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2.
Innovations (Phila) ; 19(1): 39-45, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38087894

RESUMO

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.


Assuntos
Valva Aórtica , Implante de Prótese de Valva Cardíaca , Humanos , Valva Aórtica/cirurgia , Esternotomia/métodos , Aorta Torácica/cirurgia , Resultado do Tratamento , Implante de Prótese de Valva Cardíaca/métodos , Estudos Retrospectivos , Procedimentos Cirúrgicos Minimamente Invasivos/métodos
3.
AJPM Focus ; 2(4): 100145, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37941823

RESUMO

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.

4.
Sci Rep ; 13(1): 18600, 2023 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-37903840

RESUMO

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.


Assuntos
Disautonomia Familiar , Doenças Neurodegenerativas , Camundongos , Animais , Humanos , Células Ganglionares da Retina/metabolismo , Disautonomia Familiar/genética , Disautonomia Familiar/terapia , Disautonomia Familiar/metabolismo , Doenças Neurodegenerativas/metabolismo , Splicing de RNA , Terapia Genética , Fatores de Elongação da Transcrição/genética , Fatores de Elongação da Transcrição/metabolismo
6.
Sex Transm Infect ; 99(8): 527-533, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37402567

RESUMO

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.


Assuntos
COVID-19 , Infecções por Chlamydia , Gonorreia , Minorias Sexuais e de Gênero , Masculino , Humanos , Adolescente , Adulto , Gonorreia/epidemiologia , Gonorreia/prevenção & controle , Parceiros Sexuais , Homossexualidade Masculina , Comportamento Sexual , Estudos Transversais , Pandemias , Neisseria gonorrhoeae , COVID-19/epidemiologia , Infecções por Chlamydia/epidemiologia , Infecções por Chlamydia/prevenção & controle , Chlamydia trachomatis , California/epidemiologia , Prevalência
7.
bioRxiv ; 2023 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-37293016

RESUMO

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.

8.
J Virol ; 97(4): e0167022, 2023 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-36971588

RESUMO

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.


Assuntos
Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , DNA Viral , Infecções por HIV , Linfonodos , Ativação Linfocitária , Humanos , Linfonodos/citologia , Linfonodos/imunologia , Linfonodos/virologia , DNA Viral/análise , HIV-1 , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Sangue/imunologia , Sangue/virologia , Ativação Linfocitária/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Masculino , Adulto , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/virologia
9.
J Ment Health ; 32(6): 1016, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33966570
10.
Nat Commun ; 13(1): 5055, 2022 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-36030289

RESUMO

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.


Assuntos
Infecções por HIV , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Antirretrovirais , Linfócitos T CD4-Positivos , Cloridrato de Fingolimode , Macaca mulatta , Carga Viral
11.
Child Psychiatry Hum Dev ; 53(4): 765-775, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-33835279

RESUMO

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.


Assuntos
Serviços de Saúde Mental , Saúde Mental , Adolescente , Criança , Saúde da Criança , Humanos , Ontário
12.
Front Psychol ; 13: 1027373, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36817386

RESUMO

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.

13.
Lancet Psychiatry ; 8(10): 861-862, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34537096
14.
Open Access J Sports Med ; 12: 109-117, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34377036

RESUMO

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.

15.
PLoS Pathog ; 17(8): e1009825, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34449812

RESUMO

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.


Assuntos
Antirretrovirais/farmacologia , Linfócitos T CD4-Positivos/imunologia , Citocinas/metabolismo , Infecções por HIV/virologia , Homeostase , Subpopulações de Linfócitos T/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , DNA Viral , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , HIV-1/imunologia , Humanos , Memória Imunológica/imunologia , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/virologia , Carga Viral
16.
Nat Commun ; 12(1): 2866, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001890

RESUMO

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.


Assuntos
Antirretrovirais/farmacologia , Interferon gama/farmacologia , Interleucinas/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Animais , Antivirais/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Feminino , Células Matadoras Naturais/virologia , Ativação Linfocitária/efeitos dos fármacos , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Carga Viral/efeitos dos fármacos , Viremia/sangue , Viremia/tratamento farmacológico
19.
Front Immunol ; 11: 1275, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32765488

RESUMO

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.


Assuntos
Anticorpos Monoclonais/farmacologia , Imunidade/efeitos dos fármacos , Integrinas/antagonistas & inibidores , Interleucinas/farmacologia , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Disponibilidade Biológica , Biomarcadores , Quimioterapia Combinada , Humanos , Fragmentos Fc das Imunoglobulinas/imunologia , Interleucinas/administração & dosagem , Interleucinas/efeitos adversos , Interleucinas/farmacocinética , Isoanticorpos/sangue , Isoanticorpos/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Macaca mulatta
20.
Nat Med ; 26(4): 519-528, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32284611

RESUMO

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.


Assuntos
Antirretrovirais/uso terapêutico , Anticorpos Monoclonais/farmacologia , Antígeno CTLA-4/imunologia , Receptor de Morte Celular Programada 1/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Ativação Viral/efeitos dos fármacos , Animais , Antirretrovirais/imunologia , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/farmacocinética , Antígeno CTLA-4/antagonistas & inibidores , Macaca mulatta , Masculino , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Síndrome de Imunodeficiência Adquirida dos Símios/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Carga Viral/efeitos dos fármacos , Viremia/induzido quimicamente , Replicação Viral/efeitos dos fármacos , Suspensão de Tratamento
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