HIV Infection Research Articles

Ongoing crisis across the HIV care continuum: high mortality among PWH admitted to the ICU in an urban safety-net hospital in the South

ABSTRACT We present a retrospective study of people with HIV (PWH) admitted to the medical intensive care unit (MICU) of an 862-bed academic, safety-net hospital. We aimed to determine the characteristics of ICU admissions among PWH, measure the mortality in this population and identify predictors of mortality. All patients ≥ 18 years old with a diagnosis of HIV infection admitted to the MICU between January 1, 2017 and December 31, 2019 were included. A total of 195 ICU admissions occurred during the study period. The mean age was 46.2 years, 77.4% were male and the majority were people of color. Overall, 125 (64.8%) patients had CD4<200 cells/mL and 12 (6.7%) were newly diagnosed with HIV. ICU mortality was 21.5% and hospital mortality was 24.6%. High APACHE score and CD4<200 were independent predictors of ICU mortality. Our three-year retrospective analysis of PWH admitted to the ICU in a large urban safety-net hospital in the US South during the recent modern ART era identified high ICU- and hospital mortality. We also identified a higher mortality risk at each step of the HIV care cascade, reinforcing the importance of proactive interventions including expanded HIV testing and implementation of strategies which improve engagement in care, ART adherence and virologic suppression.

Epidemiological, Clinical, Biological and Therapeutic Profile of Bacterial Meningitis and Factors Associated with Lethality: A Retrospective Study in the Clinic Infectious and Tropical Diseases of Fann Hospital (2020-2023)

Introduction: Bacterial meningitis remains a major public health problem in Africa, with a persistently high incidence and case fatality. The objective of this study is to describe the epidemiological, clinical, biological and therapeutic profile of bacterial meningitis, and to identify the factors associated with lethality. Patients and Methods: A descriptive and analytical retrospective study was conducted from the records of patients hospitalized for bacterial meningitis at the SMIT in Fann January 2020 and December 31, 2023. A multivariate regression analysis, with a significance threshold set at 5%, was performed using R software version 4.2.0. Results: During the study period, we collected 138 inpatient records of patients hospitalised for bacterial meningitis, representing a hospital frequency of 3.06%. The median age of patients was 35 years with IQR: [27-52]. HIV infection (17.39%), high blood pressure (8.76%) and diabetes (8.03%) were the most common comorbidities. Cerebrospinal fluid (CSF) was clear in nearly half of the cases (49.28%), and cytology found a predominantly polynuclear neutrophil white blood cell count in 50% of cases. The median length of hospital stay was 10 days with IQI [7-17]. The most commonly used antibiotic was ceftriaxone, which was administered to 92.04% of patients. During hospitalization, 49 patients died, i.e., a case fatality rate of 35.51%. Factors associated with death were HIV infection (aOR= 3.09; 95% CI [1.05-9.57]), p-value=0,041, a Glasgow score &lt; 13 (aOR: 3.62; 95% CI [1.57-8.57]), p-value=0,03 and CRP &gt; 96 mg/L (aOR: 2.85; 95% CI [1.25-6.72]), p-value=0,013. Conclusion: Bacterial meningitis has a high lethality rate at the Clinic of infectious and tropical diseases of Fann Hospital. Improving immunization coverage, strengthening diagnostic capacity and early management could reduce this fatality.

Longitudinal analysis of rhesus macaque metabolome during acute SIV infection reveals disruption in broad metabolite classes.

Despite significant advances in antiretroviral therapy and pre-exposure prophylaxis, HIV remains a global challenge. Understanding the underlying immune mechanisms is critical for improving HIV control and therapeutic development. Cellular metabolism represents a crucial yet underappreciated area of immune system function. Metabolite availability and metabolic pathway preferences directly influence the functional response capacity of immune cells and are highly dysregulated during HIV infection. To further the understanding of metabolic impacts of HIV infection, we utilized cutting-edge mass spectrometry-based metabolome interrogation to measure over 500 metabolites using an acute simian immunodeficiency virus infection model in rhesus macaques. Our comprehensive analysis provides insights into the dynamic metabolic landscape throughout early infection, revealing both known and novel metabolic signatures. These findings enhance our understanding of the complex interplay between metabolism and immunity in lentiviral infections, potentially informing new strategies for early detection, prevention, and treatment of HIV.

Activating PKC-ε induces HIV expression with improved tolerability

Despite suppressive antiretroviral therapy (ART), HIV-1 persists in latent reservoirs that seed new HIV infections if ART is interrupted, necessitating lifelong therapy for people with HIV. Activation of latent HIV during ART could improve recognition and elimination of infected cells by the immune system. Protein kinase C (PKC) isozymes increase HIV transcription and hence are potential latency reversal agents. However, the clinical utility of PKCs for this application is limited due to toxicity, which is poorly understood. Our studies showed that PKC activation with multiple classes of agonists leads to widespread platelet activation, consistent with disseminated intravascular coagulation, at concentrations that were similar to those required for T-cell activation. Differential expression analysis indicated that PKC-ε and PKC-η isoforms are expressed at high levels in human CD4+ T cells but not in platelets. Using structure-based drug design, we developed a novel PKC agonist, C-233, with increased selectivity for PKC-ε. C-233 increased both supernatant HIV RNA and p24 expression ex vivo after treatment of CD4+ T cells from ART-suppressed people with HIV. C-233 was 5-fold more potent for T-cell activation relative to platelet activation. Our studies support the use of structure-based drug design to create selective novel PKC agonists for the safe activation of HIV reservoirs and improved tolerability.

Conformational activation and disulfide exchange in HIV-1 Env induce cell-free lytic/fusogenic transformation and enhance infection.

Disulfide exchange is underexplored as a mechanism influencing HIV-1 entry. Prior studies demonstrated that redox enzyme inhibition can prevent HIV-1 infection but with limited mechanistic explanation. We hypothesize that ligand-driven rearrangement ("conformational activation") enables enzyme-mediated disulfide exchange in Env residues ("disulfide trigger") that promotes fusion transformations, enhancing virus entry. We tested soluble CD4 and CD4-binding site entry inhibitors as conformational activators and the ubiquitous redox enzyme thioredoxin-1 (Trx1) as disulfide trigger. We found that combination treatment caused fusion-like Env transformation and pseudovirus lysis, independent of cells. Notably, only compounds associated with gp120 shedding caused lysis when paired with Trx1. In each case, lysis was prevented by adding the fusion inhibitor T20, demonstrating that six-helix bundle formation is required as in virus-cell fusion. In contrast to conformationally activating ligands, neither the ground state stabilizer BMS-806 with Trx1 nor Trx1 alone caused lysis. Order of addition experiments reinforced conformational activation/disulfide trigger as a sequential process, with virus/activator preincubation transiently enhancing lysis and virus/Trx1 preincubation reducing lysis. Lastly, addition of exogenous Trx1 to typical pseudovirus infections exhibited dose-dependent enhancement of infection. Altogether, these data support conformational activation and disulfide triggering as a mechanism that can induce and enhance the fusogenic transformation of Env.IMPORTANCEHIV remains a global epidemic despite effective anti-retroviral therapies (ART) that suppress viral replication. Damage from early-stage infection and immune cell depletion lingers, as ART enables only partial immune system recovery, making prevention of initial virus entry preferable. In this study, we investigate disulfide exchange and its facilitating conformational rearrangements as underexplored, but critical, events in the HIV entry process. The HIV envelope (Env) protein effects cell entry by conformational rearrangement and pore formation upon interaction with immune cell surface proteins, but this transformation can be induced by Env's conformational activation and disulfide exchange by redox enzymes, which then integrates into established processes of HIV entry. The significance of this research is in identifying Env's conformational activation as a mechanistic requirement for initiating fusion by triggering disulfide exchange. This will aid the development of novel preventative strategies against HIV entry, particularly in the context of HIV-enhanced inflammation and comorbidities with redox mechanisms.

Assessing Whether Providing Regular, Free HIV Self-Testing Kits Reduces the Time to HIV Diagnosis: An Internet-Based, Randomized Controlled Trial in Men Who Have Sex With Men.

The risk of onward HIV transmission is strongly influenced by the interval between HIV infection and its diagnosis. The SELPHI trial examined whether this interval could be reduced by offering free HIV self-testing kits to men who have sex with men (MSM). Internet-based RCT of MSM aged ≥16 years, resident in England/Wales, recruited through sexual and social networking sites. The second-stage randomization of SELPHI was open to participants who used an initial free HIV self-test kit, were HIV seronegative, and reported recent condomless anal sex. They were randomized to receive a free HIV self-test kit every 3 months (repeat testing [RT] group) versus no such offer (nRT group). The primary outcome was time from randomization to a confirmed HIV diagnosis, determined from linkage to national HIV surveillance databases. The key secondary outcome was the frequency of HIV testing regardless of test modality. In total, 2308 eligible participants (1161 RT, 1147 nRT) were randomized between April 2017 and June 2018, and followed for 15-27 months. The proportion of participants reporting an HIV test in the previous 3 months was much higher in the RT group (86%) than in the nRT group (39%). Overall, 16 (9 RT, 7 nRT) confirmed HIV diagnoses were observed (0.35/100 person-years), with no difference between the groups (hazard ratio = 1.27 [95% CI: 0.47 to 3.41], P = 0.63). Providing regular free self-testing kits to sexually active MSM was highly acceptable and markedly increased HIV testing. However, in this low incidence cohort, it did not result in a demonstrably more rapid diagnosis of incident infections.

Cerebrospinal fluid biomarkers of inflammation and immune activation associated with neurocognitive impairment among U.S. Latinos living with HIV.

Examine the association between markers of inflammation in the cerebrospinal fluid (CSF) and neurocognitive impairment (NCI) among diverse persons with HIV (PWH). Latino PWH are at higher risk for NCI than non-Latino White PWH (NLW). Evidence of inflammation in cerebrospinal fluid (CSF) can be higher among racial and ethnic minority PWH and has been linked to NCI. We performed a retrospective cross-sectional analysis of 363 PWH who identified as Latinos or NLW. Neurocognitive performance was measured by a comprehensive battery. A focused panel of biomarkers [interleukin-6 (IL-6), soluble CD14 (sCD14), interferon-γ-inducible protein-10 (IP-10), neurofilament light chain (NFL)] was measured in CSF by immunoassay. Covariates included demographic, HIV disease, medical, psychiatric, and substance use characteristics. The cohort consisted of 126 Latinos and 237 NLW (age: M = 42.5, SD = 11.0, 88% male, 51.5% AIDS history; 64% on antiretroviral therapy). Latinos had significantly higher NFL levels than NLW (P < 0.0001, adjusted Cohen's d 1.15), but not among virally-suppressed PWH. In the entire cohort, higher sCD14 was associated with NCI (adjusted odds ratio (aOR) = 2.6, confidence interval (CI) = 1.1-6.5] after adjusting for statistically significant covariates. We did not identify a relationship between ethnicity, inflammation and NCI in this cohort. Future studies might examine sociocultural factors leading to increased inflammation in the CSF in diverse PWH.

The impact of delay in HIV diagnosis on patient survival: analysis of HIV infection trends from 2007 to 2023

Background and purposeHIV disease is one of the major public health challenges and its early diagnosis and timely management play a vital role in reducing mortality. This study examines factors affecting the mortality of HIV patients and the effect of delay in diagnosis on survival.MethodsIn this retrospective cohort study, data from the ART Center of Koppal District Hospital, India, from April 2007 to August 2023 were used. Of the 11,799 patients, 8,092 with complete data were included in the final analysis. Demographic and clinical variables including age, gender, HIV status, treatment, laboratory parameters, TB infection and survival were investigated. Delayed diagnosis was defined as CD4 ≤ 350. Statistical analyzes were performed with Cox regression and survival curves (Kaplan-Meier).ResultsOut of 8092 patients, 5897 (72.8%) had delayed diagnosis. The average survival time for patients with delay was 61.55 months and without delay was 84.09 months. Delay in diagnosis increases the risk of death with HR 3.01 (95% CI: 2.67–3.40) in univariate analysis and HR 1.70 (95% CI: 1.48–1.96) in multivariate analysis. TS/TG patients had a higher risk of death than women with a HR of 1.64 (95% CI: 1.52–1.78) and patients over 45 with a HR of 2.17 (95% CI: 1.94–2.43) compared to those under 30. AIDS stage patients had a higher risk of death with HR 2.54 (95% CI: 2.34–2.75) and TB patients with HR 1.43 (95% CI: 1.31–1.56).Conclusiondelay in diagnosis, age, disease stage and the presence of TB are important factors of mortality in patients with HIV. Early diagnosis and timely management of the disease can reduce the risk of death and increase the life expectancy of patients. Programs to increase awareness and access to diagnostic and treatment services should be strengthened.

Feasibility of HIV self-test implementation among Mizo youths: a field investigation from Northeast India bordering Myanmar

IntroductionThis study investigated the potential of HIV self-test (HIVST) to reach individuals who otherwise might not access testing or antiretroviral therapy (ART). The study had two main objectives: (a) to develop an HIV self-test implementation plan based on the findings from qualitative inquiries with local stakeholders and (b) to examine HIVST uptake among youths in the urban setting of Aizawl district in Mizoram.MethodologyIn the first phase, qualitative in-depth interviews (IDI) were conducted with HIV program officials, religious leaders, community influencers, youths, and key population groups. These inquiries guided the planning of strategic communication, community engagement, HIVST delivery, and linkages with HIV confirmatory testing services in phase two. Factors associated with the non-uptake of HIV confirmatory tests by youths following HIVST were analyzed quantitatively. Additionally, secondary data collected from attendees of the “Integrated Counselling and Testing Centre” (ICTC) were also analyzed.ResultsThe in-depth interviews underscored the need to introduce HIVST among Mizo youths. The respondents emphasized the importance of diverse outreach approaches and communication strategies, including the use of social media platforms, as critical components for successful HIVST implementation. They also provided valuable insights on the optimal locations and methods for making HIVST kits accessible. Among the youths who used HIVST, the majority were first-time testers (1,772/2,101; 84.3%). Those diagnosed with an undiagnosed HIV infection were started on ART. The preference for the blood-based HIVST format (1,162/2101; 55%) was noted to be slightly higher than the saliva-based format. Confirmatory test uptake was significantly higher among those with sero-reactive HIVST results (χ2 23.89; p &amp;lt; 0.001). Factors independently associated with (adjusted odds ratio; AOR with 95% CI) “no-show for HIV confirmatory tests,” which hold significant programmatic implications, included “age &amp;gt; 20 years (1.47; 1.18–1.82),” “gender (men)” (1.25; 1.01–1.55), “education below 10th standard” (5.16; 2.66–10.01), “no prior HIV testing experience” (2.12; 1.61–2.81), and “unwillingness to undergo HIV confirmatory testing” (2.85; 2.05–3.96). Individuals who opted for the blood-based HIVST were 23% less likely (AOR 0.77; 95% CI; 0.62–0.96) to drop out of the HIV confirmatory testing process. Additionally, only 1% of respondents perceived HIVST as having self-harm potential.ConclusionSustained community engagement, effective networking with HIV program officials, and strategic communication were three critical pillars supporting the successful implementation of HIVST. There was a significant increase in HIVST uptake among young first-time testers.

Factors influencing the quality of life and social skills of children living with HIV: A case-control study.

Our objective was to understand the current status of and factors influencing the quality of life and social skills of children living with HIV and to provide a reference for improving medical service management and formulating support policies. A total of 183 children aged 7-14 years, living with HIV, and admitted to the Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention from March 2022 to February 2024 were included retrospectively. We used the children's basic information and their scores from the Quality of Life Scale for Children and Adolescents (QLSCA) and Normal Development of Social Skills From Infant to Junior High School Children (S-M scale) to explore their the status of their quality of life and social skills and the factors influencing both. Four factors (life satisfaction, socio-psychological functioning, physical and mental health, and living environment) and QLSCA T-scores in the case group were significantly lower than those in the control group (p < 0.01). S-M scale scores (self-help, locomotion, operation, communication, socialization, self-direction) in the case group were significantly lower than those in the control group (p < 0.001). The main factors affecting the social skills of children living with HIV were side effects from antiretroviral therapy (odds ratio [OR] 7.365, p < 0.003), comorbidities (OR 12.948, p < 0.006), intellectual development (OR 6.045, p < 0.027), and awareness of HIV infection status (OR 0.261, p < 0.014). Children living with HIV have low quality of life and poor social skills. Clinicians should pay attention to side effects from antiretroviral therapy, comorbidities, children's intellectual development, and their awareness of their HIV infection status.

Sixty Years at the Rega Institute

I started my research career (in 1965) on interferon by identifying polyacrylic acid (PAA) as an interferon inducer. Poly(I).poly(C), discovered by Maurice Hilleman’s group, proved to be more potent as an interferon inducer, and through its mRNA, we were able to clone and express human β-interferon. The discovery of the reverse transcriptase (RT) by Temin and Baltimore (in 1970) brought me to the detection of suramin as a powerful RT inhibitor and enabled Sam Broder and his colleagues to identify suramin as the first inhibitor of HIV replication. In this capacity, it was subsequently superseded by AZT and other 2′,3′-dideoxynucleoside (ddN) analogs, including d4T. In collaboration with Antonín Holý, we discovered several acyclic nucleoside phosphonates as potent inhibitors of both HIV and HBV (hepatitis B virus) replication. In collaboration with Paul Janssen, we identified various non-nucleoside RT inhibitors (NNRTIs) of HIV-1 replication. Of the nucleotide RT inhibitors (NtRTTs), tenofovir emerged as the most promising congener. It was derivatized to its oral prodrugs TDF and TAF. To enhance their efficacy, they were combined with other anti-HIV drugs, and two of them were pursued (and found efficacious) in the Pre-Exposure Prophylaxis (PrEP) of HIV infections.

Stochastic analysis of an HIV model with various infection stages

In this study, we develop a stochastic model that captures the dynamics of HIV infection, encompassing susceptible individuals, asymptomatic HIV-positive individuals, and those exhibiting symptoms. Initially, we examine the existence and stability of both disease-free and endemic equilibria within the deterministic version of the model. Our analytical findings indicate that the basic reproduction number, R0, is a pivotal factor in determining the uniqueness and global stability of these equilibria. Furthermore, we explore the impact of environmental noise on the HIV disease model, identifying two critical thresholds, R1s and R2s (with R2s<R1s). If R1s is less than unity, the disease is likely to be eradicated; conversely, if R2s exceeds unity, the disease will persist, and a unique stationary distribution will emerge. Additionally, our numerical simulations reveal that when R2s<1<R1s, the disease may still face extinction. From an epidemiological viewpoint, our observations suggest that a decrease in environmental noise intensity results in a reduction of the oscillation amplitude in the disease dynamics. Conversely, an increase in noise intensity is associated with a lower mean of infectious individuals and a left-skewed distribution.

Disseminated Histoplasmosis as a Presentation of Advanced HIV-1 Infection in a Non-endemic Country

Disseminated Histoplasmosis as a Presentation of Advanced HIV-1 Infection in a Non-endemic Country

Anxiety, depression and neurocognitive disorder among HIV-infected people in penitentiary institutions of Azerbaijan.

This study aims to assess neurocognitive impairment, depression and anxiety level in HIV-infected individuals in penitentiary institutions of Azerbaijan. A cross-sectional design was used to recruit incarcerated individuals in penitentiary institutions of Azerbaijan meeting the inclusion criteria (diagnosed with HIV). Participants completed standardized assessments to screen anxiety and depression symptoms, hospital anxiety and depression scale and neurocognitive functioning and mini mental status examination. Demographic and clinical data, including age, gender, HIV disease progression, antiretroviral therapy adherence, history of substance abuse and duration of incarceration, were also collected as covariates of interest. The study was approved by Azerbaijan Medical University Ethics Committee (P.23 / 19.05.2022). Data were analyzed using student-Bonferroni and H-Kruskal-Wallis tests. Variance analysis was conducted using the ANOVA test, while discriminant analyses involved the χ2-Pearson test, through SPSS software, version 26. Of the 88 HIV positive patients who agreed to participate, 99% were male, with a median age of 44 years (range: 30-62), median CD4 count 453.1 cells/µl (range: 153-1,290). The prevalence of HIV-associated neurocognitive disorder was 72.7%. Occurrence of comorbid depression and anxiety symptoms was found to be 72% and 67%, respectively. Most patients (59.1%) were HIV-positive for more than five years. Increased depression and anxiety levels were identified mostly in first two years after admission to prison (p < 0.05). HIV-associated neurocognitive disorder was most commonly found among depressed patients (p = 0.009). The findings of this study provide valuable insights into the cooccurrence and interrelationships between anxiety, depression and neurocognitive disorders in individuals with HIV in prisons. It highlights the unique intersection of HIV infection, mental health challenges and incarceration in a country where research on HIV-related issues in prisons is still developing. Ultimately, this study seeks to contribute to identify targeted interventions that address the mental health needs of incarcerated individuals living with HIV in Azerbaijan, promoting their overall well-being and quality of life.

Targeting Ikaros and Aiolos with pomalidomide fails to reactivate or induce apoptosis of the latent HIV reservoir.

HIV persists in people living with HIV (PLHIV) on antiretroviral therapy (ART) in long-lived and proliferating latently infected CD4+ T cells that selectively express pro-survival proteins, including the zinc finger proteins, Ikaros and Aiolos. In this study, we investigated whether pomalidomide, an immunomodulatory agent that induces degradation of Ikaros and Aiolos, could increase the death of HIV-infected cells and/or reverse HIV latency. Using an in vitro model of CD4+ T cells infected with a green fluorescent protein (GFP) reporter virus, pomalidomide increased the expression of the pro-survival protein B cell lymphoma (Bcl)-2 and did not increase apoptosis of GFP+ HIV productively infected CD4+ T cells. Pomalidomide also increased the expression of CD155 and UL16-binding protein (ULBP) stress proteins on GFP+ HIV productively infected CD4+ T cells, but this did not translate to enhanced clearance following co-culture with a natural killer (NK) cell line. Using CD4+ T cells from PLHIV on ART, pomalidomide ex vivo activated memory CD4+ T cells resulting in elevated HLA-DR expression and induced CD4+ T cell proliferation but only in the presence of T cell receptor stimulation with anti-CD3 and anti-CD28. There was no effect on cell-associated HIV RNA or the frequency of intact HIV DNA. In conclusion, despite an increase in stress protein expression, promoting Ikaros and Aiolos degradation in CD4+ T cells using pomalidomide did not directly induce apoptosis of HIV-infected cells or induce HIV latency reversal.IMPORTANCEPeople living with HIV (PLHIV) require lifelong antiretroviral therapy (ART) due to the persistence of latently infected cells. The zinc finger proteins, Ikaros and Aiolos, have recently been implicated in promoting the persistence of latently infected cells. In this study, we investigated the effects of pomalidomide, an immunomodulatory imide drug that induces the degradation of Ikaros and Aiolos, on HIV latency reversal and death of infected cells. Using CD4+ T cells from people living with HIV on suppressive antiretroviral therapy, as well as an in vitro model of productive HIV infection, we found that pomalidomide induced T cell activation and expression of stress proteins but no evidence of latency reversal or selective death of infected cells.

Effects of GS-CA1 on nuclear envelope-associated early HIV-1 infection steps

The novel HIV-1 drugs GS-CA1 and the recently approved lenacapavir (GS-6207) target the viral structural protein capsid (CA). However, their multiple mechanisms of action have not been fully characterized. Here, we investigated the effects of GS-CA1 on the early stages of HIV-1 infection, specifically the steps involving the nuclear envelope, in comparison to the antiviral cytokine IFN-β. Mass spectrometry data indicated that nuclear envelope proteins were only modestly affected by either GS-CA1 treatment or HIV-1 infection, but combining the two had a more significant impact, altering the levels of many proteins including proteasomal components. GS-CA1 induced a small but clear accumulation of HIV-1 capsid cores at nuclear pores, as seen by microscopy, whereas IFN-β caused a strong accumulation of HIV-1 cores at the nuclear envelope but not specifically at nuclear pores. These observations are consistent with GS-CA1 inhibiting the nuclear translocation of HIV-1 capsid cores through nuclear pores.

Quality of life of children who have had infectious diseases of the respiratory, gastrointestinal tracts and HIV infection

In the article the authors consider the problem of studying the quality of children’s life who have had infectious diseases of the respiratory (acute and recurrent) and gastrointestinal tracts (rotavirus infection and chronic hepatitis C), as well as HIV-infection. The relevance of such studies is due to the significant role of infectious pathology in the structure of childhood morbidity, especially acute infections of the upper respiratory tract of multiple and unspecified localization, as well as acute intestinal infections. The methodology of using specially designed questionnaires for children and their caregivers presented, allowing for a comprehensive assessment of various aspects of their quality of life.

SHMT2 regulates CD8+ T cell senescence via the reactive oxygen species axis in HIV-1 infected patients on antiretroviral therapy.

Although antiretroviral therapy (ART) effectively inhibits viral replication, it does not fully mitigate the immunosenescence instigated by HIV infection. Cellular metabolism regulates cellular differentiation, survival, and senescence. Serine hydroxymethyltransferase 2 (SHMT2) is the first key enzyme for the entry of serine into the mitochondria from the de novo synthesis pathway that orchestrates its conversion glutathione (GSH), a key molecule in neutralising ROS and ensuring the stability of the immune system. It remains incompletely understood whether SHMT2 is involved in the senescence of CD8+ T cells, crucial for immune vigilance against HIV. HIV-infected individuals receiving antiretroviral therapy were enrolled in our study. SHMT2-siRNA was electroporated into T cells to disrupt the gene expression of SHMT2, followed by the quantification of mRNA levels of crucial serine metabolism enzymes using real-time PCR. Immunophenotyping, proliferation, cellular and mitochondrial function, and senescence-associated signalling pathways were examined using flow cytometry in CD8+ T cell subsets. Our findings revealed that CD8+ T cells in HIV-infected subjects are inclined towards senescence, and we identified that SHMT2, a key enzyme in serine metabolism, plays a role in CD8+ T cell senescence. SHMT2 can regulate glutathione (GSH) synthesis and protect mitochondrial function, thus effectively controlling intracellular reactive oxygen species (ROS) levels. Moreover, SHMT2 significantly contributes to averting immunosenescence and sustaining CD8+ T cell competence by modulating downstream DNA damage and phosphorylation cascades in pathways intricately linked to cellular senescence. Additionally, our study identified glycine can ameliorate CD8+ T cell senescence in HIV-infected individuals. Decreased SHMT2 levels in HIV-infected CD8+ T cells affect ROS levels by altering mitochondrial function and GSH content. Increased ROS levels activate senescence-related signalling pathways in the nucleus. However, glycine supplementation counteracts these effects and moderates senescence. This study was supported by grants from the National Key R&D Program of China (2021YFC2301900-2021YFC2301901), National Natural Science Foundation of China (82372240), and Department of Science and Technology of Liaoning Province Project for the High-Quality Scientific and Technological Development of China Medical University (2022JH2/20200074).

Definitive local therapy in solitary liver metastatic anal squamous cell carcinoma.

5 Background: Metastatic anal squamous cell carcinoma is rare and associated with a poor prognosis. There is limited evidence on the impact of local interventions on survival outcomes in patients with metastatic disease. We aimed to evaluate the survival of patients with liver-only metastatic anal cancer following definitive local management of liver lesions. Methods: This is a single-institution retrospective cohort study of patients with liver-limited metastatic anal cancer who underwent curative-intent local therapy. Clinical characteristics were collected and analyzed. The Kaplan-Meier method was used to calculate disease-free survival (DFS) and overall survival (OS). Prognostic factors associated with DFS and OS were assessed using Cox-proportional hazards models. Results: Twenty-five patients were included, median age was 59 years, and 92% were female. None of the patients had known HIV infection, 92% had HPV-positive disease and 76% had metachronous liver metastases following locoregional disease. All patients received chemoradiation for the primary lesion Unilobar hepatic involvement was present in 76% of the patients, with 56% having a single metastatic lesion. Pre-intervention systemic therapy was provided to 52% of the patients, including 8 who received carboplatin and paclitaxel, with a median duration of 3 months and ORR of 69%. Definitive treatment of metastatic disease included surgical resection (60%), non-surgical interventions (20%), and multimodal therapy (20%). All patients had viable tumor in the pathological specimen. With a median follow-up of 22 months, median DFS was 7.3 months, and median OS was 51.3 months. An ECOG performance status of 2, poorly differentiated histology, and extrahepatic recurrence were identified as significant prognostic factors in the univariate analysis, but not in the multivariate analysis. Conclusions: Our results demonstrate potential for long-term survival in liver-limited metastatic anal squamous cell carcinoma amenable to local therapeutic intervention combined with systemic therapy. These findings warrant further prospective study of local therapy in oligometastatic anal cancer. Characteristics N=25 (%) Median number of liver metastases (range), lesions- 1- 2-3- &gt;3 1 (1-20)14 (56)8 (32)3 (12) Median maximal diameter of liver metastases (range), cm 3 (0.9-11.9) Best response of liver metastases to chemotherapy (N=13)- Complete response- Partial response- Stable disease- Progressive disease 2 (15)7 (54)3 (23)1 (8) Surgical procedure (N=20)- Right/left hemi-hepatectomy- Segmentectomy- Wedge resection 4 (20)14 (70)2 (10) Non-surgical procedure (N=10)- Local ablation- Radiotherapy- Other 5 (50)3 (30)2 (20) Hepatic surgical margins (N=20)- Positive margins- Close margins (&lt;1mm)- Negative margins 02 (10)18 (90) Recurrent disease- Yeso Intrahepatico Extrahepatic- No 20 (80)14 (70)6 (30)5 (20)

Intersecting Structural and Psychosocial Conditions: Investigating Injection Drug Use and HIV Among Transgender Women.

Transgender women continue to face a significant burden of health disparities with HIV infection as a critical public health concern. Substance use is higher among transgender women than among cisgender women. However, little is known about transgender women who inject drugs and risk for HIV in the United States. The objectives were to explore HIV prevalence, injection-related behaviors, and HIV prevention and care outcomes among transgender women who inject drugs and to compare transgender women with a general sample of persons who inject drugs. Participants from the National HIV Behavioral Surveillance were recruited through respondent-driven sampling, interviewed, and tested for HIV infection in 2019-2020. Log-linked Poisson regression models were used to test for associations between injection drug use and selected characteristics. Among 1561 transgender women, 7% injected drugs in the past 12 months. HIV prevalence was higher among transgender women who inject (adjusted prevalence ratio = 1.5, 95% confidence interval: 1.2 to 1.8) than among those who do not. Multiple psychosocial conditions were associated with injection drug use. Among transgender women with HIV, those who inject were less likely to take antiretroviral therapy (adjusted prevalence ratio = 0.8, 95% confidence interval: 0.7 to 1.0) than those who do not. Methamphetamine was the most commonly injected drug (67%); most accessed a syringe services program (66%). Transgender women who inject have substantial challenges related to health outcomes including high HIV prevalence and exposure to psychosocial conditions, such as homelessness, incarceration, and exchange sex, that may exacerbate risks associated with injection drug use. This population may benefit from increased access to nonjudgmental and culturally competent harm reduction services.