HIV Infection Research Articles

Eosinophilic Meningitis in a Patient With Early HIV Infection, Latent Syphilis and HSV-2 Meningitis

Abstract Eosinophilic meningitis is an unusual condition, particularly in patients with HIV infection or syphilis. The detection of herpes simplex virus (HSV)-2 and HIV-1 in cerebrospinal fluid from a patient with acute eosinophilic meningitis has not been previously reported. Herein, we report a case of a 26-year-old cisgender man newly diagnosed with HIV-1 infection and latent syphilis, presenting with headache and low-grade fever. He was diagnosed with both acute eosinophilic meningitis and HSV-2 meningitis, and his condition improved after treatment with acyclovir and penicillin. The compelling case indicates that HSV-2 meningitis may manifest concurrently with acute eosinophilia meningitis in patients coinfected with HIV and Treponema pallidum. Metagenomics next-generation sequencing plays an important role in identifying and further confirming pathogens responsible for central nervous system infections.

Characterising HIV-Indicator conditions among two nationwide long-term cohorts of people living with HIV in Germany (1999-2023).

Information about occurrence and affected groups of symptoms/diagnoses indicative of an HIV infection (so-called HIV indicator conditions; HIV-ICs) is lacking. We analyse HIV-IC incidence, transmission risks and immune status among people living with HIV (PLWH) antiretroviral therapy (ART) naive. Diagnoses reported for ART-naive PLWH from two multicentre observational, prospective cohort studies between 1999-2023 were analysed. Incidence rates per 1,000 person-years (PYs) were calculated for the overall study period and time periods defined by ART treatment recommendations. For further description, CD4 counts around HIV-IC diagnosis (+ -30days) and HIV-transmission routes were collected. In total 15,940 diagnoses of 18,534 PLWH in Germany were included. Of those 81% were male (median age: 36years) and 56% reported being men, who have sex with men as the likely HIV-transmission route. Incidence rates varied between the different HIV-ICs. Syphilis had the highest incidence rate (34 per 1,000 PYs; 95% confidence interval [CI] 29-40) for sexually transmitted infections (STIs), hepatitis B was highest for viral hepatitis diagnoses (18 per 1,000 PYs; 95% CI 17-20); according to CDC-classification herpes zoster for HIV-associated diagnoses (22 per 1,000; 95% CI 20-24) and candidiasis for AIDS-defining diagnoses (30 per 1,000 PYs; 95% CI 29-32). Most PLWH with HIV-ICs (hepatitis, HIV-associated diagnoses and AIDS-defining conditions) had CD4 cell counts < 350. This analysis characterizes HIV-ICs regarding the incidence, HIV-transmission route and patients' immune status. The results underline the importance of HIV-IC-based screening to detect PLWH with already partially impaired immune status and in need of timely ART initiation.

Knowledge and utilization of HIV/AIDs preventive measures among intra-city commercial drivers in Kano State, Nigeria

Background: Intracity commercial drivers play a vital role in transportation systems in many urban centers. However, their occupation puts them at risk for HIV infection due to various factors. Despite their increased vulnerability, intracity commercial drivers face significant challenges in accessing HIV prevention, testing, and treatment services. Method: This was an observational community-based cross-sectional descriptive study conducted among intracity commercial drivers in Kano State, Nigeria through multistage sampling technique. Result: the mean age and standard deviation of respondents was 42.0 ± 11.3. About two-third (67.7%) had good aggregate knowledge score and more than half (57.4%) of the study participant had good uptake and utilization of HIV/AIDs preventive services. After adjusting for the confounding effects using logistic regression analysis; educational status of secondary school (AOR=2.25, 95% CI=1.21–13.25) and post-secondary (AOR=4.10,95%CI=2.22-17.88), monthly income of between N50,0001 – N100,000.00 (AOR=2.02, 95%CI=1.74-19.33) and &gt;N100,000.00 (AOR=4.01, 95%CI=3.11-27.33), working experience of 11 – 20 years (AOR=3.25, 95%CI= 1.16-22.56) and &gt;20 years (AOR=6.05, 95%CI= 3.03-26.77) and good aggregate knowledge scores on HIV/AIDs preventive measures (AOR=4.02 (2.13 – 14.55), 95%CI=2.13-14.55) remained significant predictors of uptake/utilization of HIV/AIDs preventive measures. Conclusion: All agencies responsible for HIV/AIDs control and their partners should take appropriate measures including various strategies to educate this occupational group on sexuality and reproductive health. Also, the establishment of STI clinics in strategic locations, as well as making condoms available, accessible, affordable, and acceptable for use by this group of people in our society, should all be part of the prevention strategy.

Effectiveness, safety, and patient-reported outcomes of emtricitabine/tenofovir alafenamide-based regimens for the treatment of HIV-1 infection: Final 24-month results from the prospective German TAFNES cohort study.

Tenofovir alafenamide (TAF) was introduced in the European Union in 2015 as a novel prodrug of tenofovir showing similar efficacy in clinical trials and a more favorable safety profile than tenofovir disoproxil fumarate (TDF). The German TAFNES cohort study (2016-2019) was conducted to generate real-world evidence. Treatment-naïve (TN) and treatment-experienced (TE) people with HIV (PWH) receiving elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF), rilpivirine/F/TAF (R/F/TAF) or F/TAF + 3rd agent were included. Month (M) 24 outcomes included virologic effectiveness (HIV RNA <50 copies/mL), treatment persistence, adverse drug reactions (ADRs) and patient-reported outcomes, using the HIV Symptom Index (HIV-SI), 36-Item Short Form Health Survey (SF-36) and HIV Treatment Satisfaction (HIVTSQ) questionnaires. The study included 767 PWH (92% men, median age 46 years; 301 TN, 466 TE; E/C/F/TAF [n = 318], R/F/TAF [n = 192], F/TAF + 3rd agent [n = 257]). Among TN, 35% had late HIV diagnosis (CD4 < 350/μL and/or AIDS). Of TE, 95% were on suppressive antiretroviral therapy (ART) before switching. D:A:D (Data Collection on Adverse Effects of Anti-HIV Drugs) 5-year risks for chronic kidney disease were high for about 1 in 10 TN and 4 in 10 TE. Overall treatment persistence at M24 was 81% (E/C/F/TAF: 88%; R/F/TAF: 86%; F/TAF + 3rd agent: 70%, with ART simplification of multiple-tablet regimens in 13%). M24 viral suppression (missing = excluded) was 96% (479/501). Discontinuations due to virologic failure or ADRs were rare, 2% (12/767) and 4% (30/767), respectively. HIV-SI and SF-36 summary scores improved in TN; HIVTSQ change scores showed an improvement in treatment satisfaction in TE. Real-world data confirmed a favorable safety profile and high virologic effectiveness with high treatment satisfaction on F/TAF-based ART.

Death and survival of gut CD4 T cells following HIV-1 infection ex vivo

Abstract The gastrointestinal (GI) tract is ground zero for the massive and sustained CD4 T cell depletion during acute HIV-1 infection. To date, the molecular mechanisms governing this fundamental pathogenic process remain unclear. HIV-1 infection in the GI tract is associated with chronic inflammation due to a disrupted epithelial barrier that results in microbial translocation. Here, we utilized the Lamina Propria Aggregate Culture model to demonstrate that the profound induction of Granzyme B (GZB) by bacteria in primary gut CD4 T cells ex vivo significantly contributes to HIV-1-mediated CD4 T cell death. Counterintuitively, a substantial fraction of gut GZB+ CD4 T cells harboring high levels of HIV-1 infection survive via a pathway linked to CD120b/TNFR2. Our findings underscore novel mechanisms governing the death and survival of gut CD4 T cells during HIV-1 infection that could inform strategies to counter HIV-1 pathogenesis and persistence in this critical tissue compartment.

Bipolar disorder in people with HIV: A nationwide, population-based matched case-control and matched cohort study.

To assess whether bipolar disorders are associated with the risk of HIV infection and whether the risk of bipolar disorders is increased among people with HIV (PWH) and their siblings. Nationwide, population-based, combined matched nested case-control and cohort study of PWH of Danish origin (1995-2021), a comparison cohort from the background population, matched on date of birth and sex, and sibling cohorts. Conditional logistic regression and Cox regression was used to calculate adjusted odds ratios (aORs) for HIV infection and hazard ratios (HRs) among PWH for bipolar disorder and receipt of lithium. We included 5322 PWH and 53,220 comparison cohort members. In the case-control study, bipolar disorder was associated with an increased risk of HIV infection (aOR: 1.9, 95% confidence interval (CI): 1.2-3.0), especially when injection drug use was the route of infection (aOR: 7.6, 95% CI: 2.0-28.9). In the cohort study, we observed an increased risk of bipolar disorders among PWH, especially in the first 2 years of observation (HR: 4.2, 95% CI: 2.4-7.4), whereas the risk of receipt of lithium was lower and the CI crossed 1. The 20-year risk of bipolar disorders for PWH was approximately 1%. Siblings of PWH also had an increased risk of bipolar disorder, but not to the same degree as PWH and not of receipt of lithium. Bipolar disorders are associated with the risk of HIV infection, and PWH have increased risk of bipolar disorder and receipt of lithium beyond what familial factors could explain.

Diagnoses of children living with HIV before and during the COVID-19 pandemic.

There is limited data on diagnoses during hospital stay among children living with HIV(CLHIV) in the antiretroviral and coronavirus disease 2019 (COVID-19) era. The aim of this study was to describe hospital diagnoses and clinical characteristics of CLHIV before and during the COVID-19 pandemic. A retrospective descriptive cross-sectional study was performed. Clinical and laboratory data were retrieved by reviewing folders and discharge summaries from January 2019 to December 2021. Period A (pre-COVID-19) was defined as the period from January 2019 to March 2020. Period B (During COVID-19) was defined as being from April 2020 to December 2021. Ninety-six children contributed 215 diagnoses over the study period. The five most common diagnoses were unspecified HIV disease (47/215, 21.9%), tuberculosis (TB) (42/215, 19.5%), pneumonia (13/215, 6.0%), encephalopathy (11/215, 5.1%) and malnutrition (11/215, 5.1%). Median CD4 count was 377 cells/mm (IQR 126, 726) and 8.0% of the children were virally suppressed. Ninety-five per cent of the children had WHO Stage 3 and 4 (95%) disease and 12.5% of children required ICU admission. No child was diagnosed with COVID-19 despite universal screening. Moreover, 81.7% of the children had a social worker referral documented. Advanced HIV disease (AHD) remains prevalent with TB being the most common diagnosis. There were no cases of COVID-19 recorded in CLHIV. The findings provide a description of the diagnoses of CLHIV in the South African setting prior to and during the COVID-19 pandemic. It highlights the need for more specific documentation of diagnoses to inform better prevention of AHD in children.

Preferences for pre-exposure prophylaxis delivery among HIV-negative pregnant and breastfeeding women in Zambia: evidence from a discrete choice experiment.

Pregnant and breastfeeding women at substantial risk for HIV infection in sub-Saharan Africa can benefit from biomedical interventions such as pre-exposure prophylaxis (PrEP). We estimated the benefit that pregnant and breastfeeding women may derive from PrEP service delivery in order to guide PrEP roll-out in the target population in Zambia. Between September and December 2021, we conducted a discrete choice experiment (DCE) among a convenient sample of 389 pregnant and breastfeeding women not living with HIV in Lusaka, Zambia. Women aged 18 years or older, with a documented negative HIV result in their antenatal card responded to a structured questionnaire containing 12 choice sets on service delivery attributes of PrEP: waiting time at the facility, travel time to the facility dispensing PrEP, location for PrEP pick-up, health care provider attitude and PrEP supply at each refill. Mixed logit regression analysis was used to determine the participant's willingness to trade off one attribute of PrEP for the other at a 5% significance level. Willingness to wait (WTW) was used to determine the relative utility derived from each attribute against waiting time. Waiting time at the facility, travel time to the facility, health care provider attitude and amount of PrEP supply at each refill were important attributes of PrEP service delivery (all p < 0.01). Participants preferred less waiting time at the facility (β = -0.27, p < 0.01). Women demonstrated a strong preference for a 3-months' supply of PrEP (β = 1.69, p < 0.01). They were willing to wait for 5 h at the facility, walk for more than an hour to a facility dispensing PrEP, encounter a health care provider with a negative attitude in order to receive PrEP enough for 3 months. Patient-centered approaches can help to inform the design and implementation of PrEP services among pregnant and breastfeeding women. In this study, we found that a reduction in clinic visits-including through multi-month dispensing of PrEP-could improve uptake of services in antenatal and postnatal settings.

Stochastic optimal control of pre-exposure prophylaxis for HIV infection for a jump model.

We analyze a stochastic optimal control problem for the PReP vaccine in a model for the spread of HIV. To do so, we use a stochastic model for HIV/AIDS with PReP, where we include jumps in the model. This generalizes previous works in the field. First, we prove that there exists a positive, unique, global solution to the system of stochastic differential equations which makes up the model. Further, we introduce a stochastic control problem for dynamically choosing an optimal percentage of the population to receive PReP. By using the stochastic maximum principle, we derive an explicit expression for the stochastic optimal control. Furthermore, via a generalized Lagrange multiplier method in combination with the stochastic maximum principle, we study two types of budget constraints. We illustrate the results by numerical examples, both in the fixed control case and in the stochastic control case.

HIV-1 latency reversal agent boosting is not limited by opioid use.

Opioid use may impact the HIV-1 reservoir and its reversal from latency. We studied forty-seven virally suppressed people with HIV (PWH) and observed that lower concentration of HIV-1 latency reversal agents (LRA), used in combination with small molecules that did not reverse latency, synergistically increased the magnitude of HIV-1 re-activation ex vivo, regardless of opioid use. This LRA boosting, which combined a Smac mimetic or low-dose protein kinase C agonist with histone deacetylase inhibitors, generated significantly more unspliced HIV-1 transcription than phorbol 12-myristate 13-acetate (PMA) with ionomycin (PMAi), the maximal known HIV-1 reactivator. LRA boosting associated with greater histone acetylation, modulated surface activation-induced markers, and altered T cell production of TNFα, IL-2, and IFNγ. HIV-1 reservoirs in PWH contained unspliced and polyadenylated (polyA) virus mRNA, the ratios of which were greater in resting than total CD4+ T cells and correct to 1:1 with PMAi exposure. We characterized treated suppressed HIV-1 infection as a period of inefficient, not absent, virus transcription. Multiply spliced HIV-1 transcripts and virion production did not consistently increase with LRA boosting, suggesting the presence of a persistent post-transcriptional block. LRA boosting can be leveraged to probe mechanisms of an effective cellular HIV-1 latency reversal program.

Central Memory CD4 T Cells from Persons with HIV Accumulate DNA Content Defects During Proliferative Response.

Central memory (TCM) cells are a subpopulation of CD4 T cells that sustain overall CD4 T cell counts in HIV infection. The mechanisms underlying their eventual demise, which leads to loss of CD4 T cell counts, are not known. To understand their proneness to death despite their increased movement to proliferation, we examined cell division together with possible cell accumulation in different phases of the cell cycle. Purified circulating TCM cells from untreated people living with HIV (PLWH) (n = 9) and healthy controls (n = 10) were stimulated in vitro using anti-CD3/CD28 agonistic antibodies plus IL-2 and cultured for 4 days. Cell viability, DNA content, proliferation, and cyclin A and cyclin B expression were measured. We found that PLWH TCM cells more frequently had a DNA content lower than G0/G1, compared with controls (p = .043). These cells accumulated with each division. The proportion of cells with sub-G0/G1 DNA content that were cycling (expressing cyclin A) was greater in the PLWH group (p = .003). The percentage of TCM cells expressing cyclin A+ among those in G0/G1 and was also greater in the PLWH group (p = .043), suggesting arrest before G2/M. While TCM cells from PLWH can proliferate, during this process some of them accumulate defects in DNA content that are incompatible with viability, suggesting that they could be intrinsically prone to cell cycle-dependent death. This provides a possible mechanism underlying the increased TCM cell turnover in HIV infection.

Efficacy of specific drug class therapy in pulmonary arterial hypertension associated with HIV, portal hypertension or both: a single Center experience

Abstract Background Pulmonary arterial hypertension (PAH) is a rare complication of both HIV infection (HIV-PAH) and portal hypertension (Po-PAH); it can occur in patients with both diseases (HIV/Po-PAH). The use of the PAH-specific drug classes (prostanoids, endothelin-1 receptor antagonists [ERA] and phosphodiesterase-5 inhibitors [PDE5-i]) is largely justified by retrospective and observational case reports since, to date, there are no randomized clinical trials except for the PORTICO trial which demonstrated the efficacy of macitentan in Po-PAH. Purpose the aim of the study was to evaluate the efficacy of PAH-specific drugs, both monotherapy and dual oral upfront therapy (ERA + PDE5i started within 1 month apart), in patients with Po-PAH, HIV/Po-PAH and HIV-PAH. Methods Between 1998 and 2023 we enrolled patients with Po-PAH, HIV-PAH and HIV/Po-PAH referred to our Center and undergoing monotherapy with prostanoid, ERA and PDE5-I or dual upfront oral therapy. The efficacy of the drugs was assessed by comparing clinical parameters (NYHA functional class), exercise capacity (six-minute walking test) and hemodynamic parameters at baseline and after a treatment period of 3-6 months. The data are expressed as mean and standard deviation and were compared with Student's t-test for paired data. Results 128 patients were enrolled (83 Po-PAH, 23 HIV/Po-PAH and 22 HIV-PAH). 20 were treated with ERA monotherapy, 90 with PDE5-I, 13 with prostanoids and 5 treated with dual oral upfront therapy. Conclusions Prostanoids, ERAs and PDE5-Is, both in monotherapy and as dual upfront oral therapy, are associated with a significant improvement in functional class, exercise capacity and hemodynamic parameters. The effect of such drugs is similar to patients suffering from other forms of PAH.

Effect of antiretroviral treatment on myocardial work and arterial function of treatment-naive patients with HIV

Abstract Background/Aim HIV infection is related with cardiovascular adverse events. We investigated the effects of antiretroviral treatment in myocardial and vascular function of newly diagnosed patients with HIV. Patients and methods A total of 70 newly diagnosed HIV patients (41.2±8.7 years old, 87 % male) were enrolled. Patients were randomized to the newer integrase inhibitor Dolutegravir or to the older protease inhibitor Darunavir/Cobicistat. We measured at baseline and 12 months posttreatment: (a) Left Ventricular (LV) Global Longitudinal Strain (GLS), (b) LV Global Work Index (GWI), Global Constructive Work (GCW), Global Wasted Work (GWW), Global Work Efficiency (GWE), (c) Coronary Flow Reserve (CFR) of Left Anterior Descending Artery. At baseline, we compared the HIV patients with 35 healthy matched controls. Results At baseline patients with HIV had impaired myocardial function, endothelial function and endothelial glycocalyx compared with healthy controls. Twelve months after intervention HIV patients improved myocardial function, as assessed by GLS, GWI, GCW, GWW and GWE (p&amp;lt;0.05). Moreover, twelve months after intervention HIV patients improved endothelial function, as evaluated by an increase in CFR and a decrease in PBR5-25 (p&amp;lt;0.05). Response to therapy was similar between the two groups of treatment. Nevertheless, in HIV patients 12 months post treatment myocardial, endothelial function and endothelial glycocaylyx was impaired in comparison with healthy controls. Conclusions Treatment with antiretroviral therapy partially improves myocardial and arterial function 12 months post treatment.

An integrated approach to enhance vaccine uptake in chronic patients – the VacciNetwork project

Abstract Issue/problem Individuals with chronic illnesses are at a higher risk of infections and their complications. Vaccinations are crucial in reducing this risk and their integration in chronic care pathways can enhance vaccine uptake, but it requires a collaborative approach and increased awareness in care personnel, caregivers and patients. Description of the problem The Local Health Authority of Rome 2 (ASL Roma 2, with approx. 1.3 million residents) initiated an active promotion plan for recommended vaccinations in chronic patients in January 2023, and a Clinical Vaccinology Workbook was produced to guide healthcare workers in promoting vaccinations across various care settings. The plan aims to establish collaborative agreements with hospitals and territorial structures that manage these patients, integrating vaccination plans with clinical and healthcare pathways for a more holistic approach to chronic disease management, a model that could benefit similar populations globally. Results Data was extracted from administrative databases regarding vaccinations performed in 2022 and 2023 on fragile subjects, i.e., those with a marked ‘risk condition’, aged ≥18 years. The results showed that vaccine uptake was more than doubled (6675 vs. 2041; +227%). Notably, vaccinations rose among those with oncological-hematological diseases (+212%), asplenia (+185%), chronic kidney failure or on dialysis (+190%) and those with an HIV infection (+160%). Increases were also significant in other immunocompromised conditions (+194%). Lessons The practice underlines the importance of targeted vaccination programs within chronic care management. Collaborative healthcare frameworks can significantly improve vaccination rates, reducing the burden of infectious diseases in high-risk populations. These results underscore the potential applicability of such a model in other regions and countries, highlighting the universal relevance of integrated healthcare solutions. Key messages • Collaborative, integrated frameworks between clinical and vaccination services can represent a model for increasing vaccine uptake in chronic disease patients. • Strategic partnerships and education in healthcare settings can improve vaccination rates and contribute to more holistic chronic disease management.

High rates of Treponema pallidum, Neisseria gonorrhoeae, Chlamydia trachomatis, or Trichomonas vaginalis co-infection in people with HIV: a systematic review and meta-analysis.

People living with HIV (PWH) experience a disproportionate burden of sexually transmitted infections (STIs), leading to more severe health outcomes and increasing the risk of HIV transmission. The presence of untreated STIs can accelerate HIV disease progression, while HIV infection can complicate STI diagnosis and treatment. Despite this interconnectedness, comprehensive data on the global prevalence of specific STIs among PWH remain limited. This systematic review aims to synthesize existing data to provide a more accurate picture of the prevalence of co-infection with Treponema pallidum, Neisseria gonorrhoeae, Chlamydia trachomatis or Trichomonas vaginalis in PWH, while also identifying critical knowledge gaps and informing future research priorities. We searched databases for eligible studies reporting the prevalence of Treponema pallidum, Neisseria gonorrhoeae, Chlamydia trachomatis, or Trichomonas vaginalis among PWH, published from January 1, 2000, to February 1, 2023. From 22,290 identified articles, 127 independent studies meeting the inclusion criteria were included in this meta-analysis. The overall global co-infection prevalence of Treponema pallidum, Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis in PWH, was 4.8% (95%CI: 4.7-5.0%), 0.8% (95%CI: 0.6-0.9%), 2.5% (95%CI: 2.2-2.7%), and 3.0% (95%CI: 2.7-3.3%), respectively. The global prevalence of these four STIs in PWH is high, especially in Africa and Southeast Asia and in MSM and TGW populations. Based on the subgroup analyses, we further found that there was a high prevalence of Treponema pallidum and Chlamydia trachomatis in Southeast Asia and a high infection of Trichomonas vaginalis in the whole of Africa. Treponema pallidum infection was more common in males than females, and Chlamydia trachomatis and Trichomonas vaginalis infections were more common in females than males. Besides, high infection rates of Treponema pallidum, Neisseria gonorrhoeae, and Chlamydia trachomatis were detected in men who have sex with men (MSM) + transgender women (TGW), while high infection rates of Trichomonas vaginalis were found in sex workers and pregnant women. The study confirmed high prevalence of four sexually transmitted pathogens in PWH, noting regional, gender, and subpopulation-specific differences. It offered insights for targeted interventions and healthcare strategies. The research underscored the necessity for enhanced data collection and expanded screening/treatment for vulnerable populations and regions.

Exploring the associations of tobacco smoking and serum cotinine levels with selected inflammatory markers in adults with HIV in South Africa

This study examined the associations between tobacco smoking and serum cotinine levels, an objective biochemical measure of tobacco smoke exposure, with markers of inflammation, i.e., interferon-gamma (IFN-γ), interleukin 10 (IL-10), interleukin 2 (IL-2) and tumour necrosis factor-alpha (TNF-α) in people living with HIV (PLWH).These specific markers were selected because of their hypothesised associations with smoking, PLWH and their outcomes. In a random sample of ≥ 18-year-old PLWH receiving care at 17 public healthcare facilities across the Western Cape Province in South Africa, data collection included self-reported smoking history, and serum levels of cotinine and selected inflammatory markers. The inflammatory marker data were log transformed because of the skewedness of their distribution. Linear regression models (1) adjusted for age and gender, and (2) fully adjusted for age, gender, current alcohol use, body mass index and CD4 counts were used to examine the associations between smoking tobacco or serum cotinine and inflammatory markers. Level of significance was p < 0.05. Among 749 PLWH who were mainly women (79%), the mean age was 38.5 (8.9) years and similar when stratified by smoking status. Serum cotinine levels exhibited a striking discrepancy, with a median of 154 ng/mL among current smokers, in stark contrast to the consistent median values of 10 ng/mL observed among past and never smokers. In regression models adjusted for age and gender, current smoking and frequent smoking were associated with lower IL-2 but higher TNF-α. Log-cotinine exhibited associations with IFN-γ, IL-10, and TNF-α, while cotinine levels ≥ 10 ng/mL compared to < 10 ng/mL were associated with higher IFN-γ and TNF-α. In fully adjusted models, log-cotinine and cotinine levels ≥ 10 ng/mL displayed significant associations with higher IFN-γ and lower IL-2. This study underscores the importance of investigating the interplay between smoking tobacco or serum cotinine levels with pro-inflammatory cytokines in PLWH. It signals the need for comprehensive research to unravel the potential synergistic impacts of smoking tobacco and HIV infection on chronic inflammation and immune dysregulation, shedding light on critical avenues for intervention and management strategies.

HIV-1 transmission clusters and drug resistance in men who have sex with men in Portugal

Abstract Introduction In 2022, 45.8% of diagnoses in the EU/EEA with known route of transmission were in Men who have Sex with Men (MSM). We aim to characterise HIV transmission clusters and transmission of drug resistance (TDR), as well as its determinants, using integrated sociodemographic, behavioural, clinical, and viral genomic data of MSMs newly diagnosed in Portugal between 2014 and 2019. Methods This study included data from 340 MSM who were diagnosed with HIV-1 infection. These individuals were newly diagnosed at 17 hospitals in Portugal between September 2014 and December 2019. Phylogenies were constructed and transmission clusters were identified with branch support ≥ 90% and 1.5% genetic distance. Logistic regression models were computed to examine the factors associated with clusters of transmission and with the presence of TDR. Results We identified 38 transmission clusters with 104 MSM, which included 26.6% of the total 305 MSM from our database used for cluster analysis. The overall prevalence of TDR was 8.2%. Only subtype C was significantly associated with TDR. 10.5% of the clusters had at least 1 drug resistance mutation (K103N, L90M or N88S). There was no significant difference in the prevalence of TDR between MSM inside and outside clusters. 50% of the clusters were composed of portuguese native MSM only, whereas 16% had exclusively migrant MSMs. No significant difference was found in the proportion of portuguese and migrant MSM inside and outside clusters. Factors associated with HIV-1 transmission clusters were age at diagnosis, district of residence, unprotected anal or vaginal sex with a woman, HIV testing frequency, presenter status and subtype. 87% of men engaged in sexual activity only with other men, while 13% with both men and women. Conclusions Specific subgroups of MSM are contributing to HIV dissemination in Portugal. Direct and precise prevention measures based on molecular epidemiology should be developed. Key messages • Specific subgroups of MSM are contributing to HIV dissemination in Portugal. • Direct and precise prevention measures based on molecular epidemiology should be developed.

The impacts of tobacco and nicotine on HIV-1 infection, inflammation, and the blood-brain barrier in the central nervous system.

Human immunodeficiency virus (HIV-1) remains a persistent global health crisis. Even while successfully virologically suppressed, people with HIV (PWH) experience a higher risk for inflammatory disorders such as HIV-associated neurocognitive disorder (HAND). Tobacco use puts PWH at higher risk for neurocognitive symptoms resulting from HIV-associated neuroinflammation. The NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome has been implicated as a driver of HIV-associated inflammation, including HAND. Nicotine, the psychoactive component of tobacco smoke, has also been shown to signal through the NLRP3 inflammasome and modulate inflammatory signaling in the CNS. Here, we explore the impacts of nicotine and tobacco on the complex neurobiology of HAND, including effects on cognition, inflammation, viral latency, and blood-brain barrier integrity. We outline nicotine's role in the establishment of active and latent infection in the brain and posit the NLRP3 inflammasome as a common pathway by which HIV-1 and nicotine promote neuroinflammation in PWH.

Potent broadly neutralizing antibodies mediate efficient antibody-dependent phagocytosis of HIV-infected cells.

Antibody-dependent cellular phagocytosis (ADCP) has been implicated in protection against HIV-1. However, methods for measuring ADCP currently rely on the phagocytosis of gp120- or gp41-coated beads that do not reflect physiologically relevant conformations of the viral envelope glycoprotein or the size of a virus-infected cell. We therefore developed a novel approach for measuring ADCP of HIV-infected cells expressing natural conformations of Env. A monocytic cell line (THP-1 cells) or primary human monocytes were incubated with a CD4+ T cell line that expresses eGFP upon HIV-1 infection in the presence of antibodies and ADCP was measured as the accumulation of eGFP+ material by flow cytometry. The internalization of HIV-infected cells by monocytes was confirmed visually by image-capture flow cytometry. Cytoskeletal remodeling, pseudopod formation and phagocytosis were also observed by confocal microscopy. We found that potent broadly neutralizing antibodies (bnAbs), but not non-neutralizing antibodies (nnAbs), mediate efficient phagocytosis of cells infected with either primary or lab-adapted HIV-1. A nnAb to a CD4-inducible epitope of gp120 (A32) failed to enable ADCP of HIV-infected cells but mediated efficient phagocytosis of gp120-coated beads. Conversely, a bnAb specific to intact Env trimers (PGT145) mediated potent ADCP of HIV-infected cells but did not facilitate the uptake of gp120-coated beads. These results underscore the importance of measuring ADCP of HIV-infected cells expressing physiologically relevant conformations of Env and show that most antibodies that are capable of binding to Env trimers on virions to neutralize virus infectivity are also capable of binding to Env on the surface of virus-infected cells to mediate ADCP.

Footprints of innate immune activity during HIV-1 reservoir cell evolution in early-treated infection.

Antiretroviral treatment (ART) initiation during the early stages of HIV-1 infection is associated with a higher probability of maintaining drug-free viral control during subsequent treatment interruptions, for reasons that remain unclear. Using samples from a randomized-controlled human clinical trial evaluating therapeutic HIV-1 vaccines, we here show that early ART commencement is frequently associated with accelerated and efficient selection of genome-intact HIV-1 proviruses in repressive chromatin locations during the first year after treatment initiation. This selection process was unaffected by vaccine-induced HIV-1-specific T cell responses. Single-cell proteogenomic profiling demonstrated that cells harboring intact HIV-1 displayed a discrete phenotypic signature of immune selection by innate immune responses, characterized by a slight but significant upregulation of HLA-C, HLA-G, the IL-10 receptor, and other markers involved in innate immune regulation. Together, these results suggest an accelerated immune selection of viral reservoir cells during early-treated HIV-1 infection that seems at least partially driven by innate immune responses.