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The fusion of a vesicle to a target membrane is mediated by temporally and spatially regulated interactions within a set of evolutionarily conserved proteins. Integral to proper fusion is the interaction between proteins originating on both vesicle and target membranes to form a protein bridge between the two membranes, known as the SNARE complex. This protein complex includes the single-pass transmembrane helix proteins: syntaxin and synaptobrevin. Experimental data and amino acid sequence analysis suggest that an interface of interaction is conserved between the transmembrane regions of the two proteins. However, conflicting reports have been presented on the role of the synaptobrevin transmembrane domain in mediating important protein–protein interactions. To address this question, a thermodynamic study was carried out to determine quantitatively the self-association propensities of the transmembrane domains of synaptobrevin and syntaxin. Our results show that the transmembrane domain of synaptobrevin has only a modest ability to self-associate, whereas the transmembrane domain of syntaxin is able to form stable homodimers. Nevertheless, by a single amino acid substitution, synaptobrevin can be driven to dimerize with the same affinity as syntaxin. Furthermore, crosslinking studies show that dimerization of synaptobrevin is promoted by oxidizing agents. Despite the presence of a conserved cysteine residue in the same location as in synaptobrevin, syntaxin dimerization is not promoted by oxidization. This analysis suggests that subtle yet distinct differences are present between the two transmembrane dimer interfaces. A syntaxin/synaptobrevin heterodimer is able to form under oxidizing conditions, and we propose that the interface of interaction for the heterodimer may resemble the homodimer interface formed by the synaptobrevin transmembrane domain. Computational analysis of the transmembrane sequences of syntaxin and synaptobrevin reveal structural models that correlate with the experimental data. These data may provide insight into the role of transmembrane segments in the mechanism of vesicle fusion. [Copyright &y& Elsevier]

A retrospective cohort study of people living with human immunodeficiency virus in Ontario, Canada which found no association between previous syphilis and neurocognition. Background: About 40% to 60% of people living with human immunodeficiency virus (HIV) experience neurocognitive impairments, irrespective of antiretroviral status. We hypothesized that a history of syphilis or neurosyphilis would be associated with worse neurocognitive outcomes in this population. Methods: Among health care–engaged people living with HIV in Ontario older than 16 years enrolled in the OHTN Cohort Study, neurocognitive outcomes were as follows: (1) self-reported Medical Outcome Study–HIV Health Survey 4-item cognitive scale; (2) average T score summary scores based on objective neuropsychological testing of complex attention, speed of processing, and learning/memory; and (3) global deficit score dichotomized into impaired/unimpaired neurocognitive status. Syphilis history was determined by laboratory data or chart review. Univariable and multivariable generalized linear mixed models assessed the association between each of: syphilis, number of episodes of syphilis, and years since syphilis diagnosis with these neurocognitive outcomes controlling for age, sex, race, education, income, years of HIV, nadir and most recent CD4 count, most recent HIV viral load, substance use, depression, and number of prior neurocognitive tests. Results: Of 1288 eligible participants, 218 (16.9%) had a history of syphilis at baseline and an additional 53 were diagnosed during follow up for a total of 271 (21.0%) at the most recent visit. Of those with past infection at baseline, 179 (82.1%) had 1 and 39 (17.9%) had 2 or more episodes of syphilis. In longitudinal multivariable models, we observed no relationship between syphilis diagnosis or years since syphilis diagnosis and any of the neurocognitive outcomes. Conclusions: In this sample, prior syphilis was not associated with worse neurocognitive outcomes over time according to self-reported scales or objective neuropsychological testing. [ABSTRACT FROM AUTHOR]

Background: People with HIV are at higher risk of infectionrelated cancers than the general population, which could be due, in part, to immune dysfunction. Our objective was to examine associations between 4 CD4 count measures as indicators of immune function and infection-related and infection-unrelated cancer risk. Setting: We conducted a cohort study of adults with HIV who were diagnosed with cancer in Ontario, Canada. Incident cancers were identified from January 1, 1997 to December 31, 2020. Methods: We estimated adjusted hazard ratios (aHR) for the associations between CD4 measures (baseline CD4, nadir CD4, time-updated CD4, time-updated CD4:CD8) and cancer incidence rates using competing risk analyses, adjusted for socio-demographic factors, history of hepatitis B or C infection, baseline viral load, smoking, and alcohol use. Results: Among 4771 people with HIV, contributing 59,111 person-years of observation, a total of 549 cancers were observed. Low baseline CD4 (,200 cells/mL) (aHR 2.08 [95% CI: 1.38 to 3.13], nadir (,200 cells/mL) (aHR 2.01 [95% CI: 1.49 to 2.71]), low time-updated CD4 (aHR 3.52 [95% CI: 2.36 to 5.24]) and time-updated CD4:CD8 ratio (,0.4) (aHR 2.02 [95% CI: 1.08 to 3.79]) were associated with an increased rate of infection-related cancer. No associations were observed for infection-unrelated cancers. Conclusions: Low CD4 counts and indices were associated with increased rates of infection-related cancers among people with HIV, irrespective of the CD4 measure used. Early diagnosis and linkage to care and high antiretroviral therapy uptake may lead to improved immune function and could add to cancer prevention strategies such as screening and vaccine uptake. [ABSTRACT FROM AUTHOR]

Background: With combination antiretroviral therapy (ART) and increased longevity, cancer is a leading cause of morbidity among people with HIV. We characterized trends in cancer burden among people with HIV in Ontario, Canada, between 1997 and 2020. Methods: We conducted a population-based, retrospective cohort study of adults with HIV using linked administrative health databases from Jan. 1, 1997, to Nov. 1, 2020. We grouped cancers as infection-related AIDS-defining cancers (ADCs), infection-related non-ADCs (NADCs) and infection-unrelated cancers. We calculated age-standardized incidence rates per 100 000 person-years with 95% confidence intervals (CIs) using direct standardization, stratified by calendar period and sex. We also calculated limited-duration prevalence. Results: Among 19 403 adults living with HIV (79% males), 1275 incident cancers were diagnosed. From 1997-2000 to 2016-2020, we saw a decrease in the incidence of all cancers (1113.9 [95% CI 657.7-1765.6] to 683.5 [95% CI 613.4-759.4] per 100 000 person -years), ADCs (403.1 [95% CI 194.2-739.0] to 103.8 [95% CI 79.2-133.6] per 100 000 person-years) and infection-related NADCs (196.6 [95% CI 37.9-591.9] to 121.9 [95% CI 94.3-154.9] per 100 000 person-years). The incidence of infection-unrelated cancers was stable at 451.0 per 100 000 person-years (95% CI 410.3-494.7). The incidence of cancer among females increased over time but was similar to that of males in 2016-2020. Interpretation: Over a 24-year period, the incidence of cancer decreased overall, largely driven by a considerable decrease in the incidence of ADC, whereas the incidence of infection-unrelated cancer remained unchanged and contributed to the greatest burden of cancer. These findings could reflect combination ART-mediated changes in infectious comorbidity and increased life expectancy; targeted cancer screening and prevention strategies are needed. [ABSTRACT FROM AUTHOR]

In Ontario, front-line HIV workers play a critical role in knowledge translation and are an instrumental link between research literature and the people most at risk for HIV. However, the way people use and interact with HIV information is influenced by a number of factors. The current study explored the challenges that Ontario front-line HIV workers face and their successful strategies, in order to better understand how to help those at risk access and use critical HIV information. Focus groups were conducted with Ontario front-line HIV workers (n = 20). A follow-up survey was used to confirm the emergent themes with a larger sample of front-line workers (n = 51) and to collect additional information. A number of important themes emerged from these analyses. One of the biggest challenges reported by front-line workers was regarding statistical and other numeric data related to HIV risk. Many front-line workers were not comfortable discussing numeric information in their work because either they felt people would not understand, or they themselves had difficulty. The survey data confirmed this theme and provided additional information about how front-line workers best understand statistics as well as their preferred format for HIV risk information. The findings of the current study offer insights into the strengths and challenges front-line HIV workers experience in their work with those at-risk for sexually transmitted HIV. Importantly, these findings provide valuable information about how knowledge producers (e.g., researchers) and providers (e.g., federal and provincial HIV organizations) can better tailor the latest information about HIV to more effectively support front-line workers. [ABSTRACT FROM AUTHOR]

Background: The HIV cascade is an important framework for assessing systems of care, but population-based assessment is lacking for most jurisdictions worldwide. We measured cascade indicators over time in a population-based cohort of diagnosed people living with HIV (PLWH) in Ontario, Canada. Methods: We created a retrospective cohort of diagnosed PLWH using a centralized laboratory database with HIV diagnostic and viral load (VL) test records linked at the individual-level. Individuals enter the cohort with record of a nominal HIV-positive diagnostic test or VL test, and remain unless administratively lost to follow-up (LTFU, >2 consecutive years with no VL test and no VL test in later years). We calculated the annual percent of diagnosed PLWH (cohort individuals not LTFU) between 2000 and 2015 who were in care (≥1 VL test), on ART (as documented on VL test requisition) or virally suppressed (<200 copies/ml). We also calculated time from diagnosis to linkage to care and viral suppression among individuals newly diagnosed with HIV. Analyses were stratified by sex and age. Upper/lower bounds were calculated using alternative indicator definitions. Results: The number of diagnosed PLWH increased from 8,859 (8,859–11,389) in 2000 to 16,110 (16,110–17,423) in 2015. Over this 16-year period, the percent of diagnosed PLWH who were: in care increased from 81% (63–81%) to 87% (81–87%), on ART increased from 55% (34–60%) to 81% (70–82%) and virally suppressed increased from 41% (23–46%) to 80% (67–81%). Between 2000 and 2014, the percent of newly diagnosed individuals who linked to care within three months of diagnosis or achieved viral suppression within six months of diagnosis increased from 67% to 82% and from 22% to 42%, respectively. Estimates were generally lower for females and younger individuals. Discussion: HIV cascade indicators among diagnosed PLWH in Ontario improved between 2000 and 2015, but gaps still remain—particularly for younger individuals. [ABSTRACT FROM AUTHOR]