HIV-1 DNA and Immune Activation Levels Differ for Long-Lived T-Cells in Lymph Nodes, Compared with Peripheral Blood, during Antiretroviral Therapy.

Elucidating the mechanisms underlying the persistence and location of the HIV reservoir is critical for developing cure interventions. While it has been shown that levels of T-cell activation and the size of the HIV reservoir are greater in rectal tissue and lymph nodes (LN) than in blood, the relative contributions of T-cell subsets to this anatomic difference are unknown. We measured and compared HIV-1 DNA content, expression of the T-cell activation markers CD38 and HLA-DR, and expression of the exhaustion markers programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) in naive, central memory (CM), transitional memory (TM), and effector memory (EM) CD4+ and CD8+ T-cells in paired blood and LN samples among 14 people with HIV who were receiving antiretroviral therapy. HIV-1 DNA levels, T-cell immune activation, and TIGIT expression were higher in LN than in blood, especially in CM and TM CD4+ T-cell subsets. Immune activation was significantly higher in all CD8+ T-cell subsets, and memory CD8+ T-cell subsets from LN had higher levels of PD-1 expression, compared with blood, while TIGIT expression levels were significantly lower in TM CD8+ T-cells. The differences seen in CM and TM CD4+ T-cell subsets were more pronounced among participants with CD4+ T-cell counts of <500 cells/µL within 2 years after antiretroviral therapy initiation, thus highlighting increased residual dysregulation in LN as a distinguishing feature of and a potential mechanism for individuals with suboptimal CD4+ T-cell recovery during antiretroviral therapy. IMPORTANCE This study provides new insights into the contributions of different CD4+ and CD8+ T-cell subsets to the anatomic differences between LN and blood in individuals with HIV who have optimal versus suboptimal CD4+ T-cell recovery. To our knowledge, this is the first study comparing paired LN and blood CD4+ and CD8+ T-cell differentiation subsets, as well as those subsets in immunological responders versus immunological suboptimal responders.

Increased homeostatic cytokines and stability of HIV-infected memory CD4 T-cells identify individuals with suboptimal CD4 T-cell recovery on-ART.

Clinical outcomes are inferior for individuals with HIV having suboptimal CD4 T-cell recovery during antiretroviral therapy (ART). We investigated if the levels of infection and the response to homeostatic cytokines of CD4 T-cell subsets contributed to divergent CD4 T-cell recovery and HIV reservoir during ART by studying virologically-suppressed immunologic responders (IR, achieving a CD4 cell count >500 cells/µL on or before two years after ART initiation), and virologically-suppressed suboptimal responders (ISR, did not achieve a CD4 cell count >500 cells/µL in the first two years after ART initiation). Compared to IR, ISR demonstrated higher levels of HIV-DNA in naïve, central (CM), transitional (TM), and effector (EM) memory CD4 T-cells in blood, both pre- and on-ART, and specifically in CM CD4 T-cells in LN on-ART. Furthermore, ISR had higher pre-ART plasma levels of IL-7 and IL-15, cytokines regulating T-cell homeostasis. Notably, pre-ART PD-1 and TIGIT expression levels were higher in blood CM and TM CD4 T-cells for ISR; this was associated with a significantly lower fold-changes in HIV-DNA levels between pre- and on-ART time points exclusively on CM and TM T-cell subsets, but not naïve or EM T-cells. Finally, the frequency of CM CD4 T-cells expressing PD-1 or TIGIT pre-ART as well as plasma levels of IL-7 and IL-15 predicted HIV-DNA content on-ART. Our results establish the association between infection, T-cell homeostasis, and expression of PD-1 and TIGIT in long-lived CD4 T-cell subsets prior to ART with CD4 T-cell recovery and HIV persistence on-ART.

Association between where men who have sex with men (MSM) meet sexual partners and chlamydia/gonorrhoea infection before and during the COVID-19 pandemic in San Diego, California.

BACKGROUND: Meeting sex partners online is associated with increased risk of acquiring sexually transmitted infections. We examined whether different venues where men who have sex with men (MSM) meet sex partners was associated with prevalent Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infection, and whether prevalence increased during (vs before) the COVID-19 pandemic. METHODS: We conducted a cross-sectional analysis of data from San Diego's 'Good To Go' sexual health clinic from two enrolment periods: (1) March-September 2019 (pre-COVID-19) and (2) March-September 2021 (during COVID-19). Participants completed self-administered intake assessments. This analysis included males aged ≥18 years self-reporting sex with males within 3 months before enrolment. Participants were categorised as (1) meeting new sex partners in-person only (eg, bars, clubs), (2) meeting new sex partners online (eg, applications, websites) or (3) having sex only with existing partners. We used multivariable logistic regression, adjusting for year, age, race, ethnicity, number of sex partners, pre-exposure prophylaxis use and drug use to examine whether venue or enrolment period were associated with CT/NG infection (either vs none). RESULTS: Among 2546 participants, mean age was 35.5 (range: 18-79) years, 27.9% were non-white and 37.0% were Hispanic. Overall, CT/NG prevalence was 14.8% and was higher during COVID-19 vs pre-COVID-19 (17.0% vs 13.3%). Participants met sex partners online (56.9%), in-person (16.9%) or only had existing partners (26.2%) in the past 3 months. Compared with having only existing sex partners, meeting partners online was associated with higher CT/NG prevalence (adjusted OR (aOR) 2.32; 95% CI 1.51 to 3.65), while meeting partners in-person was not associated with CT/NG prevalence (aOR 1.59; 95% CI 0.87 to 2.89). Enrolment during COVID-19 was associated with higher CT/NG prevalence compared with pre-COVID-19 (aOR 1.42; 95% CI 1.13 to 1.79). CONCLUSIONS: CT/NG prevalence appeared to increase among MSM during COVID-19, and meeting sex partners online was associated with higher prevalence.

Mental Health Service Urgency in Children's Mental Health: Factors Impacting the Need for Expedited Services.

Delayed access to mental health services for children and adolescents has been linked to an increased risk of harm and nonattendance to scheduled appointments. While studies suggest that the lack of standardized assessments for prioritizing individuals has contributed to long wait times, the inconsistent use of assessments across service sectors in Ontario continues to persist. This has contributed to a paucity of information surrounding which children and adolescents may require urgent mental health services. Using a large secondary data set, this study examined whether service sector (e.g., school), and other individual client characteristics (e.g., age, sex, legal guardianship, interpersonal and school conflict) predicted greater mental health service urgency in 61,448 children and adolescents assessed using the interRAI Child and Youth Mental Health Screener. Binary logistic regression revealed that all predictors, except for sector, showed a significant effect on service urgency. Findings are instrumental in prioritization, reducing the likelihood that children with acute needs remain on waitlists.

Fingolimod retains cytolytic T cells and limits T follicular helper cell infection in lymphoid sites of SIV persistence.

Lymph nodes (LN) and their resident T follicular helper CD4+ T cells (Tfh) are a critical site for HIV replication and persistence. Therefore, optimizing antiviral activity in lymphoid tissues will be needed to reduce or eliminate the HIV reservoir. In this study, we retained effector immune cells in LN of cART-suppressed, SIV-infected rhesus macaques by treatment with the lysophospholipid sphingosine-1 phosphate receptor modulator FTY720 (fingolimod). FTY720 was remarkably effective in reducing circulating CD4+ and CD8+ T cells, including those with cytolytic potential, and in increasing the number of these T cells retained in LN, as determined directly in situ by histocytometry and immunohistochemistry. The FTY720-induced inhibition of T cell egress from LN resulted in a measurable decrease of SIV-DNA content in blood as well as in LN Tfh cells in most treated animals. In conclusion, FTY720 administration has the potential to limit viral persistence, including in the critical Tfh cellular reservoir. These findings provide rationale for strategies designed to retain antiviral T cells in lymphoid tissues to target HIV remission.

Bone Marrow-Derived CD4+ T Cells Are Depleted in Simian Immunodeficiency Virus-Infected Macaques and Contribute to the Size of the Replication-Competent Reservoir.

The bone marrow (BM) is the key anatomic site for hematopoiesis and plays a significant role in the homeostasis of mature T cells. However, very little is known on the phenotype of BM-derived CD4+ T cells, their fate during simian immunodeficiency virus (SIV) infection, and their contribution to viral persistence during antiretroviral therapy (ART). In this study, we characterized the immunologic and virologic status of BM-derived CD4+ T cells in rhesus macaques prior to SIV infection, during the early chronic phase of infection, and during ART. We found that BM memory CD4+ T cells are significantly depleted following SIV infection, at levels that are similar to those measured in the peripheral blood (PB). In addition, BM-derived memory CD4+ T cells include a high frequency of cells that express the coinhibitory receptors CTLA-4 and PD-1, two subsets previously shown to be enriched in the viral reservoir; these cells express Ki-67 at levels similar to or higher than the same cells in PB. Finally, when we analyzed SIV-infected RMs in which viral replication was effectively suppressed by 12 months of ART, we found that BM CD4+ T cells harbor SIV DNA and SIV RNA at levels comparable to those of PB CD4+ T cells, including replication-competent SIV. Thus, BM is a largely understudied anatomic site of the latent reservoir which contributes to viral persistence during ART and needs to be further characterized and targeted when designing therapies for a functional or sterilizing cure to HIV.IMPORTANCE The latent viral reservoir is one of the major obstacles in purging the immune system of HIV. It is paramount that we elucidate which anatomic compartments harbor replication-competent virus, which upon ART interruption results in viral rebound and pathogenesis. In this study, using the rhesus macaque model of SIV infection and ART, we examined the immunologic status of the BM and its role as a potential sanctuary for latent virus. We found that the BM compartment undergoes a similar depletion of memory CD4+ T cells as PB, and during ART treatment the BM-derived memory CD4+ T cells contain high levels of cells expressing CTLA-4 and PD-1, as well as amounts of cell-associated SIV DNA, SIV RNA, and replication-competent virus comparable to those in PB. These results enrich our understanding of which anatomic compartments harbor replication virus and suggest that BM-derived CD4+ T cells need to be targeted by therapeutic strategies aimed at achieving an HIV cure.

Bringing together coproduction and community participatory research approaches: Using first person reflective narrative to explore coproduction and community involvement in mental health research.

BACKGROUND: A growing literature explores the coproduction of research knowledge. Barriers to coproduction in mental health research have been identified, especially for the people from marginalized communities. There is an established body of participatory research that has potential to inform coproduction in mental health research. OBJECTIVES: To explore and articulate how learning from community participatory approaches to research enable barriers to knowledge coproduction to be overcome in mental health research. SETTING: An evaluation of a primary care mental health service, led by an experienced survivor researcher, supported by a health service researcher and involving a team of community co-researchers. DESIGN: Cycles of reflective writing (first-person narrative) by the authors, and feedback from the co-researcher team, on their experiences of undertaking the evaluation were used to explore the ways in which community actors, including those from marginalized communities, might be meaningfully involved in producing research knowledge about mental health services. RESULTS: A space was created where community co-researchers, including those from traditionally marginalized communities, felt safe and empowered to move beyond essentialized "service user" identities and bring a range of skills and expertise to the evaluation. There was meaningful rebalancing of power between traditional university and community roles, although the issues around leadership remained complex and more could be done to explore how our different experiences of race and mental health shape the research we do. CONCLUSIONS: Potential was demonstrated for participatory research approaches to inform coproduction of knowledge in mental health research that fully reflects the diversity of identity and experience.

Upper Hemisternotomy Versus Full Sternotomy for Replacement of the Supracoronary Ascending Aorta and Aortic Valve.

OBJECTIVE: Upper hemisternotomy (UHS) for supracoronary ascending aorta replacement (scAAR) with concomitant aortic valve replacement (AVR) results in less trauma and potentially faster convalescence compared with full sternotomy (FS). Direct head-to-head studies are lacking. We compared a group of UHS patients with a matched group of FS patients undergoing scAAR and AVR. METHODS: There were 198 patients who underwent scAAR and AVR procedures by a single surgeon between 1999 and 2020. After matching 6 preoperative characteristics, there were 50 UHS and 50 FS patients. Patients who required acute type A aortic dissection repair, reoperations, concomitant procedures, or hypothermic circulatory arrest were excluded. RESULTS: In the matched sample, the hospital mortality rate was 1% (1 of 100). The median cardiopulmonary bypass time was 150 (interquartile range [IQR], 131 to 172) min and 164.5 (IQR, 138 to 190) min, respectively, for the UHS and FS groups (P = 0.08). The median aortic cross-clamp time was 121 (IQR, 107 to 139) min during UHS and 131 (IQR, 115 to 159) min during FS (P = 0.05). The median ventilation time was 7 (IQR, 3 to 14) h versus 17 (IQR, 10 to 24) h, respectively, after UHS and FS (P = 0.005). The median hospital length of stay was 7 (IQR, 6 to 9) days after UHS and 8 (IQR, 7 to 11) days after FS (P = 0.05). CONCLUSIONS: The low morbidity and mortality support the wider use of UHS for scAAR and AVR in appropriately selected patients. Larger studies are needed to confirm these initial findings.

Nutritional Avocado Intervention Improves Physical Activity Measures in Hispanic/Latino Families: A Cluster RCT.

Introduction: Nutrition and physical activity are key components for the prevention of cardiovascular disease. There remains a paucity of trial data on the effect of specific nutritional interventions on physical activity and sedentary time. One question is how a common nutrient-dense food such as avocado may impact physical activity and sedentary time in Hispanic/Latino families, a group that reports the lowest levels of physical activity. Design: This is a 6-month clustered RCT. Setting/participants: Seventy-two families (235 individuals) who identified as Hispanic/Latino were enrolled through the San Ysidro Health Center (San Diego, CA) between April 2017 and June 2018. Intervention: After a 2-week run-in period, 35 families were randomized to the intervention arm (14 avocados/family/week), and 37 families were assigned to the control arm (3 avocados/family/week). Main outcome measures: Linear mixed-effects models were used to assess changes in physical activity (MET minutes per week) between the groups during the 6-month trial. Secondary outcomes included sedentary time (minutes/week), BMI, and systolic and diastolic blood pressures. Results: An adherence goal of >80% was achieved for both arms. Total mean physical activity increased by 2,197 MET minutes per week more in the intervention group (p<0.01) than in the control group, driven by between-group differences in moderate (p<0.01) versus vigorous (p=0.06) physical activity. After accounting for longitudinal repeated measures per participant and nested family effects, total adult physical activity remained significantly higher in the intervention than in the control group (+1,163 MET minutes per week on average per participant), with a significant intervention interaction term (p<0.01). There were no significant changes in sedentary time, BMI, or blood pressure. Conclusions: Higher allocation of avocados was associated with significantly higher physical activity and no adverse changes in BMI or blood pressure, suggesting that this nutritional intervention may have beneficial pleiotropic effects.Trial registration: This study is registered at www.clinicaltrials.gov as NCT02903433.

Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators.

Familial dysautonomia (FD) is a rare neurodevelopmental and neurodegenerative disease caused by a splicing mutation in the Elongator Acetyltransferase Complex Subunit 1 (ELP1) gene. The reduction in ELP1 mRNA and protein leads to the death of retinal ganglion cells (RGCs) and visual impairment in all FD patients. Currently patient symptoms are managed, but there is no treatment for the disease. We sought to test the hypothesis that restoring levels of Elp1 would thwart the death of RGCs in FD. To this end, we tested the effectiveness of two therapeutic strategies for rescuing RGCs. Here we provide proof-of-concept data that gene replacement therapy and small molecule splicing modifiers effectively reduce the death of RGCs in mouse models for FD and provide pre-clinical foundational data for translation to FD patients.

Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators.

Familial dysautonomia (FD) is a rare neurodevelopmental and neurodegenerative disease caused by a splicing mutation in the Elongator Acetyltransferase Complex Subunit 1 ( ELP1 ) gene. The reduction in ELP1 mRNA and protein leads to the death of retinal ganglion cells (RGCs) and visual impairment in all FD patients. Currently, patient symptoms are managed, but there is no treatment for the disease. We sought to test the hypothesis that restoring levels of Elp1 would thwart the death of RGCs in FD. To this end, we tested the effectiveness of two therapeutic strategies for rescuing RGCs. Here we provide proof-of-concept data that gene replacement therapy and small molecule splicing modifiers effectively reduce the death of RGCs in mouse models for FD and provide pre-clinical data foundation for translation to FD patients.

A cross-sectional examination of service complexity in youths with co-occurring autism spectrum disorder and psychiatric or medical diagnoses across service sectors.

Introduction: Autism spectrum disorder (ASD) is a heterogeneous, life-long, and complex condition. Youth diagnosed with ASD require several supports addressing core symptoms associated with the disorder, but also those resulting from co-occurring mental and physical health conditions. As a result, their care is overseen by numerous professionals spanning various service sectors, but communication between sectors is hindered due to the absence of a standardized assessment system to identify and triage youth to services. A paucity of information surrounding this population's service use lingers and a siloed delivery system persists. Methods: Using archival data collected from 1,020 youth between 12 and 18 years of age, this study explored service complexity among autistic youth with and without psychiatric and medical co-occurring conditions in Ontario, Canada. In doing so, a negative binomial regression was utilized to investigate which predisposing, enabling, and need variables were associated with service complexity. Results: Results revealed that experiencing financial difficulties was not associated with service complexity. However, age, sex, caregiver distress, comorbidity, intellectual disability, and evaluated health status were significant predictors. More specifically, female youth and youth with distressed caregivers had greater mental health service complexity scores. Additionally, youth diagnosed with two or more conditions in addition to ASD who required longer durations of programming, controlling for other predictors, had greater mental health service complexity scores. Yet, youth with an intellectual disability had lower service complexity scores. Discussion: Clinical implications of this study are discussed to inform future investments into mental health efforts for autistic youth.

Limited impact of fingolimod treatment during the initial weeks of ART in SIV-infected rhesus macaques.

Antiretroviral therapy (ART) is not curative due to the persistence of a reservoir of HIV-infected cells, particularly in tissues such as lymph nodes, with the potential to cause viral rebound after treatment cessation. In this study, fingolimod (FTY720), a lysophospholipid sphingosine-1-phosphate receptor modulator is administered to SIV-infected rhesus macaques at initiation of ART to block the egress from lymphoid tissues of natural killer and T-cells, thereby promoting proximity between cytolytic cells and infected CD4+ T-cells. When compared with the ART-only controls, FTY720 treatment during the initial weeks of ART induces a profound lymphopenia and increases frequencies of CD8+ T-cells expressing perforin in lymph nodes, but not their killing capacity; FTY720 also increases frequencies of cytolytic NK cells in lymph nodes. This increase of cytolytic cells, however, does not limit measures of viral persistence during ART, including intact proviral genomes. After ART interruption, a subset of animals that initially receives FTY720 displays a modest delay in viral rebound, with reduced plasma viremia and frequencies of infected T follicular helper cells. Further research is needed to optimize the potential utility of FTY720 when coupled with strategies that boost the antiviral function of T-cells in lymphoid tissues.

Blowing the Whistle on Concussion Knowledge and Education in Youth Sport Referees.

PURPOSE: To gain an understanding of referee concussion knowledge, what sporting organizations were doing to prepare their referees to recognize concussions in youth sport, and what role referees could play in overall concussion safety. MATERIALS AND METHODS: A total of 134 referees participated in the study across four provincial sporting organizations (rugby, soccer, ice hockey, and football). Participants completed a concussion knowledge questionnaire that explored knowledge about concussion education, recognition, management, preparedness, and the role of the referee in overall concussion management. RESULTS: Overall, the sample was found to be moderately knowledgeable about concussions. Referees that received previous formal concussion education had statistically significant higher average scores when compared to those without formalized concussion education (P=0.001). However, only 24% of respondents reported receiving any formal education from their sporting body or referee organization. About 85% felt that referees could play an important role in concussion recognition in youth sport, but only 41% felt they were adequately equipped with the knowledge and skills to recognize these injuries. CONCLUSION: The findings from this study suggest that national, provincial, and individual sporting organizations should ensure that all stakeholders (including referees) are formally educated about concussions to encourage a safety-first environment for youth athletes. Educational sessions should focus on the general aspects of SRC while also focusing on the specific role of the referee in concussion recognition.

IL-21 and IFNα therapy rescues terminally differentiated NK cells and limits SIV reservoir in ART-treated macaques.

Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy, nonpathogenic infections in natural hosts, such African green monkeys, are characterized by a lack of gut microbial translocation and robust secondary lymphoid natural killer cell responses resulting in an absence of chronic inflammation and limited SIV dissemination in lymph node B-cell follicles. Here we report, using the pathogenic model of antiretroviral therapy-treated, SIV-infected rhesus macaques that sequential interleukin-21 and interferon alpha therapy generate terminally differentiated blood natural killer cells (NKG2a/clowCD16+) with potent human leukocyte antigen-E-restricted activity in response to SIV envelope peptides. This is in contrast to control macaques, where less differentiated, interferon gamma-producing natural killer cells predominate. The frequency and activity of terminally differentiated NKG2a/clowCD16+ natural killer cells correlates with a reduction of replication-competent SIV in lymph node during antiretroviral therapy and time to viral rebound following analytical treatment interruption. These data demonstrate that African green monkey-like natural killer cell differentiation profiles can be rescued in rhesus macaques to promote viral clearance in tissues.

Simulating a self-inflicted facial gunshot wound with moulage to improve perceived realism, immersion, and learning in simulation-based airway management training.

Moulage is used to create mock wounds and injuries for clinical education and training. We developed a moulage technique to simulate a facial gunshot wound for use in simulation-based training. We removed sections of a manikin's face and used moulage materials to mock various aspects of the wound. The manikin was used in a simulated scenario that teaches clinicians how to manage a complicated airway. The moulage was evaluated with a self-report questionnaire that assessed participants' perceptions of the realism of the wound, the degree to which the wound contributed to their scenario immersion, and the degree to which the wound enhanced their learning experience on a 5-point Likert scale ranging from 'strongly disagree' to 'strongly agree'. Participants' average response to each item was significantly higher than the neutral midpoint, and the median response was 'strongly agree'. Our work suggests that the simulated facial gunshot wound contributed to perceived scenario immersion and enhancement of the learning experience, supporting existing literature that suggests moulage is a valuable tool in healthcare simulation. Future work could investigate the effect of moulage using objective measures and explore the potential to use extended reality technology in conjunction with moulage to improve immersion even further.

Safety and Immunological Evaluation of Interleukin-21 Plus Anti-α4ß7 mAb Combination Therapy in Rhesus Macaques.

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections compromise gut immunological barriers, inducing high levels of inflammation and a severe depletion of intestinal CD4+ T cells. Expression of α4ß7 integrin promotes homing of activated T cells to intestinal sites where they become preferentially infected; blockade of α4ß7 with an anti-α4ß7 monoclonal antibody (mAb) prior to infection has been reported to reduce gut SIV viremia in rhesus macaques (RMs). Interleukin-21 (IL-21) administration in antiretroviral therapy-treated, SIV-infected RMs reduces gut inflammation and improves gut integrity. We therefore hypothesized that the combination of IL-21 and anti-α4ß7 mAb therapies could synergize to reduce inflammation and HIV persistence. We co-administered two intravenous doses of rhesus anti-α4ß7 mAb (50 mg/kg) combined with seven weekly subcutaneous infusions of IL-21-IgFc (100 µg/kg) in four healthy, SIV-uninfected RMs to evaluate the safety and immunological profiles of this intervention in blood and gut. Co-administration of IL-21 and anti-α4ß7 mAb showed no toxicity at the given dosages as assessed by multiple hematological and chemical parameters and did not alter the bioavailability of the therapeutics or result in the generation of antibodies against the anti-α4ß7 mAb or IL-21-IgFc. Upon treatment, the frequency of CD4 memory T cells expressing ß7 increased in blood and decreased in gut, consistent with an inhibition of activated CD4 T-cell homing to the gut. Furthermore, the frequency of T cells expressing proliferation and immune activation markers decreased in blood and, more profoundly, in gut. The combined IL-21 plus anti-α4ß7 mAb therapy is well-tolerated in SIV-uninfected RMs and reduces the gut homing of α4ß7+ CD4 T cells as well as the levels of gut immune activation.

CTLA-4 and PD-1 dual blockade induces SIV reactivation without control of rebound after antiretroviral therapy interruption.

The primary human immunodeficiency virus (HIV) reservoir is composed of resting memory CD4+ T cells, which often express the immune checkpoint receptors programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which limit T cell activation via synergistic mechanisms. Using simian immunodeficiency virus (SIV)-infected, long-term antiretroviral therapy (ART)-treated rhesus macaques, we demonstrate that PD-1, CTLA-4 and dual CTLA-4/PD-1 immune checkpoint blockade using monoclonal antibodies is well tolerated, with evidence of bioactivity in blood and lymph nodes. Dual blockade was remarkably more effective than PD-1 blockade alone in enhancing T cell cycling and differentiation, expanding effector-memory T cells and inducing robust viral reactivation in plasma and peripheral blood mononuclear cells. In lymph nodes, dual CTLA-4/PD-1 blockade, but not PD-1 alone, decreased the total and intact SIV-DNA in CD4+ T cells, and SIV-DNA and SIV-RNA in B cell follicles, a major site of viral persistence during ART. None of the tested interventions enhanced SIV-specific CD8+ T cell responses during ART or viral control after ART interruption. Thus, despite CTLA-4/PD-1 blockade inducing robust latency reversal and reducing total levels of integrated virus, the degree of reservoir clearance was still insufficient to achieve viral control. These results suggest that immune checkpoint blockade regimens targeting PD-1 and/or CTLA-4, if performed in people living with HIV with sustained aviremia, are unlikely to induce HIV remission in the absence of additional interventions.