scholarly journals Early ART-initiation and longer ART duration reduces HIV-1 proviral DNA levels in children from the CHER trial

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Helen Payne ◽  
Man K. Chan ◽  
Sarah A. Watters ◽  
Kennedy Otwombe ◽  
Nei-Yuan Hsiao ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Factors Associated ◽  
Proviral Dna ◽  
Art Initiation ◽  
Latent Hiv ◽  
Dna Reduction ◽  
Living With Hiv ◽  
Hiv 1

Abstract Background Reduction of the reservoir of latent HIV-infected cells might increase the possibility of long-term remission in individuals living with HIV. We investigated factors associated with HIV-1 proviral DNA levels in children receiving different antiretroviral therapy (ART) strategies in the children with HIV early antiretroviral therapy (CHER) trial. Methods Infants with HIV  <  12 weeks old with CD4%  ≥  25% were randomized in the CHER trial to early limited ART for 40 or 96 weeks (ART-40 W, ART-96 W), or deferred ART (ART-Def). For ART-Def infants or following ART interruption in ART-40 W/ART-96 W, ART was started/re-started for clinical progression or CD4%  <  25%. In 229 participants, HIV-1 proviral DNA was quantified by PCR from stored peripheral blood mononuclear cells from children who had received  ≥  24 weeks ART and two consecutive undetectable HIV-1 RNA 12–24 weeks apart. HIV-1 proviral DNA was compared between ART-Def and ART-96 W at week 96, and in all arms at week 248. Factors associated with HIV-1 proviral DNA levels were evaluated using linear regression. Findings Longer duration of ART was significantly associated with lower HIV-1 proviral DNA at both 96 (p  =  0.0003) and 248 weeks (p  =  0.0011). Higher total CD8 count at ART initiation was associated with lower HIV-1 proviral DNA at both 96 (p  =  0.0225) and 248 weeks (p  =  0.0398). Week 248 HIV-1 proviral DNA was significantly higher in those with positive HIV-1 serology at week 84 than those with negative serology (p  =  0.0042). Intepretation Longer ART duration is key to HIV-1 proviral DNA reduction. Further understanding is needed of the effects of “immune-attenuation” through early HIV-1 exposure. Funding Wellcome Trust, National Institutes of Health, Medical Research Council.

scholarly journals Early ART-initiation Reduces HIV-1 Proviral DNA Levels in Children from the CHER Trial

2021 ◽  
Author(s):  
Helen Payne ◽  
Man Chan ◽  
Sarah Watters ◽  
Kennedy Otwombe ◽  
Yuan Hsiao ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Factors Associated ◽  
Proviral Dna ◽  
Art Initiation ◽  
Latent Hiv ◽  
Dna Reduction ◽  
Living With Hiv ◽  
Hiv 1

Abstract BACKGROUND: Reduction of the reservoir of latent HIV-infected cells might increase the possibility of long-term remission in individuals living with HIV. We investigated factors associated with HIV-1 proviral DNA levels in children receiving different antiretroviral therapy (ART) strategies in the Children with HIV Early Antiretroviral Therapy (CHER) trial. METHODS: Infants with HIV <12 weeks old with CD4% ≥25% were randomized in the CHER trial to early limited ART for 40 or 96 weeks (ART-40W, ART-96W), or deferred ART (ART-Def). For ART-Def infants or following ART interruption in ART-40W/ART-96W, ART was started/re-started for clinical progression or CD4% <25%. In 229 participants, HIV-1 proviral DNA was quantified by PCR from stored peripheral blood mononuclear cells from children who had received ≥24 weeks ART and two consecutive undetectable HIV-1 RNA 12-24 weeks apart. HIV-1 proviral DNA was compared between ART-Def and ART-96W at week 96, and in all arms at week 248. Factors associated with HIV-1 proviral DNA levels were evaluated using linear regression.FINDINGS: Longer duration of ART was significantly associated with lower HIV-1 proviral DNA at both 96 (p=0.0003) and 248 weeks (p=0.0011). Higher total CD8 count at ART initiation was associated with lower HIV-1 proviral DNA at both 96 (p=0.0225) and 248 weeks (p=0.0398). Week 248 HIV-1 proviral DNA was significantly higher in those with positive HIV-1 serology at week 84 than those with negative serology (p=0.0042).INTEPRETATION: Longer ART duration is key to HIV-1 proviral DNA reduction. Further understanding is needed of the effects of “immune-attenuation” through early HIV-1 exposure.FUNDING: Wellcome Trust, National Institutes of Health, Medical Research Council.

scholarly journals Epigenetic Compound Screening Uncovers Small Molecules for Reactivation of Latent HIV-1

2020 ◽  
Vol 65 (1) ◽  
pp. e01815-20
Author(s):  
Ariane Zutz ◽  
Lin Chen ◽  
Franziska Sippl ◽  
Andreas Humpe ◽  
Christian Schölz
Keyword(s):  
High Throughput Screening ◽  
Mononuclear Cells ◽  
Model Systems ◽  
Reporter System ◽  
Peripheral Blood Mononuclear ◽  
Compound Screening ◽  
Immunological Destruction ◽  
New Treatment ◽  
Latent Hiv ◽  
Hiv 1

ABSTRACTDuring infection with the human immunodeficiency virus type 1 (HIV-1), latent reservoirs are established that circumvent full eradication of the virus by antiretroviral therapy (ART) and are the source for viral rebound after cessation of therapy. As these reservoirs are phenotypically indistinguishable from infected cells, current strategies aim to reactivate these reservoirs, followed by pharmaceutical and immunological destruction of the cells. Here, we employed a simple and convenient cell-based reporter system, which enables sample handling under biosafety level (BSL)-1 conditions, to screen for compounds that were able to reactivate latent HIV-1. The assay showed a high dynamic signal range and reproducibility with an average Z-factor of 0.77, classifying the system as robust. The assay was used for high-throughput screening (HTS) of an epigenetic compound library in combination with titration and cell-toxicity studies and revealed several potential new latency-reversing agents (LRAs). Further validation in well-known latency model systems verified earlier studies and identified two novel compounds with very high reactivation efficiencies and low toxicity. Both drugs, namely, N-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide (HPOB) and 2′,3′-difluoro-[1,1′-biphenyl]-4-carboxylic acid, 2-butylhydrazide (SR-4370), showed comparable performances to other already known LRAs, did not activate CD4+ T cells, and did not cause changes in the composition of peripheral blood mononuclear cells (PBMCs), as shown by flow cytometry analyses. Both compounds may represent effective new treatment possibilities for reversal of latency in HIV-1-infected individuals.

scholarly journals Toll-Like Receptor 7 Agonist GS-9620 Induces HIV Expression and HIV-Specific Immunity in Cells from HIV-Infected Individuals on Suppressive Antiretroviral Therapy

2017 ◽  
Vol 91 (8) ◽  
Author(s):  
Angela Tsai ◽  
Alivelu Irrinki ◽  
Jasmine Kaur ◽  
Tomas Cihlar ◽  
George Kukolj ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Mononuclear Cells ◽  
Antiviral Immunity ◽  
Type I ◽  
Toll Like Receptor ◽  
Peripheral Blood Mononuclear ◽  
Effector Functions ◽  
Latently Infected ◽  
Infected Cells ◽  
Latent Hiv

ABSTRACT Antiretroviral therapy can suppress HIV replication to undetectable levels but does not eliminate latent HIV, thus necessitating lifelong therapy. Recent efforts to target this persistent reservoir have focused on inducing the expression of latent HIV so that infected cells may be recognized and eliminated by the immune system. Toll-like receptor (TLR) activation stimulates antiviral immunity and has been shown to induce HIV from latently infected cells. Activation of TLR7 leads to the production of several stimulatory cytokines, including type I interferons (IFNs). In this study, we show that the selective TLR7 agonist GS-9620 induced HIV in peripheral blood mononuclear cells (PBMCs) from HIV-infected individuals on suppressive antiretroviral therapy. GS-9620 increased extracellular HIV RNA 1.5- to 2-fold through a mechanism that required type I IFN signaling. GS-9620 also activated HIV-specific T cells and enhanced antibody-mediated clearance of HIV-infected cells. Activation by GS-9620 in combination with HIV peptide stimulation increased CD8 T cell degranulation, production of intracellular cytokines, and cytolytic activity. T cell activation was again dependent on type I IFNs produced by plasmacytoid dendritic cells. GS-9620 induced phagocytic cell maturation and improved effector-mediated killing of HIV-infected CD4 T cells by the HIV envelope-specific broadly neutralizing antibody PGT121. Collectively, these data show that GS-9620 can activate HIV production and improve the effector functions that target latently infected cells. GS-9620 may effectively complement orthogonal therapies designed to stimulate antiviral immunity, such as therapeutic vaccines or broadly neutralizing antibodies. Clinical studies are under way to determine if GS-9620 can target HIV reservoirs. IMPORTANCE Though antiretroviral therapies effectively suppress viral replication, they do not eliminate integrated proviral DNA. This stable intermediate of viral infection is persistently maintained in reservoirs of latently infected cells. Consequently, lifelong therapy is required to maintain viral suppression. Ultimately, new therapies that specifically target and eliminate the latent HIV reservoir are needed. Toll-like receptor agonists are potent enhancers of innate antiviral immunity that can also improve the adaptive immune response. Here, we show that a highly selective TLR7 agonist, GS-9620, activated HIV from peripheral blood mononuclear cells isolated from HIV-infected individuals with suppressed infection. GS-9620 also improved immune effector functions that specifically targeted HIV-infected cells. Previously published studies on the compound in other chronic viral infections show that it can effectively induce immune activation at safe and tolerable clinical doses. Together, the results of these studies suggest that GS-9620 may be useful for treating HIV-infected individuals on suppressive antiretroviral therapy.

scholarly journals Restriction of HIV-1 Infection in Sickle Cell Trait

2021 ◽  
Author(s):  
Namita Kumari ◽  
Seyed Mehdi Nouraie ◽  
Asrar Ahmad ◽  
Hatajai Lassiter ◽  
Javed I Khan ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Mononuclear Cells ◽  
Sickle Cell Trait ◽  
Ex Vivo ◽  
Heme Oxygenase 1 ◽  
Mrna Levels ◽  
Peripheral Blood Mononuclear ◽  
Protein Levels ◽  
Living With Hiv ◽  
Hiv 1

Patients with Sickle cell disease (SCD) have lower risk for HIV-1 infection. We showed restriction of ex vivo HIV-1 infection in SCD peripheral blood mononuclear cells (PBMCs) that was due, in part, to the upregulation of antiviral, inflammatory and hemolytic factors including heme oxygenase-1 (HO-1). Here, we investigated whether individuals with sickle cell trait (SCT), who develop mild hemolysis, also restrict HIV-1 infection. Ex vivo infection of SCT PBMCs demonstrated ~2-fold reduction of HIV-1 replication and lower levels of HIV-1 reverse transcription products, 2-Long Terminal Repeats (LTR) circles, HIV-1 integration and gag RNA expression. SCT PBMCs had higher HO-1 mRNA and protein levels and reduced ribonucleotide reductase 2 (RNR2) protein levels. HO-1 inhibition by tin porphyrin eliminated ex vivo HIV-1 restriction. Among Howard University clinic recruits, higher levels of HO-1 and RNR2 mRNA and lower HIV-1 env mRNA levels were found in SCT individuals living with HIV-1. To determine the population level effect of SCT on HIV-1 prevalence, we assessed SCT trait among women living with HIV (WLH) in the Women Interagency HIV-1 Study (WIHS). Among WIHS African American participants, prevalence of SCT was lower among women with HIV compared with uninfected women (8.7% vs 14.2%; OR 0.57; 95%CI = 0.36-0.92, p=0.020). WIHS WLH with SCT had higher levels of CD4+/CD8+ ratios over 20 years of follow up (p=0.003) than matched WLH without SCT. Together, our findings suggest that HIV-1 restriction factors including HO-1 and RNR2 might restrict HIV-1 infection among individuals with SCT and limit the pathogenicity of HIV.

The burden of neuropsychiatric disorders in patients living with HIV-1 treated with antiretroviral therapies—A perspective from US Medicaid data

2021 ◽  
pp. 095646242110528
Author(s):  
Wing Chow ◽  
Hélène Hardy ◽  
Ji Song ◽  
Nancy Connolly ◽  
Bingcao Wu
Keyword(s):  
Antiretroviral Therapy ◽  
Primary Outcome ◽  
Neuropsychiatric Disorders ◽  
Administrative Claims ◽  
Art Initiation ◽  
Immunodeficiency Virus ◽  
High Prevalence ◽  
The Mean ◽  
Living With Hiv ◽  
Hiv 1

Background People with human immunodeficiency virus (HIV)-1 face challenges with treatment adherence for various reasons, including consideration of neuropsychiatric disorders and neuropsychiatric adverse reactions associated with antiretroviral therapy (ART). Methods A retrospective cohort study was conducted using administrative claims data from the IBM MarketScan® Multi-State Medicaid Database (1/1/2014–12/31/2017). Adults (≥18 years) diagnosed with HIV-1 and newly initiated on antiretroviral therapy with continuous health plan enrollment were included. Primary outcome was the 6-month period prevalence of neuropsychiatric events (NPEs) of interest after ART initiation. Results Among 1971 newly treated patients included in the study, mean age (standard deviation [SD]) was 38.5 (12.7) years, and 41.4% were female. During the 6 months after ART initiation, 51.4% of patients had a claim for ≥1 NPE versus 30.3% of matched patients without HIV. Among newly treated patients, the most common (≥10%) NPE claims were for depression (42.2%), anxiety (15.8%), headache (11.9%), and bipolar/manic depression (10.1%). Also in this group, the mean (SD) total all-cause healthcare cost during the 6-month post-ART initiation was $16,632 ($33,928), of which $2914 ($18,233) was NPE-related. Conclusions In summary, in this Medicaid study of people newly initiated on ART, there was a high prevalence of NPEs, and incremental NPE-associated costs were considerable.

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