AIDS

BackgroundChronic 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. MethodsCross-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. ResultsIn 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). ConclusionSoluble 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 pointsSoluble 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.

Persistence of HIV antigens may drive chronic inflammation, leading to early-onset comorbidity among people living with HIV. We found that the presence of soluble glycoprotein 120 in plasma is associated with increased coronary inflammation, as measured by the pericoronary fat attenuation index (PFAI), a predictor of overt cardiovascular disease.

While antiretroviral therapy efficiently suppresses viral replication, inflammation and immune dysfunction persist in some people living with HIV-1 (PLWH). Soluble gp120 (sgp120) has been detected in PLWH plasma and its presence is linked to immune dysfunction. It was reported that sgp120 binding to CD4 on uninfected bystander CD4+ T cells sensitizes them to antibody-dependent cellular-cytotoxicity (ADCC) mediated by non-neutralizing antibodies present in PLWH plasma. Using three independent PLWH cohorts, we observed that non-neutralizing anti-cluster A antibodies are negatively associated with CD4+ T cell counts. Anti-CD4BS antibodies blocked the coating of uninfected bystander cells by sgp120, thereby preventing their elimination by ADCC. Supporting a protective role of anti-CD4BS antibodies, PLWH having these antibodies didnt show a negative association between CD4 T cell counts and anti-cluster A. Our results reveal that anti-cluster A antibodies are associated with immune dysfunction in PLWH and anti-CD4BS antibodies might have a beneficial impact in these individuals.

BackgroundDepression and anxiety have been associated with increased risk of myocardial infarction (MI) in the general population and among people with HIV (PWH) but with limited attention to MI type. We examined the association between depression and/or anxiety and incident Type 1 (T1MI) or Type 2 (T2MI) MI among PWH. MethodsWe examined data from seven NA-ACCORD clinical cohorts (1997-2019) with adjudicated first MI; outcomes included T1MI (plaque rupture or cardiac intervention) or T2MI (demand ischemia). We defined depression or anxiety as a time-varying ICD-9/10-coded diagnosis prior to incident MI. We censored participants at death, disengagement from care, or first MI (if not the outcome of interest). We used Cox proportional hazard models to estimate the association between depression or anxiety and MI by type, adjusting for demographics and risk factors for MI. ResultsOf the 32,358 study participants, 13,751 (42.5%) had a depression diagnosis, 9,132 (28.2%) had an anxiety diagnosis, and 15,970 (47.3%) never had diagnosed depression or anxiety. After adjusting for MI risk factors, depression was associated with T1MI (aHR, 1.22 [95% CI, 1.00-1.48]), and anxiety had a protective association (albeit not statistically significant) with T1MI (aHR, 0.86 [95% CI, 0.70-1.07]). Depression had a null association (aHR, 1.05 [95% CI, 0.83-1.33] with T2MI, and anxiety was non-significantly associated with T2MI (aHR, 1.16 [95% CI, 0.89-1.51]). ConclusionsDiagnosed depression was associated with T1MI but not T2MI, whereas anxiety was not statistically significantly associated with either MI type. Mental health diagnosis and treatment may play an important role in cardiovascular health among PWH.

ObjectivesTo quantify the all-cause excess death rate of people living with HIV/AIDS (PWHA) during the multi-year 2020-2022 COVID-19 pandemic in the United States (U.S.), including stratifications by sex, age, race/ethnicity, and region. DesignUsing publicly available data from the CDC NCHHSTP AtlasPlus dashboard, we employed the ensemble n-subepidemic modeling framework (SubEpiPredict toolbox). This dynamic, uncertainty-aware approach was used to generate counterfactual forecasts of U.S. deaths among PWHA for 2020-2022. MethodsThe models were calibrated using 12 years of pre-pandemic mortality trends (2008-2019), with the median excess death rate calculated as the difference between forecasted and observed death rates. Results were stratified by age, sex, race/ethnicity, and U.S. region. ResultsOverall excess mortality among PWHA was estimated at 7,783 crude excess deaths (95% prediction interval [PI]: 5,098-10,525), corresponding to 2.77 excess deaths per 100,000 people (95% PI: 1.81-3.75), with the largest burden observed in 2021. Excess death rates were highest among males (3.39), individuals aged 55-64 years (4.94), multiracial populations (12.82), and residents of the Northeast U.S. (4.12). In contrast, the largest absolute number of excess deaths occurred among males (4,692), adults aged 65 years and older (2,560), Black/African American individuals (3,969), and residents of the Southern U.S. (4,025). ConclusionsThese systematic, model-based results reveal stark heterogeneities among PWHA by exposing recent mortality patterns that may not be captured by disease-specific mortality reporting alone. These heterogeneous findings can inform future public health programming and resource allocation and support tailored interventions for vulnerable populations.

ImportanceEstimating the medical complexity of people aging with HIV can inform clinical programs and policy to meet future healthcare needs. ObjectiveTo project the prevalence of comorbidities and multimorbidity among people with HIV (PWH) using antiretroviral therapy (ART) in the US through 2030. DesignAgent-based simulation model SettingHIV clinics in the United States in the recent past (2020) and near future (2030) ParticipantsIn 2020, 674,531 PWH were using ART; 9% were men and 4% women with history of injection drug use; 60% were men who have sex with men (MSM); 8% were heterosexual men and 19% heterosexual women; 44% were non-Hispanic Black/African American (Black); 32% were non-Hispanic White (White); and 23% were Hispanic. Exposure(s)Demographic and HIV acquisition risk subgroups Main Outcomes and MeasuresProjected prevalence of anxiety, depression, stage [≥]3 chronic kidney disease (CKD), dyslipidemia, diabetes, hypertension, cancer, end-stage liver disease (ESLD), myocardial infarction (MI), and multimorbidity ([≥]2 mental or physical comorbidities, other than HIV). ResultsWe projected 914,738 PWH using ART in the US in 2030. Multimorbidity increased from 58% in 2020 to 63% in 2030. The prevalence of depression and/or anxiety was high and increased from 60% in 2020 to 64% in 2030. Hypertension and dyslipidemia decreased, diabetes and CKD increased, MI increased steeply, but there was little change in cancer and ESLD. Among Black women with history of injection drug use (oldest demographic subgroup in 2030), CKD, anxiety, hypertension, and depression were most prevalent and 93% were multimorbid. Among Black MSM (youngest demographic subgroup in 2030), depression was highly prevalent, followed by hypertension and 48% were multimorbid. Comparatively, 67% of White MSM were multimorbid in 2030 (median age in 2030=59 years) and anxiety, depression, dyslipidemia, CKD, and hypertension were highly prevalent. Conclusion and relevanceThe distribution of multimorbidity will continue to differ by race/ethnicity, gender, and HIV acquisition risk subgroups, and be influenced by age and risk factor distributions that reflect the impact of social disparities of the health on women, people of color, and people who use drugs. HIV clinical care models and funding are urgently required to meet the healthcare needs of people with HIV in the next decade. KEY POINTS QuestionHow will the prevalence of multimorbidity change among people with HIV (PWH) using antiretroviral therapy in the US from 2020 to 2030? FindingsIn this agent-based simulation study using data from the NA-ACCORD and the CDC, multimorbidity ([≥]2 mental/physical comorbidities other than HIV) will increase from 58% in 2020 to 63% in 2030. The composition of comorbidities among multimorbid PWH vary by race/ethnicity, gender, and HIV acquisition risk group. MeaningHIV clinical programs and policy makers must act now to identify resources and care models to meet the increasingly complex medical needs of PWH over time, particularly mental healthcare needs.

Iron homeostasis is essential for brain health, and iron is also required for HIV replication, but the role of iron is largely unexplored in HIV-associated neurocognitive disorders. These disorders remain extremely common in people with HIV, despite antiretroviral therapy capable of suppressing viral replication, and they involve damage to white matter tracts and synaptodendritic architecture in the brain. We hypothesized that cerebrospinal fluid (CSF) levels of iron and two proteins involved in iron delivery, mitochondrial function, and protection against iron-mediated oxidative stress (H-ferritin and transferrin) are associated with neurocognitive performance over time in adults with HIV. These CSF iron-related biomarkers were measured at baseline (entry) in 403 adults with HIV from a large, prospective observational study who underwent comprehensive neurocognitive assessments at 6-month intervals. All participants were assigned a Global Deficit Score (GDS) and neurocognitive change status (improving/stable/declining), compared to baseline, at each visit. Biomarker associations with change status, and GDS differences over 30, 36, and 42 months of follow-up, were evaluated by multivariable regression. GDS-defined neurocognitive impairment was present in 120 study participants at entry (29.8%); 73% were on antiretroviral therapy. Of 267 participants with longitudinal follow-up, 16% were improving neurocognitively, and 20% were declining at their last follow-up visit (median 36 months). In multivariable-adjusted analyses, higher baseline CSF H-ferritin predicted improving neurocognitive performance at the last assessment (p=0.029), and a better GDS over at least 30 months. Higher H-ferritin levels were also associated with better GDS-defined neurocognitive performance over 30, 36, and 42 months in virally suppressed individuals (p-values <0.01 at all three time-points) and individuals aged<50 (all p-values <0.05). Higher CSF transferrin beneficially influenced GDS-defined neurocognitive performance at all three follow-up visits (all p<0.05), particularly in viremic individuals and people with HIV aged 50 and over, but the associations lost statistical significance in analyses restricted to virally suppressed persons. Significant multiplicative interactions with comorbidity were observed for both H-ferritin and transferrin in viremic adults. In summary, higher CSF H-ferritin is associated with better neurocognitive performance over time in adults with HIV, particularly in younger and virally suppressed individuals on antiretroviral therapy. Higher CSF transferrin may be particularly neuroprotective in pro-inflammatory settings such as in older and/or viremic people with HIV. Overall, our findings could reflect better iron delivery to neurons and myelinating oligodendrocytes, better mitochondrial function, and reduced oxidative stress under specific scenarios (e.g., viremia/aviremia) of HIV infection, and they may provide a rationale for the use of iron-modulating interventions to prevent or treat neurocognitive decline in people with HIV.

The persistence of HIV-1 proviruses in latently infected cells allows viremia to resume upon treatment cessation. To characterize the resulting immune response, we compare plasma proteomics and single-cell transcriptomics of peripheral blood mononuclear cells (PBMCs) before, during, and after detectable plasma viremia. We observe unique transcriptional signatures prior to viral rebound including a significant increase in CD16++ monocytes with increased anti-viral gene expression. Inflammatory proteins were identified in plasma after detectable rebound. Identifying early signals of imminent viral rebound after treatment cessation will aid in the development of strategies to prolong time to viral rebound and cure HIV-1.

In order to reach the first 95 (i.e., 95% of people living with HIV having knowledge of their status) of the 2030 UNAIDS 95-95-95 targets, it is crucial to better understand the contextual or structural factors driving socioeconomic inequalities in HIV testing uptake. It is still unclear whether they are mostly influenced by epidemiological or by macro-economic factors. Here, to shed light on this issue, we measured and decomposed socioeconomic inequalities in HIV testing in sub-Saharan Africa in relation to contextual factors using a novel method, the Recentered Influence Function decomposition method. Indeed, we found that HIV testing uptake was more concentrated among the rich in 12 of 16 sub-Saharan African countries based on population-based surveys. The level of the HIV epidemic seems to drive the level of response of HIV testing programs, rather than the per capita Gross Domestic Product of a country (i.e., national indicator of economic development). Our results suggest that when responding to the HIV epidemic, there is a need to monitor and assess inequalities in addition to monitoring HIV incidence and prevalence.

BackgroundIn the US, transgender and gender-diverse (TGD) individuals, particularly trans feminine individuals, experience a disproportionately high burden of HIV relative to their cisgender counterparts. While engagement in the HIV Care Continuum (e.g., HIV care visits, antiretroviral (ART) prescribed, ART adherence) is essential to reduce viral load, HIV transmission, and related morbidity, the extent to which TGD people engage in one or more steps of the HIV Care Continuum at similar levels as cisgender people is understudied on a national level and by gendered subgroups. Methods and FindingsWe used Medicare Fee-for-Service claims data from 2009 to 2017 to identify TGD (trans feminine and non-binary (TFN), trans masculine and non-binary (TMN), unclassified gender) and cisgender (male, female) beneficiaries with HIV. Using a retrospective cross-sectional design, we explored within- and between-gender group differences in the predicted probability (PP) of engaging in one or more steps of the HIV Care Continuum. TGD individuals had a higher predicted probability of every HIV Care Continuum outcome compared to cisgender individuals [HIV Care Visits: TGD PP=0.22, 95% Confidence Intervals (CI)=0.22-0.24; cisgender PP=0.21, 95% CI=0.21-0.22); Sexually Transmitted Infection (STI) Screening (TGD PP=0.12, 95% CI=0.11-0.12; cisgender PP=0.09, 95% CI=0.09-0.10); ART Prescribed (TGD PP=0.61, 95% CI=0.59-0.63; cisgender PP=0.52, 95% CI=0.52-0.54); and ART Persistence or adherence (90% persistence: TGD PP=0.27, 95% CI=0.25-0.28; 95% persistence: TGD PP=0.13, 95% CI=0.12-0.14; 90% persistence: cisgender PP=0.23, 95% CI=0.22-0.23; 95% persistence: cisgender PP=0.11, 95% CI=0.11-0.12)]. Notably, TFN individuals had the highest probability of every outcome (HIV Care Visits PP =0.25, 95% CI=0.24-0.27; STI Screening PP =0.22, 95% CI=0.21-0.24; ART Prescribed PP=0.71, 95% CI=0.69-0.74; 90% ART Persistence PP=0.30, 95% CI=0.28-0.32; 95% ART Persistence PP=0.15, 95% CI=0.14-0.16) and TMN people or cisgender females had the lowest probability of every outcome (HIV Care Visits: TMN PP =0.18, 95% CI=0.14-0.22; STI Screening: Cisgender Female PP =0.11, 95% CI=0.11-0.12; ART Receipt: Cisgender Female PP=0.40, 95% CI=0.39-0.42; 90% ART Persistence: TMN PP=0.15, 95% CI=0.11-0.20; 95% ART Persistence: TMN PP=0.07, 95% CI=0.04-0.10). The main limitation of this research is that TGD and cisgender beneficiaries were included based on their observed care, whereas individuals who did not access relevant care through Fee-for-Service Medicare at any point during the study period were not included. Thus, our findings may not be generalizable to all TGD and cisgender individuals with HIV, including those with Medicare Advantage or other types of insurance. ConclusionsAlthough TGD beneficiaries living with HIV had superior engagement in the HIV Care Continuum than cisgender individuals, findings highlight notable disparities in engagement for TMN individuals and cisgender females, and engagement was still low for all Medicare beneficiaries, independent of gender. Interventions are needed to reduce barriers to HIV care engagement for all Medicare beneficiaries to improve treatment outcomes and reduce HIV-related morbidity and mortality in the US.

IntroductionTo prioritize and tailor interventions for ending AIDS by 2030 in Africa, it is important to characterize the population groups in which HIV viraemia is concentrating. MethodsWe analysed HIV testing and viral load data collected between 2013-2019 from the open, population-based Rakai Community Cohort Study (RCCS) in Uganda, to estimate HIV seroprevalence and population viral suppression over time by gender, one-year age bands and residence in inland and fishing communities. All estimates were standardized to the underlying source population using census data. We then assessed 95-95-95 targets in their ability to identify the populations in which viraemia concentrates. ResultsFollowing the implementation of Universal Test and Treat, the proportion of individuals with viraemia decreased from 4.9% (4.6%-5.3%) in 2013 to 1.9% (1.7%-2.2%) in 2019 in inland communities and from 19.1% (18.0%-20.4%) in 2013 to 4.7% (4.0%-5.5%) in 2019 in fishing communities. Viraemia did not concentrate in the age and gender groups furthest from achieving 95-95-95 targets. Instead, in both inland and fishing communities, women aged 25-29 and men aged 30-34 were the 5-year age groups that contributed most to population-level viraemia in 2019, despite these groups being close to or had already achieved 95-95-95 targets. ConclusionsThe 95-95-95 targets provide a useful benchmark for monitoring progress towards HIV epidemic control, but do not contextualize underlying population structures and so may direct interventions towards groups that represent a marginal fraction of the population with viraemia.

PurposeWe developed metrics to estimate the number of people who could benefit from PrEP using clinical, behavioral, and economic considerations. MethodsWe estimated the distribution of annual HIV acquisition risk in the U.S. population and the number who would benefit from PrEP based on HIV acquisition risk thresholds. Estimates were generated for men who have sex with men (MSM), men who have sex with women (MSW), women who have sex with men (WSM), and people who inject drugs (PWID). Populations were stratified by state, age, and race and ethnicity. Adult PWID were stratified by state and sex. We also derived a measure anchored on a willingness-to-pay threshold to gain one quality-adjusted life year (QALY). ResultsWe estimated 31-57% of MSM could benefit from PrEP by HIV acquisition risk thresholds, and 30% when using the cost-per-QALY threshold. For PWID, estimates ranged from 7% (cost-per-QALY) to 60% (highest risk threshold). MSW and WSM had the lowest proportions estimated to benefit (0-11%), but the absolute number of individuals remained large due to the size of these populations. DiscussionThese estimates provide a broader framework in which to examine need for PrEP at the population and program level in the United States.

ImportancePeople living with HIV (PLWH) are at increased risk for cardiovascular disease (CVD), which includes both cardiac and cerebrovascular outcomes. Current CVD prediction models underestimate risk in this population, highlighting the need for improved risk stratification tools. ObjectiveTo assess whether adding neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), emerging biomarkers of systemic inflammation derived from routine complete blood counts to the Atherosclerotic Cardiovascular Disease (ASCVD) risk score improves 10-year CVD prediction in PLWH. DesignRetrospective cohort study from 2009 to 2019 using electronic health records from the Bronx Regional Health Information Organization. SettingRegional public health information exchange (Bronx, New York). ParticipantsAdults aged [&ge;]18 years, including 11,334 PLWH and 31,276 demographically matched people without HIV (1:3 ratio). Individuals with pre-existing CVD were excluded. Mean age was 49 years, 45% female, 67% Black/African American, 39% Hispanic/Latino. ExposuresHIV status, ASCVD risk scores, and inflammatory markers (NLR, PLR quartiles) derived from routine complete blood count parameters. Main Outcomes and MeasuresIncident CVD identified via ICD-9/10 diagnostic codes over 10-year follow-up. Multivariable logistic regression models assessed associations between HIV status, ASCVD risk, and inflammatory marker quartiles with outcomes. Model performance was compared using likelihood ratio tests. ResultsPLWH were younger (47 vs. 49 years), more likely to be current smokers (53% vs. 33%), and had lower total cholesterol levels (173 vs. 187 mg/dL) (all p<0.001). PLWH had higher incident CVD rates (26% vs. 22%, p<0.001), including cerebrovascular disease (9.6% vs. 6.5%, p<0.001). In the fully adjusted model, HIV-positive status was associated with 32% higher odds of CVD (OR 1.316; 95% CI: 1.249-1.386). The highest NLR quartile was strongly associated with increased disease odds (OR 1.540; 95% CI: 1.430-1.658), while higher PLR quartiles showed protective effects. The full model achieved an AUC of 0.70, with likelihood ratio tests confirming significant improvements in predictive power (all p[&le;]0.0004). Conclusions and RelevanceAdding NLR and PLR quartiles to ASCVD risk scores significantly improves 10-year CVD prediction in PLWH. These routine, low-cost, readily available biomarkers could enhance cardiovascular risk stratification for this high-risk population.

BackgroundDespite advances in HIV treatment and prevention, men who have sex with men (MSM) remain disproportionately affected by HIV worldwide. This systematic review summarizes the results of mathematical modeling studies that evaluated whether interventions might eliminate HIV in MSM populations by geographical setting, type of intervention(s), elimination definition, and model characteristics. MethodsWe searched Embase and PubMed for modeling studies published between July 1, 2016 and January 7, 2025. Studies were included if they used a dynamic model to assess the impact of interventions on HIV transmission among MSM. Data were extracted on article information, study population, interventions, elimination definitions, model type, model structure, and calibration. The studies were critically appraised by evaluating the comprehensiveness of their models in addressing elimination. FindingsOf the 3,250 identified records, 89 studies were included. MSM populations in only five of the eight Joint United Nations Programme on HIV/AIDS (UNAIDS) regions were modeled, with over half of the models considering MSM in the USA. Complex agent-based models (ABMs) were as common as simpler compartmental models overall, with ABMs more frequently used in Western and Central Europe and North America (WCENA), while compartmental models predominated elsewhere. Thirty-nine of the 89 studies defined elimination as reductions or thresholds in HIV incidence or prevalence, a reproduction number below one, or the elimination of racial disparities. Elimination was achieved in 36 out of 50 modeled scenarios, but the authors of only six of these 36 scenarios thought the interventions required to achieve elimination were feasible. The six feasible elimination scenarios were reported in compartmental models for few countries in Western Europe and Asia. Models in which elimination was achieved most commonly used a combination of interventions that included pre-exposure prophylaxis (PrEP) and/or test-and-treat, except in Africa, where PrEP was not included. InterpretationModeling efforts to understand HIV elimination prospects among MSM outside WCENA should be intensified. To enhance study comparability and for models to contribute effectively to public health policy, the use of an elimination definition based on an incidence threshold would be the most valuable. Furthermore, by identifying gaps in current studies, we recommend novel research directions for modeling to inform a coordinated global response for HIV elimination among MSM.

BackgroundAntiretroviral therapy (ART) suppresses viral replication in most people living with HIV-1 (PLWH). However, PLWH remain at risk of viral rebound. HIV-1 infection modifies the content of extracellular vesicles (EVs). The changes in microRNA content in EVs are biomarkers of immune activation and viral replication in PLWH. Moreover, viral molecules are enclosed in EVs produced from infected cells. Our objective was to assess the value of EV-associated HIV-1 RNA as a biomarker of immune activation and viral replication in PLWH. MethodsPlasma samples were obtained from a cohort of 53 PLWH with a detectable viremia. Large and small EVs were respectively purified by plasma centrifugation at 17,000 x g and by precipitation with ExoQuick. HIV-1 RNA and microRNAs were quantified in the EV subtypes by RT-qPCR. FindingsHIV-1 RNA content was higher in large EVs of ART-naive PLWH. Small EVs HIV-1 RNA was equivalent in ART-naive and ART-treated PLWH and positively correlated with CD4/CD8 T cell ratio. In ART-naive PLWH, HIV-1 RNA content of large EVs correlated with small EV-associated miR-29a, miR-146a and miR-155, biomarkers of viral replication and immune activation. A receiver operating characteristics analysis showed that HIV-1 RNA in large EVs discriminated PLWH with a high CD8 T cell count. InterpretationHIV-1 RNA in large EVs was associated with viral replication and immune activation biomarkers. Inversely, HIV-1 RNA in small EVs was related to immune restoration. Overall, these results suggest that HIV-1 RNA quantification in purified EVs could be a useful parameter to monitor HIV-1 infection. FundingCanadian Institutes of Health Research (CIHR) grants MOP-391232; MOP-188726; MOP-267056 (HIV/AIDS initiative) Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAntiretroviral therapy (ART) suppress viral replication to make HIV-1 infection manageable, but fails to clear the virus from people living with HIV-1 (PLWH). Hence, the infection becomes a chronic condition characterized by a dysfunction of the immune system caused by repeated activation and a persistent risk of a resurgence of viral replication (viral rebound). New biomarkers are required to improve the care of PLWH by identifying the individuals with a greater immune dysfunction and/or a higher risk of viral rebound. HIV-1 infection modifies the abundance, size and content of plasmatic extracellular vesicles (EVs). Specific host microRNAs enrcichment in EVs correlates with immune activation and viral rebound. In addition, viral proteins and genomic material are found within EVs. Various EV subtypes are released by infected cells, all using different biogenesis machinery. The distribution of HIV-1 RNA in EV subtypes has never been assessed and this novel parameter could provide information on the infection progression. Added value of this studyThis study provides the first quantification of HIV-1 RNA in two EV subtypes, large and small, from the plasma of PLWH. Large EVs HIV-1 RNA was lower in ART-treated PLWH and decreased with the duration of treatment. HIV-1 RNA associated to large EVs was a better predictor of immune activation than the standard plasma viral load. Inversely, the HIV-1 RNA concentration in small EVs was unaffected by ART and linked to better immune functions. Overall, the results presented in this study suggest that HIV-1 RNA in large EVs originates from ongoing viral replication, while HIV-1 in small EVs is the produce of proviral transcription. Implications of all the evidenceThe standard procedure for the clinical care of PLWH is to quantify HIV-1 RNA in the whole plasma, disregarding the context of its production. We show that the differential distribution of HIV-1 RNA in large and small EVs seems to be an indicator of disease progression. The purification of plasmatic EVs is considered as a non-invasive liquid biopsy to assess the progression of diseases. PLWH could benefit from the analysis of their plasmatic EVs to monitor the infection with an improved precision.

BackgroundInterleukin-17A (IL-17A) is a key cytokine in inflammation and autoimmunity. However, its systemic correlates, particularly in a high HIV burden population, are not fully elucidated. This study aimed to identify the sociodemographic, clinical, inflammatory, metabolic, and renal factors independently associated with plasma IL-17A levels. MethodsThis cross-sectional analysis enrolled a cohort of adults from Livingstone Teaching Hospital in Zambia. Sociodemographic and clinical variables were systematically collected. Associations between plasma IL-17A levels and a range of covariates were assessed using simple and multiple linear regression analyses in StatCrunch to identify independent correlates. Statistical significance was set at p<0.05. ResultsA cohort of 366 participants was analyzed, characterized by a predominance of females (70.2%) and people living with HIV (73.5%), the vast majority of whom were receiving integrase strand transfer inhibitors (INSTI)-based antiretroviral therapy. Initial bivariate analysis revealed weak associations between IL-17A and various metabolic and inflammatory markers. In the final multivariable model (Model 1), which included all significant univariate variables, five factors were independently associated with IL-17A: IFN-{gamma} ({beta}: 1.17, 95% CI: 1.01-1.33, p<0.0001), IL-1 ({beta}: 1.60, 95% CI: 0.74-2.47, p=0.0004), IL-5 ({beta}: -0.34, 95% CI: -0.65 - -0.040, p=0.0268), soluble ST2 ({beta}: -26.01, 95% CI: -38.15 - -13.87, p<0.0001), and D-dimer ({beta}: -0.006, 95% CI: -0.009 - -0.002, p=0.0012). Plasma potassium was not significant in this full model ({beta}: 0.78, 95% CI: -3.99-5.56, p=0.744). HIV status was not an independent correlate ({beta}: 95.73, 95% CI: -499.68-691.15, p=0.749). A second model (Model 2) was constructed by adjusting for HIV status only. In this model, plasma potassium was a significant independent correlate of IL-17A ({beta}: 10.07, 95% CI: 4.39-15.76, p=0.0006), along with triglycerides, LDL cholesterol, VLDL, IL-6, TNF-, IL-1, IL-5, soluble ST2, fasting glucose, and lymphocyte count. ConclusionIn a comprehensive model, inflammatory markers (IFN-{gamma}, IL-1, IL-5, sST2) and D-dimer were the independent correlates of IL-17A. The relationship between plasma potassium and IL-17A was context-dependent, significant only in a model excluding other inflammatory cytokines. HIV status was not independently associated with IL-17A when inflammatory markers were considered. These findings highlight complex immune interactions and warrant further investigation.

AimsHIV infection is associated with dyslipidemia and an increased risk for cardiovascular diseases. HIV Nef protein downregulates the generation of nascent HDL. The interplay between HIV-RNA, HDL-c level and CD4/CD8 ratio in naive HIV patients remains to be elucidated. MethodsWe included untreated persons living with HIV (PLWH) of the ICONA Foundation Study cohort if they also had [&ge;]2 viral load (VL) measurements prior to ART initiation. We performed unadjusted correlation and linear regression analyses evaluating the effect of VLset on HDL-C. Vlset and CD4/CD8 ratio were fit in the log10 scale, while HDL-c, was fitted in the untransformed raw scale. ResultsWe included 3,980 untreated PLWH. Fifty-eighty (1.5%) were aviremic. We observed a negative correlation between HDL-c and VLset (Pearson R2=0.03), from fitting an unadjusted linear regression model -8.5 mg/dl (95% CI: -15,9 --0,84 p<0.03). There was a dose-response relationship between HDL-c levels and VLset, however, this association was somewhat attenuated after further controlling for gender. Despite a positive correlation between HDL-c and CD4/CD8 ratio, the HDL-c plasma concentration does not satisfy the criteria for a strong surrogate marker. ConclusionsOur data show that HDL-c plasma concentration is significantly lower per higher level of VLSet although this was in part explained by gender. Further analyses should be promoted to better understand the molecular mechanisms that underline the relationship between HIV replication, HDL-c formation, and diseases progression.

BackgroundEpigenome studies of human HIV-1 (HIV) in whole blood have uncovered a growing list of differentially methylated genes associated with either HIV acquisition, disease progression, or both. Cocaine use is associated with increased disease severity, and methylation changes in some of the HIV-associated genes mediate this effect. Many of these genes are critical players in innate immune response, including both regulators and targets of interferon-alpha and NF-kB activation. However, no study to date has evaluated the gene expression dynamics for these genes in the context of HIV. MethodsTargeted gene expression analyses were performed on 588 people who used illicit drugs within a harmonized cohort comprised of the Vancouver People Who Inject Drugs Study (VPWIDS) using RNAseq in whole blood, including 227 people living with HIV (PLWH). Eighteen genes were selected from six recent epigenome-wide association studies to test for differential expression by HIV status. Both gene-level and transcript-level expression changes were estimated using negative binomial regression models. ResultsNine of the 18 target genes exhibited significant upregulation in PLWH after multiple hypothesis testing correction: EPSTI1, IFI44L, IFIT3, MX1, NLRC5, PARP9, PLSCR1, RIN2, and RSAD2. Transcript-level analysis detected additional upregulation of isoforms for genes CD44, RASSF3, and TAP1. Stratified analysis by cocaine use revealed MX1 and RSAD2 to be exclusively upregulated among PLWH who recently used cocaine. Pathway analysis identified significant dysregulation in the interferon alpha/beta signaling pathway. ConclusionsWe confirm the dysregulation of genes previously reported to have differential methylation among PLWH. Results from this study support the model of epigenetic changes altering gene expression for key immune genes such as NLRC5 and MX1, and demonstrate systemic dysregulation of genes involved in innate immune function.

Despite antiretroviral therapy (ART), people with HIV (PWH) on ART experience higher rates of morbidity and mortality vs. age-matched HIV negative controls, which may be driven by chronic inflammation due to persistent virus. We performed bulk RNA sequencing (RNA-seq) on peripheral CD4+ T cells, as well as quantified plasma immune marker levels from 154 PWH on ART to identify host immune signatures associated with immune recovery (CD4:CD8) and HIV persistence (cell-associated HIV DNA and RNA). Using a novel dimension reduction tool - Pairwise Controlled Manifold Approximation (PaCMAP), we defined three distinct participant transcriptomic clusters. We found that these three clusters were largely defined by differential expression of genes regulated by the transcription factor NF-{kappa}B. While clustering was not associated with HIV reservoir size, we observed an association with CD4:CD8 ratio, a marker of immune recovery and prognostic factor for mortality in PWH on ART. Furthermore, distinct patterns of plasma IL-1{beta}, TNF- and GCSF were also strongly associated with the clusters, suggesting that these immune markers play a key role in CD4+ T cell transcriptomic diversity and immune recovery in PWH on ART. These findings reveal novel subgroups of PWH on ART with distinct immunological characteristics, and define a transcriptional signature associated with clinically significant immune parameters for PWH. A deeper understanding of these subgroups could advance clinical strategies to treat HIV-associated immune dysfunction.

BackgroundDaily oral pre-exposure prophylaxis (PrEP) provides effective protection against HIV. Since September 2019, the costs of PrEP have been reimbursed by statutory health insurance in Germany. While a considerable fraction of PrEP-eligible individuals receives PrEP, coverage is inhomogeneous across Germany. This study aims to identify potential barriers associated with PrEP non-use. MethodsBased on the PrApp online cross-sectional study, we analyzed 1,027 PrEP users and 431 non-PrEP users. A PrEP indication was assumed for cis-MSM with an STI diagnosis (12 months), [&ge;] 2 sex partners or sexualized drug use (6 months). Characteristics between PrEP users and PrEP non-users were compared descriptively and using multivariable logistic regression. ResultsNon-PrEP users were more likely to be aged 18-29 years old (P < 0.05) and to use drugs during sex (P < 0.01). The highest PrEP prescriber density (P < 0.01) was associated with PrEP use. Fear of side effects (54.5%) was the most common barrier. Persons with sexualized drug use were more likely to report daily PrEP use as a barrier (34.3% vs. 16.9%, P < 0.01, adjusted P < 0.05). ConclusionsOur analyses indicated structural barriers to PrEP use in federal states with a low HIV-specialists density. For those engaging in sexualized drug use, daily PrEP uptake could potentially be overcome by long-acting PrEP.