perspective highlights HIV cure research participant candidates' need for education about research procedures.

Near full-length HIV sequencing in multiple tissues collected postmortem reveals shared clonal expansions across distinct reservoirs during ART.

HIV persists in tissues during antiretroviral therapy (ART), but the relative contribution of different anatomical compartments to the viral reservoir in humans remains unknown. We performed an extensive characterization of HIV reservoirs in two men who donated their bodies to HIV cure research and who had been on suppressive ART for years. HIV DNA is detected in all tissues, with large variations across anatomical compartments and between participants. Intact HIV genomes represent 2% and 25% of all proviruses in the two participants and are mainly detected in secondary lymphoid organs, with the spleen and mediastinal lymph nodes harboring intact viral genomes in both individuals. Multiple copies of identical HIV genomes are found in all tissues, indicating that clonal expansions are common in anatomical sites. The majority (>85%) of these expanded clones are shared across multiple tissues. These findings suggest that infected cells expand, migrate, and possibly circulate between anatomical sites.

The Use of CBD and Its Synthetic Analog HU308 in HIV-1-Infected Myeloid Cells.

Currently, there is no cure for human immunodeficiency virus type 1 (HIV-1) infection. However, combined antiretroviral therapy (cART) aids in viral latency and prevents the progression of HIV-1 infection into acquired immunodeficiency syndrome (AIDS). cART has extended many lives, but people living with HIV-1 (PLWH) face lifelong ailments such as HIV-associated neurocognitive disorders (HAND) that range from asymptomatic HAND to HIV-1-associated dementia. HAND has been attributed to chronic inflammation and low-level infection within the central nervous system (CNS) caused by proinflammatory cytokines and viral products. These molecules are shuttled into the CNS within extracellular vesicles (EVs), lipid bound nanoparticles, and are released from cells as a form of intercellular communication. This study investigates the impact of cannabidiol (CBD), as a promising and potential therapeutic for HAND patients, and a similar synthetic molecule, HU308, on the EVs released from HIV-1-infected myeloid cells as well as HIV-1-infected 3D neurospheres. The data shows that both CBD and HU308 decrease non-coding and coding viral RNA (TAR and env) as well as proinflammatory cytokines as IL-1ß and TNF-α mRNA. This decrease in viral RNA occurs in in vitro differentiated primary macrophages, in EVs released from HIV-1-infected cells monocytes, and infected neurospheres. Furthermore, a 3D neurosphere model shows an overall decrease in proinflammatory mRNA with HU308. Finally, using a humanized mouse model of HIV-1 infection, plasma viral RNA was shown to significantly decrease with HU308 alone and was most effective in combination with cART, even when compared to the typical cART treatment. Overall, CBD or HU308 may be a viable option to decrease EV release and associated cytokines which would dampen the virus spread and may be used in effective treatment of HAND in combination with cART.

Impact of in vitro HIV infection on human thymic regulatory T cell differentiation.

Background: The differentiation and function of immunosuppressive regulatory T cells (Tregs) is dictated by the master transcription factor FoxP3. During HIV infection, there is an increase in Treg frequencies in the peripheral blood and lymphoid tissues. This accentuates immune dysfunction and disease progression. Expression of FoxP3 by thymic Tregs (tTregs) is partially controlled by TGF-ß. This cytokine also contributes to Treg development in the peripheral blood and lymphoid tissues. Although TGF-ß mediates lymphoid tissue fibrosis and peripheral Treg differentiation in HIV-infected individuals, its role in the induction and maintenance of Tregs within the thymus during HIV infection remains unclear. Methods: Thymocytes were isolated from fresh human thymic tissues obtained from pediatric patients undergoing cardiac surgery. Infection by both R5- and X4-tropic HIV-1 strains and TGF-ß treatment of human thymocytes was performed in an in vitro co-culture model with OP9-DL1 cells expressing Notch ligand delta-like 1 without T cell receptor (TCR) activation. Results: Despite high expression of CCR5 and CXCR4 by tTregs, FoxP3 + CD3highCD8- thymocytes were much less prone to in vitro infection with R5- and X4-tropic HIV strains compared to FoxP3-CD3highCD8- thymocytes. As expected, CD3highCD4+ thymocytes, when treated with TGF-ß1, upregulated CD127 and this treatment resulted in increased FoxP3 expression and Treg differentiation, but did not affect the rate of HIV infection. FoxP3 expression and Treg frequencies remained unchanged following in vitro HIV infection alone or in combination with TGF-ß1. Conclusion: FoxP3 expression and tTreg differentiation is not affected by in vitro HIV infection alone or the combination of in vitro HIV infection and TGF-ß treatment.

Antibody neutralization capacity after coronavirus disease 2019 vaccination in people with HIV in Canada.

OBJECTIVES: Many vaccines require higher/additional doses or adjuvants to provide adequate protection for people with HIV (PWH). Here, we compare coronavirus disease 2019 (COVID-19) vaccine-induced antibody neutralization capacity in PWH vs. HIV-negative individuals following two vaccine doses. DESIGN: In Canadian prospective observational cohorts, including a multicentre study of PWH receiving at least two COVID-19 vaccinations (mRNA or ChAdOx1-S), and a parallel study of HIV-negative controls (Stop the Spread Ottawa Cohort), we measured vaccine-induced neutralization capacity 3 months post dose 2 (±1 month). METHODS: COVID-19 neutralization efficiency was measured by calculating the half maximal inhibitory dilution (ID50) using a high-throughput protein-based neutralization assay for Ancestral (Wuhan), Delta and Omicron (BA.1) spike variants. Univariable and multivariable quantile regression were used to compare COVID-19-specific antibody neutralization capacity by HIV status. RESULTS: Neutralization assays were performed on 256 PWH and 256 controls based on specimen availability at the timepoint of interest, having received two vaccines and known date of vaccination. There was a significant interaction between HIV status and previous COVID-19 infection status in median ID50. There were no differences in median ID50 for HIV+ vs. HIV-negative persons without past COVID-19 infection. For participants with past COVID-19 infection, median ICD50 was significantly higher in controls than in PWH for ancestral SARS-CoV-2 and Omicron variants, with a trend for the Delta variant in the same direction. CONCLUSION: Vaccine-induced SARS-CoV-2 neutralization capacity was similar between PWH vs. HIV-negative persons without past COVID-19 infection, demonstrating favourable humoral-mediated immunogenicity. Both HIV+ and HIV-negative persons demonstrated hybrid immunity. TRIAL REGISTRATION: clinicaltrials.gov NCT04894448.

Effects of Oral Cannabinoids on Systemic Inflammation and Viral Reservoir Markers in People with HIV on Antiretroviral Therapy: Results of the CTN PT028 Pilot Clinical Trial.

Chronic HIV infection is characterized by persistent inflammation despite antiretroviral therapy (ART). Cannabinoids may help reduce systemic inflammation in people with HIV (PWH). To assess the effects of oral cannabinoids during HIV, ten PWH on ART were randomized (n = 5/group) to increasing doses of oral Δ9-tetrahydrocannabinol (THC): cannabidiol (CBD) combination (2.5:2.5-15:15 mg/day) capsules or CBD-only (200-800 mg/day) capsules for 12 weeks. Blood specimens were collected prospectively 7-21 days prior to treatment initiation and at weeks 0 to 14. Plasma cytokine levels were determined via Luminex and ELISA. Immune cell subsets were characterized by flow cytometry. HIV DNA/RNA were measured in circulating CD4 T-cells and sperm by ultra-sensitive qPCR. Results from both arms were combined for statistical analysis. Plasma levels of IFN-γ, IL-1ß, sTNFRII, and REG-3α were significantly reduced at the end of treatment (p ˂ 0.05). A significant decrease in frequencies of PD1+ memory CD4 T-cells, CD73+ regulatory CD4 T-cells, and M-DC8+ intermediate monocytes was also observed (p ˂ 0.05), along with a transient decrease in CD28-CD57+ senescent CD4 and CD8 T-cells. Ki-67+ CD4 T-cells, CCR2+ non-classical monocytes, and myeloid dendritic cells increased over time (p ˂ 0.05). There were no significant changes in other inflammatory markers or HIV DNA/RNA levels. These findings can guide future large clinical trials investigating cannabinoid anti-inflammatory properties.

Early ART reduces viral seeding and innate immunity in liver and lungs of SIV-infected macaques.

Identifying immune cells and anatomical tissues that contribute to the establishment of viral reservoirs is of central importance in HIV-1 cure research. Herein, we used rhesus macaques (RMs) infected with SIVmac251 to analyze viral seeding in the liver and lungs of either untreated or early antiretroviral therapy-treated (ART-treated) RMs. Consistent with viral replication and sensing, transcriptomic analyses showed higher levels of inflammation, pyroptosis, and chemokine genes as well as of interferon-stimulating gene (ISG) transcripts, in the absence of ART. Our results highlighted the infiltration of monocyte-derived macrophages (HLA-DR+CD11b+CD14+CD16+) in inflamed liver and lung tissues associated with the expression of CD183 and CX3CR1 but also with markers of tissue-resident macrophages (CD206+ and LYVE+). Sorting of myeloid cell subsets demonstrated that CD14+CD206-, CD14+CD206+, and CD14-CD206+ cell populations were infected, in the liver and lungs, in SIVmac251-infected RMs. Of importance, early ART drastically reduced viral seeding consistent with the absence of ISG detection but also of genes related to inflammation and tissue damage. Viral DNA was only detected in CD206+HLA-DR+CD11b+ cells in ART-treated RMs. The observation of pulmonary and hepatic viral rebound after ART interruption reinforces the importance of early ART implementation to limit viral seeding and inflammatory reactions.

SARS-CoV-2 Vaccine-Induced T-Cell Response after Three Doses in People Living with HIV on Antiretroviral Therapy Compared to Seronegative Controls (CTN 328 COVAXHIV Study).

People living with HIV (PLWH) may be at risk for poor immunogenicity to certain vaccines, including the ability to develop immunological memory. Here, we assessed T-cell immunogenicity following three SARS-CoV-2 vaccine doses in PLWH versus uninfected controls. Blood was collected from 38 PLWH on antiretroviral therapy and 24 age-matched HIV-negative controls, pre-vaccination and after 1st/2nd/3rd dose of SARS-CoV-2 vaccines, without prior SARS-CoV-2 infection. Flow cytometry was used to assess ex vivo T-cell immunophenotypes and intracellular Tumor necrosis factor (TNF)-α/interferon(IFN)-γ/interleukin(IL)-2 following SARS-CoV-2-Spike-peptide stimulation. Comparisons were made using Wilcoxon signed-rank test for paired variables and Mann-Whitney for unpaired. In PLWH, Spike-specific CD4 T-cell frequencies plateaued post-2nd dose, with no significant differences in polyfunctional SARS-CoV-2-specific T-cell proportions between PLWH and uninfected controls post-3rd dose. PLWH had higher frequencies of TNFα+CD4 T-cells and lower frequencies of IFNγ+CD8 T-cells than seronegative participants post-3rd dose. Regardless of HIV status, an increase in naive, regulatory, and PD1+ T-cell frequencies was observed post-3rd dose. In summary, two doses of SARS-CoV-2 vaccine induced a robust T-cell immune response in PLWH, which was maintained after the 3rd dose, with no significant differences in polyfunctional SARS-CoV-2-specific T-cell proportions between PLWH and uninfected controls post-3rd dose.

Immuno-metabolic control of the balance between Th17-polarized and regulatory T-cells during HIV infection.

Th17-polarized CD4+ effector T-cells together with their immunosuppressive regulatory T-cell (Treg) counterparts, with transcriptional profiles governed by the lineage transcription factors RORγt/RORC2 and FOXP3, respectively, are important gatekeepers at mucosal interfaces. Alterations in the Th17/Treg ratios, due to the rapid depletion of Th17 cells and increased Treg frequencies, are a hallmark of both HIV and SIV infections and a marker of disease progression. The shift in Th17/Treg balance, in favor of increased Treg frequencies, contributes to gut mucosal permeability, immune dysfunction, and microbial translocation, subsequently leading to chronic immune activation/inflammation and disease progression. Of particular interest, Th17 cells and Tregs share developmental routes, with changes in the Th17 versus Treg fate decision influencing the pro-inflammatory versus anti-inflammatory responses. The differentiation and function of Th17 cells and Tregs rely on independent yet complementary metabolic pathways. Several pathways have been described in the literature to be involved in Th17 versus Treg polarization, including 1) the activity of ectonucleotidases CD39/CD73; 2) the increase in TGF-ß1 production; 3) a hypoxic environment, and subsequent upregulation in hypoxia-inducible factor-1α (HIF-1α); 4) the increased mTOR activity and glycolysis induction; 5) the lipid metabolism, including fatty acid synthesis, fatty acids oxidation, cholesterol synthesis, and lipid storage, which are regulated by the AMPK, mevalonate and PPARγ pathways; and 6) the tryptophan catabolism. These metabolic pathways are understudied in the context of HIV-1 infection. The purpose of this review is to summarize the current knowledge on metabolic pathways that are dysregulated during HIV-1 infection and their impact on Th17/Treg balance.

COVID-19 vaccine immunogenicity in people with HIV.

OBJECTIVES: Many vaccines require higher/additional doses or adjuvants to provide adequate protection for people with HIV (PWH). Our objective was to compare COVID-19 vaccine immunogenicity in PWH to HIV-negative individuals. DESIGN: In a Canadian multi-center prospective, observational cohort of PWH receiving at least two COVID-19 vaccinations, we measured vaccine-induced immunity at 3 and 6 months post 2nd and 1-month post 3rd doses. METHODS: The primary outcome was the percentage of PWH mounting vaccine-induced immunity [co-positivity for anti-IgG against SARS-CoV2 Spike(S) and receptor-binding domain proteins] 6 months post 2nd dose. Univariable and multivariable logistic regressions were used to compare COVID-19-specific immune responses between groups and within subgroups. RESULTS: Data from 294 PWH and 267 controls were analyzed. Immunogenicity was achieved in over 90% at each time point in both groups. The proportions of participants achieving comparable anti-receptor-binding domain levels were similar between the group at each time point. Anti-S IgG levels were similar by group at month 3 post 2nd dose and 1-month post 3rd dose. A lower proportion of PWH vs. controls maintained vaccine-induced anti-S IgG immunity 6 months post 2nd dose [92% vs. 99%; odds ratio: 0.14 (95% confidence interval: 0.03, 0.80; P = 0.027)]. In multivariable analyses, neither age, immune non-response, multimorbidity, sex, vaccine type, or timing between doses were associated with reduced IgG response. CONCLUSION: Vaccine-induced IgG was elicited in the vast majority of PWH and was overall similar between groups. A slightly lower proportion of PWH vs. controls maintained vaccine-induced anti-S IgG immunity 6 months post 2nd dose demonstrating the importance of timely boosting in this population.

Disentangling Medicinal and Recreational cannabis Use Among People Living with HIV: An Ecological Momentary Assessment Study.

This study examined the feasibility of using ecological momentary assessment (EMA) to disentangle medicinal cannabis use (MCU) from recreational cannabis use (RCU) among people living HIV (PLWH). Over a 14-day period, PLWH (N = 29) who engaged in both MCU and RCU completed a smartphone-based survey before and after every cannabis use event assessing general motivation for cannabis use (MCU-only, RCU-only, or mixed MCU/RCU), cannabis use behavior, and several antecedents and outcomes of cannabis use. A total of 739 pre-cannabis surveys were completed; 590 (80%) of the prompted post-cannabis surveys were completed. Motives for cannabis use were reported as MCU-only on 24%, RCU-only on 30%, and mixed MCU/RCU on 46% of pre-cannabis surveys. Mixed effects models examined within-person differences across MCU-only, RCU-only, and mixed MCU/RCU events. Results showed that relative to RCU-only events, MCU-only events were more likely to involve symptom management and drug substitution motives, physical and sleep-related symptoms, solitary cannabis use, and use of cannabis oils and sprays; MCU-only events were less likely to involve relaxation, happiness, and wellness motives, cannabis flower use, and positive cannabis consequences. Differences between mixed MCU/RCU and RCU-only events were similar, except that mixed MCU/RCU events were additionally associated with stress reduction motives and symptoms of anxiety and depression. Findings support the feasibility of partially disentangling MCU and RCU behavior among PLWH who engage in concurrent MCU and RCU. This study highlights the need for more EMA studies isolating MCU from RCU to inform ongoing changes to cannabis policies.

Association Between the Development of Subclinical Cardiovascular Disease and Human Immunodeficiency Virus (HIV) Reservoir Markers in People With HIV on Suppressive Antiretroviral Therapy.

We report that people with human immunodeficiency virus (HIV) diagnosed with coronary artery atherosclerotic plaques display higher levels of HIV DNA compared with those without atherosclerotic plaques. In a multivariable prediction model that included 27 traditional and HIV-related risk factors, measures of HIV DNA were among the most important predictors of atherosclerotic plaque formation.

Safety and Tolerability of Oral Cannabinoids in People Living with HIV on Long-Term ART: A Randomized, Open-Label, Interventional Pilot Clinical Trial (CTNPT 028).

BACKGROUND: With anti-inflammatory properties, cannabinoids may be a potential strategy to reduce immune activation in people living with HIV (PLWH) but more information on their safety and tolerability is needed. METHODS: We conducted an open-label interventional pilot study at the McGill University Health Centre in Montreal, Canada. PLWH were randomized to oral Δ9-tetrahydrocannabinol (THC): cannabidiol (CBD) combination (THC 2.5 mg/CBD 2.5 mg) or CBD-only capsules (CBD 200 mg). Individuals titrated doses as tolerated to a maximum daily dose THC 15 mg/CBD 15 mg or 800 mg CBD, respectively, for 12 weeks. The primary outcome was the percentage of participants without any significant toxicity based on the WHO toxicity scale (Grades 0-2 scores). RESULTS: Out of ten individuals, eight completed the study. Two from the CBD-only arm were withdrawn for safety concerns: phlebotomy aggravating pre-existing anemia and severe hepatitis on 800 mg CBD with newly discovered pancreatic adenocarcinoma, respectively. Seven did not have any significant toxicity. Cannabinoids did not alter hematology/biochemistry profiles. CD4 count, CD4/CD8 ratio, and HIV suppression remained stable. Most adverse effects were mild-moderate. CONCLUSIONS: In PLWH, cannabinoids seem generally safe and well-tolerated, though larger studies are needed. Screening for occult liver pathology should be performed and hepatic enzymes monitored, especially with high CBD doses.

Interplay between the Lung Microbiome, Pulmonary Immunity and Viral Reservoirs in People Living with HIV under Antiretroviral Therapy.

Pulmonary dysbiosis may predispose people living with HIV (PLWH) to chronic lung disease. Herein, we assessed whether intrapulmonary HIV reservoir size and immune disruption are associated with reduced bacterial lung diversity in PLWH. Bacterial DNA was extracted and PCR-amplified from cell-free bronchoalveolar lavage (BAL) fluid from 28 PLWH and 9 HIV-negative controls. Amplicon sequence variant (ASV) relative abundances and taxonomic identities were analyzed using joint species distribution modeling. HIV-DNA was quantified from blood and pulmonary CD4+ T-cells using ultra-sensitive qPCR. Immunophenotyping of BAL T-cells was performed using flow cytometry. Lung microbiome diversity was lower in smokers than non-smokers and microbiome composition was more variable in PLWH than HIV-negative individuals. Frequencies of effector memory BAL CD4+ and CD8+ T-cells positively correlated with abundance of several bacterial families while frequencies of BAL activated CD4+ T-cells negatively correlated with abundance of most lung bacterial families. Higher HIV-DNA levels in blood, but not in BAL, as well as frequencies of senescent CD4+ T-cells were associated with reduced bacterial diversity. These findings suggest that HIV infection may weaken the relationship between the lung microbiome and smoking status. Viral reservoir and immune activation levels may impact the lung microbiome, predisposing PLWH to pulmonary comorbidities.