HIV Suppression Research Articles

An exploration of how broadly neutralizing antibodies might induce HIV remission: the 'vaccinal' effect.

Broadly neutralizing antibodies (bNAbs) are a potential new therapeutic strategy to treat HIV infection. This review explores possible mechanisms of action of bNAbs and summarizes the current evidence supporting their immunomodulatory properties, which might lead to sustained virological remission - the 'vaccinal effect'. Antiretroviral therapy (ART) is required to confer lasting HIV suppression; stopping ART almost invariably leads to HIV recrudescence from a persistent pool of virally infected cells - the HIV reservoir. HIV-specific broadly neutralizing antibodies (bNAbs) may confer viral control after ART cessation predominantly through blockade of viral entry into uninfected target cells. In some human and animal studies, HIV bNAbs also conferred lasting viral suppression after therapeutic bNAb plasma levels had declined. Immune-modulatory mechanisms have been postulated to underlie this observation - the 'vaccinal effect'. Hypothesized mechanisms include the formation of immune complexes between bNAbs and HIV envelope protein, thereby enhancing antigen presentation and uptake by immune cells, with boosted adaptive immune responses subsequently controlling the HIV reservoir. There is emerging evidence for potent antiviral efficacy of bNAb therapy. Whether bNAbs can induce sustained viral suppression after dropping below therapeutic levels remains controversial. Mechanistic data from on-going and future clinical trials will help answer these questions.

Expression Profile and Biological Role of Immune Checkpoints in Disease Progression of HIV/SIV Infection.

During HIV/SIV infection, the upregulation of immune checkpoint (IC) markers, programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), T cell immunoglobulin and ITIM domain (TIGIT), lymphocyte-activation gene-3 (LAG-3), T cell immunoglobulin and mucin domain-3 (Tim-3), CD160, 2B4 (CD244), and V-domain Ig suppressor of T cell activation (VISTA), can lead to chronic T cell exhaustion. These ICs play predominant roles in regulating the progression of HIV/SIV infection by mediating T cell responses as well as enriching latent viral reservoirs. It has been demonstrated that enhanced expression of ICs on CD4+ and CD8+ T cells could inhibit cell proliferation and cytokine production. Overexpression of ICs on CD4+ T cells could also format and prolong HIV/SIV persistence. IC blockers have shown promising clinical results in HIV therapy, implying that targeting ICs may optimize antiretroviral therapy in the context of HIV suppression. Here, we systematically review the expression profile, biological regulation, and therapeutic efficacy of targeted immune checkpoints in HIV/SIV infection.

America's HIV Epidemic Analysis Dashboard: Protocol for a Data Resource to Support Ending the HIV Epidemic in the United States.

BackgroundThe Ending the HIV Epidemic (EHE) plan aims to end the HIV epidemic in the United States by 2030. Having timely and accessible data to assess progress toward EHE goals at the local level is a critical resource to achieve this goal.ObjectiveThe aim of this paper was to introduce America’s HIV Epidemic Analysis Dashboard (AHEAD), a data visualization tool that displays relevant data on the 6 HIV indicators provided by the Centers for Disease Control and Prevention. AHEAD can be used to monitor progress toward ending the HIV epidemic in local communities across the United States. Its objective is to make data available to stakeholders, which can be used to measure national and local progress toward 2025 and 2030 EHE goals and to help jurisdictions make local decisions that are grounded in high-quality data.MethodsAHEAD displays data from public health data systems (eg, surveillance systems and census data), organized around the 6 EHE indicators (HIV incidence, knowledge of HIV status, HIV diagnoses, linkage to HIV medical care, viral HIV suppression, and preexposure prophylaxis coverage). Data are displayed for each of the EHE priority areas (48 counties in Washington, District of Columbia, and San Juan, Puerto Rico) which accounted for more than 50% of all US HIV diagnoses in 2016 and 2017 and 7 primarily southern states with high rates of HIV in rural communities. AHEAD also displays data for the 43 remaining states for which data are available. Data features prioritize interactive data visualization tools that allow users to compare indicator data stratified by sex at birth, race or ethnicity, age, and transmission category within a jurisdiction (when available) or compare data on EHE indicators between jurisdictions.ResultsAHEAD was launched on August 14, 2020. In the 11 months since its launch, the Dashboard has been visited 26,591 times by 17,600 unique users. About one-quarter of all users returned to the Dashboard at least once. On average, users engaged with 2.4 pages during their visit to the Dashboard, indicating that the average user goes beyond the informational landing page to engage with 1 or more pages of data and content. The most frequently visited content pages are the jurisdiction webpages.ConclusionsThe Ending the HIV Epidemic plan is described as a “whole of society” effort. Societal public health initiatives require objective indicators and require that all societal stakeholders have transparent access to indicator data at the level of the health jurisdictions responsible for meeting the goals of the plan. Data transparency empowers local stakeholders to track movement toward EHE goals, identify areas with needs for improvement, and make data-informed adjustments to deploy the expertise and resources required to locally tailor and implement strategies to end the HIV epidemic in their jurisdiction.

Determinants of suboptimal immune recovery among a Chinese Yi ethnicity population with sustained HIV suppression

ObjectivesDespite sustained viral suppression with effective antiretroviral therapy (ART), HIV-infected patients with suboptimal immune recovery are still at high risk of both non-AIDS-related and AIDS-related events. The aim of this study was to investigate determinants potentially associated with suboptimal CD4 + T cell count recovery during free ART with sustained viral suppression among an HIV-infected Yi ethnicity population in Liangshan Prefecture, an area in China with high HIV prevalence.MethodsThis retrospective study included HIV-infected Yi adults (≥ 18 years and baseline CD4 + T cell count less than 500 cells/μL) for whom ART supported by National Free Antiretroviral Treatment Program was initiated between January 2015 and December 2018 in Zhaojue County, Liangshan Prefecture. Virological suppression (viral load < 50 copies/mL) was achieved within 12 months after ART initiation, and sustained virological suppression was maintained. Multivariate log-binomial regression analysis was used to assess determinants of suboptimal immune recovery.ResultsThere were 140 female and 137 male patients in this study, with a mean age of 36.57 ± 7.63 years. Most of the Yi patients were infected through IDU (48.7%) or heterosexual contact (49.8%), and the anti-HCV antibody prevalence was high (43.7%, 121/277). Of the 277 patients with a mean ART duration of 3.77 ± 1.21 years, complete immune recovery occurred in only 32.9%. The baseline CD4 + T cell count in patients with suboptimal and intermediate immune recovery was 248.64 ± 108.10 and 288.59 ± 108.86 cells/μL, respectively, which was much lower than the baseline 320.02 ± 123.65 cells/μL in patients who achieved complete immune recovery (p < 0.001). Multivariable analysis demonstrated that low pre-ART CD4 + cell count and coinfection with HCV were associated with immune recovery of the HIV patients.ConclusionsOur study suggests that for HIV-infected Yi patients in Liangshan Prefecture, prompt ART initiation after diagnosis of HIV infection should be applied, and curative HCV treatment should be given to patients with HCV/HIV coinfection to improve the immunological effectiveness of ART.Trial registration None

The Association Between HIV Status, Estradiol, and Sex Hormone Binding Globulin Among Premenopausal Women in the Women's Interagency HIV Study.

Background: Characterizing estradiol among women with HIV may have implications for breast cancer and cardiovascular disease risk but has not been adequately explored. We quantified differences in total (E2), free (FE2) estradiol, and sex hormone binding globulin (SHBG) by HIV and viral suppression status. Methods: Women from a substudy (2003-2006) within the Women's Interagency HIV Study (IRB approved at each participating site) were included if they reported: a period in the last six months, were not pregnant/breastfeeding, no oophorectomy, and no exogenous hormone use in the prior year. Serum was collected on days 2-4 of the menstrual cycle. We assessed differences in biomarkers at 25th, 50th, and 75th percentiles by HIV and viral suppression status using weighted quantile regression. Results: Among 643 women (68% with HIV) median age was 37 years. All E2 percentiles were significantly (p < 0.05) lower in women with suppressed viral load versus women without HIV (4-10 pg/mL). The 25th and 50th percentile of E2 were 4-5 pg/mL lower in women with unsuppressed viral load compared to women without HIV (p < 0.05). The 25th and 50th percentile of SHBG was significantly higher in women with unsuppressed viral load compared to women without HIV (10 and 12 nmol/L, respectively). There were no consistent differences in estradiol or SHBG by suppression status. Conclusions: There were no differences in FE2 but significantly lower E2 and higher SHBG among women with HIV versus without HIV. Further research is merited in a large contemporary sample to clarify the clinical implications of these findings.

Aging, trends in CD4+/CD8+ cell ratio, and clinical outcomes with persistent HIV suppression in a dynamic cohort of ambulatory HIV patients.

Age blunts CD4+ lymphocyte cell count/μl (CD4+) improvements observed with antiretroviral therapy (ART)-induced viral suppression among people with HIV (PWH). Prolonged viral suppression reduces immune dysregulation, reflected by rising CD4+/CD8+ ratios (CD4+/CD8+). We studied CD4+/CD8+ over time to determine whether it predicts risk for select comorbidities and mortality among aging PWH with viral suppression. We studied HIV Outpatient Study (HOPS) participants prescribed ART during 2000-2018 who achieved a viral load less than 200 copies/ml on or after 1 January 2000, and remained virally suppressed at least 1 year thereafter. We modeled associations of CD4+/CD8+ with select incident comorbidities and all-cause mortality using Cox regression and controlling for demographic and clinical factors. Of 2480 eligible participants,1145 (46%) were aged less than 40 years, 835 (34%) 40-49 years, and 500 (20%) ≥ 50 years. At baseline, median CD4+/CD8+ was 0.53 (interquartile range: 0.30-0.84) and similar among all age groups (P = 0.18). CD4+/CD8+ values and percentage of participants with CD4+/CD8+ at least 0.70 increased within each age group (P < 0.001 for all). CD4+/CD8+ increase was greatest for PWH aged less than 40 years at baseline. In adjusted models, most recent CD4+/CD8+less than 1.00 and less than 0.70 were independently associated with higher risk of non-AIDS cancer and mortality, respectively. Pretreatment immune dysregulation may persist as indicated by CD4+/CD8+ less than 0.70. Persistent viral suppression can improve immune dysregulation over time, reducing comorbidity, and mortality risk. Monitoring CD4+/CD8+ among ART-treated PWH with lower values provide a means to assess for mortality and comorbidity risk.

Human Hematopoietic Stem Cell (HSC)-Engrafted NSG Mice for HIV Latency Research.

Combination antiretroviral therapy (cART) suppresses HIV in most patients, but it cannot cure HIV infection. The main challenge to a cure is the presence of latent replication-competent HIV in resting CD4+ T cells in blood and tissues, which reignite infection after cART removal. The long half-life of this reservoir is a major barrier to a cure, and its elimination is a main goal of current HIV research. Animal models that recapitulate HIV latency can provide key insights into the establishment of HIV latency and, more importantly, enable the testing of HIV eradication strategies. We describe a protocol for the generation of humanized mice by intrahepatic injection of human cord blood-derived CD34+ hematopoietic stem cells (HSC) into newborn NSG mice, the HSC-NSG mouse model. We also describe a protocol for establishing HIV latency in this model. HSC-NSG mice have provided proof-of-concept for an approach combining HIV gene editing and HIV suppression in tissues that may cure HIV in infected humans.

Evaluation of the Expression Pattern of 4 microRNAs and their Correlation with Cellular/viral Factors in PBMCs of Long Term Non-progressors and HIV Infected Naïve Individuals.

Long-term non-progressors (LTNPs) are small subsets of HIV-infected subjects that can control HIV-1 replication for several years without receiving ART. The exact mechanism of HIV-1 suppression has not yet been completely elucidated. Although the modulatory role of microRNAs (miRNAs) in HIV-1 replication has been reported, their importance in LTNPs is unclear. The aim of this cross-sectional study was to assess the expression pattern of miR-27b, -29, -150, and -221, as well as their relationship with CD4+ T-cell count, HIV-1 viral load, and nef gene expression in peripheral blood mononuclear cells (PBMCs) of untreated viremic patients and in LTNPs. MiRNAs expression levels were evaluated with real-time PCR assay using RNA isolated from PBMCs of LTNPs, HIV-1 infected naive patients, and healthy people. Moreover, CD4 T-cell count, HIV viral load, and nef gene expression were assessed. The expression level of all miRNAs significantly decreased in the HIV-1 patient group compared to the control group, while the expression pattern of miRNAs in the LNTPs group was similar to that in the healthy subject group. In addition, there were significant correlations between some miRNA expression with viral load, CD4+ T-cell count, and nef gene expression. The significant similarity and difference of the miRNA expression pattern between LNTPs and healthy individuals as well as between elite controllers and HIV-infected patients, respectively, showed that these miRNAs could be used as diagnostic biomarkers. Further, positive and negative correlations between miRNAs expression and viral/cellular factors could justify the role of these miRNAs in HIV-1 disease monitoring.

Effect of HIV suppression on the cytokine network in blood and seminal plasma.

HIV infection disrupts the cytokine network and this disruption is not completely reversed by antiretroviral therapy (ART). Characterization of cytokine changes in blood and genital secretions is important for understanding HIV pathogenesis and the mechanisms of HIV sexual transmission. Here, we characterized the cytokine network in individuals longitudinally sampled before they began ART and after achieving suppression of HIV RNA. We measured concentrations of 34 cytokine/chemokines using multiplex bead-based assay in blood and seminal plasma of 19 men with HIV-1 prior to and after viral suppression. We used Partial Least Squares Discriminant Analysis (PLS-DA) to visualize the difference in cytokine pattern between the time points. Any cytokines with VIP scores exceeding 1 were deemed important in predicting suppression status and were subsequently tested using Wilcoxon Signed Rank Tests. PLS-DA projections in blood were fairly similar before and after viral suppression. In contrast, the difference in PLS-DA projection observed in semen emphasizes that the immunological landscape and immunological needs are very different before and after ART in the male genital compartment. When tested individually, four cytokines were significantly different across time points in semen (MIG, IL-15, IL-7, I-TAC), and two in blood (MIG and IP-10). Viral suppression with ART impacts the inflammatory milieu in seminal plasma. In contrast, the overall effect on the network of cytokines in blood was modest but consistent with prior analyses. These results identify specific changes in the cytokine networks in semen and blood as the immune system acclimates to chronic, suppressed HIV infection.

834. Characterization of Heavily Treatment Experienced HIV-1 Infected Clinical Trial Participants Infected with SARS-CoV-2 COVID 19: Fostemsavir BRIGHTE Phase 3 Clinical Trial

BackgroundBRIGHTE is an ongoing global study evaluating the gp120 attachment inhibitor fostemsavir (FTR) in heavily treatment-experienced (HTE) adults with multidrug resistant (MDR) HIV-1 unable to form a viable antiretroviral (ARV) regimen. An estimated 2 million people living with HIV-1 have been infected with SARS-CoV-2. Those with HIV viremia and/or low CD4+ counts are at increased risk of serious adverse outcome. We describe the reported COVID cases in a clinical trial population of people living with MDR HIV and immune suppression. MethodsAt the start of the COVID pandemic, all ongoing BRIGHTE subjects had achieved ≥ 192 weeks on FTR and optimized background ARVs; results through Week 96 were presented previously. Investigators used WHO guidelines for COVID diagnosis and reported exposure, testing results and symptom presence.Figure 1. BRIGHTE Study Design Results371 subjects [272 Randomized Cohort (RC), 99 Non-Randomized Cohort (NC)] were enrolled; 44% were ≥ 50 years of age and 86% had an AIDS history. Median CD4+ count at study start of was 80 cells/mm3 (IQR 11–202); 30% with ≤ 20 cells/mm3. 250 subjects remained in BRIGHTE at pandemic start. By April 2021, 17 subjects (14 RC, 3 NC) had confirmed COVID infection (positive PCR test). Severity was Grade 1-3, all cases resolved with no deaths. Six subjects were hospitalized (Table 1); most recent CD4+ count prior to COVID were 293-1641 cells/mm3 and 5/6 subjects were virologically suppressed. Treatments often included prophylactic anticoagulants and supplemental oxygen; no cART changes were made. The remaining 11/17 confirmed cases were managed outpatient. Five more subjects had suspect COVID not confirmed by PCR and 2 subjects had negative PCR tests.Table 1. Characterization of Participants with Serious AEs of Confirmed COVID-19 Infections – All Hospitalizations ConclusionA total of 22/250 COVID-19 cases (17 confirmed, 5 unconfirmed) have been reported in BRIGHTE. Outcomes were reassuring with no deaths or known persistent sequelae, despite having advanced HIV and comorbid diseases at baseline associated with poorer COVID outcomes. Outcomes may have benefitted from immunologic improvement during the trial. Disclosures Shiven Chabria, MD, Viiv Healthcare (Employee) Stephane De Wit, MD, Gilead (Grant/Research Support)Janssen (Grant/Research Support)Merck Sharpe & Dohme (Grant/Research Support)ViiV Healthcare (Grant/Research Support) Amy Pierce, BS, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Bronagh M. Shepherd, PhD, GlaxoSmithKline (Employee, Shareholder) Michael Warwick-Sanders, BM BSc DPM MFPM, GSK (Employee) Marcia Wang, PhD, GlaxoSmithKline (Employee, Shareholder) Andrew Clark, MD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Peter Ackerman, MD, GSK/ViiV Healthcare (Employee, Shareholder)

902. Unreturned Pill Bottles in the 1489 and 1490 Clinical Trials: An Important Measure of Poor Adherence that Is Often Ignored in Pill Count Calculations

Abstract Background Adherence to antiretroviral therapy is important for HIV suppression. In clinical trials, adherence is commonly measured by pill count; limitations are that unreturned pills may not have been taken and unreturned pill bottle data are omitted. This analysis focuses on the relationship between unreturned pill bottles as a measure of poor adherence and the overall effect on virologic success rates across all treatment groups. Methods Pill bottle return category (all bottles returned or ≥1 bottle unreturned) and return rates for participants across all treatment groups from two treatment-naïve INSTI clinical trials (Studies 1489 and 1490) were calculated. Association of bottle return category or rates with virologic events through week 144, including last on-treatment observation carried forward (LOCF) outcome, was determined; comparisons used Fisher’s exact or Wilcoxon rank sum test. Results Virologic suppression with ≥95% adherence by pill count can differ for those with unreturned pill bottles (Figure). In these studies, 60% of participants returned all their pill bottles through week 144; if one visit with ≥1 unreturned bottle was allowed, this percentage increased to 81%. The mean bottle return rate was 94% and did not differ by study, treatment arm, or sex. Failure to return pill bottles was significantly associated with lower suppression rates. Additionally, significant differences in pill bottle return rate (p &amp;lt; 0.01) were observed by week 144 LOCF outcome (95% vs 77% mean return rate for those with HIV RNA &amp;lt; 50 c/mL vs ≥50 c/mL), need for resistance testing (95% vs 77% return rate for those not tested vs tested), confirmed virologic failure (VF) (94% vs 90% return rate for those without VF vs with VF) and blip status (95% vs 92% return rate for those without blips vs with blips). HIV-1 Viral Loads of Two Participants with ≥95% Adherence by Pill Count through Week 144 Conclusion In these treatment-naïve INSTI clinical trials, failure to return pill bottles was associated with lower suppression rates. Although the calculated adherence rates in these studies was relatively high (median ≥95%), these calculations did not account for unreturned pill bottles. We believe that assessing adherence by both pill count and pill bottle return rate may provide a more complete picture of adherence in clinical trials. Disclosures Rima K. Acosta, BS, Gilead Sciences, Inc. (Employee, Shareholder) Grace Q. Chen, BS, Gilead Sciences, Inc. (Employee) Hailin Huang, PhD, Gilead Sciences, Inc. (Employee, Shareholder) Hui Liu, PhD, Gilead Sciences, Inc. (Employee, Shareholder) Kirsten L. White, PhD, Gilead Sciences, Inc (Employee, Shareholder)

629. High Efficacy of Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) in African American Adults with HIV Including Those with Preexisting Resistance, Viral Blips, and Suboptimal Adherence

BackgroundBRAAVE 2020 demonstrated the efficacy of switching to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) among African American adults with suppressed HIV through Week (W) 48 (Figure 1). We present resistance, viral blips, adherence, and virologic outcomes through W72.Figure 1. BRAAVE 2020 study design (phase 3, randomized, open-label, multicenter [USA], active-controlled study) and virologic suppression at weeks 24 and 48 *Allowed 3rd agents: any FDA-approved protease inhibitor, nonnucleoside reverse transcriptase inhibitor (except etravirine), integrase strand transfer inhibitor (except bictegravir), or maraviroc.MethodsEnrollment criteria permitted NNRTI resistance (-R), PI-R, and certain NRTI-R (M184V/I allowed; K65R/E/N, ≥3 thymidine analog mutations [TAMs], or T69-insertions excluded) and excluded known primary INSTI-R. Preexisting drug resistance was assessed with historical genotypes and retrospective baseline proviral DNA genotyping. Adherence was calculated by pill count. Viral blips (transient HIV-1 RNA ≥50 copies/mL) and outcomes based on last available on-treatment HIV-1 RNA were assessed.Results489 participants received B/F/TAF and had ≥1 post-switch HIV-1 RNA measurement. Baseline genotypic data from cumulative historical and/or proviral genotypes were available for 96% (468/489) in protease/reverse transcriptase and 93% (453/489) in integrase. Preexisting NRTI-R, M184V/I, ≥1 TAMs, NNRTI-R, and PI-R were observed in 15% (68/468), 11% (50/468), 8% (36/468), 22% (101/468), and 13% (61/468), respectively. Primary INSTI-R was detected post-randomization in 2% (11/453); all remained in the study and were included in efficacy analyses. Through W72, 99% (486/489) of participants had HIV-1 RNA < 50 copies/mL at their last study visit, including all with baseline NRTI-R or INSTI-R (Figure 2). Mean frequency of viral blips was 1% per timepoint, and blips were not associated with virologic failure. 112 participants (23%) had < 95% adherence by pill count, 98% (110/112) of whom had HIV-1 RNA < 50 copies/mL at last visit, including 14 of 14 (100%) with < 80% adherence. No participant discontinued due to lack of efficacy or had treatment emergent resistance to study drugs.Figure 2. Virologic suppression by preexisting resistance, viral blips, and adherence ConclusionVirologic suppression was maintained through W72 of B/F/TAF treatment, including those with preexisting resistance, viral blips, and suboptimal adherence. Continued HIV suppression and absence of treatment-emergent resistance demonstrate the efficacy of B/F/TAF in African Americans regardless of adherence or preexisting resistance to NNRTIs, PIs, or non-tenofovir NRTIs.Disclosures Kristen Andreatta, MSc, Gilead Sciences, Inc (Employee, Shareholder) Michelle L. D'Antoni, PhD, Gilead Sciences (Employee, Shareholder)Gilead Sciences, Inc (Employee, Shareholder) Silvia Chang, Masters, Gilead Sciences, Inc (Employee, Shareholder) Aiyappa Parvangada, MS Computational Biology, Gilead Sciences, Inc (Employee, Shareholder) Ross Martin, PhD, Gilead Sciences, Inc (Employee, Shareholder) Christiana Blair, MS, Gilead Sciences, Inc (Employee, Shareholder) Sean E. Collins, MD, MS, Gilead Sciences, Inc (Employee, Shareholder) Kirsten L. White, PhD, Gilead Sciences, Inc (Employee, Shareholder)

T cell receptor-targeted immunotherapeutics drive selective in vivo HIV- and CMV-specific T cell expansion in humanized mice.

To delineate the in vivo role of different costimulatory signals in activating and expanding highly functional virus-specific cytotoxic CD8+ T cells, we designed synTacs, infusible biologics that recapitulate antigen-specific T cell activation signals delivered by antigen-presenting cells. We constructed synTacs consisting of dimeric Fc-domain scaffolds linking CD28- or 4-1BB-specific ligands to HLA-A2 MHC molecules covalently tethered to HIV- or CMV-derived peptides. Treatment of HIV-infected donor PBMCs with synTacs bearing HIV- or CMV-derived peptides induced vigorous and selective ex vivo expansion of highly functional HIV- and/or CMV-specific CD8+ T cells, respectively, with potent antiviral activities. Intravenous injection of HIV- or CMV-specific synTacs into immunodeficient mice intrasplenically engrafted with donor PBMCs markedly and selectively expanded HIV-specific (32-fold) or CMV-specific (46-fold) human CD8+ T cells populating their spleens. Notably, these expanded HIV- or CMV-specific CD8+ T cells directed potent in vivo suppression of HIV or CMV infections in the humanized mice, providing strong rationale for consideration of synTac-based approaches as a therapeutic strategy to cure HIV and treat CMV and other viral infections. The synTac platform flexibility supports facile delineation of in vivo effects of different costimulatory signals on patient-derived virus-specific CD8+ T cells, enabling optimization of individualized therapies, including HIV cure strategies.

Inhibition of the H3K27 demethylase UTX enhances the epigenetic silencing of HIV proviruses and induces HIV-1 DNA hypermethylation but fails to permanently block HIV reactivation.

One strategy for a functional cure of HIV-1 is "block and lock", which seeks to permanently suppress the rebound of quiescent HIV-1 by epigenetic silencing. For the bivalent promoter in the HIV LTR, both histone 3 lysine 27 tri-methylation (H3K27me3) and DNA methylation are associated with viral suppression, while H3K4 tri-methylation (H3K4me3) is correlated with viral expression. However, H3K27me3 is readily reversed upon activation of T-cells through the T-cell receptor. In an attempt to suppress latent HIV-1 in a stable fashion, we knocked down the expression or inhibited the activity of UTX/KDM6A, the major H3K27 demethylase, and investigated its impact on latent HIV-1 reactivation in T cells. Inhibition of UTX dramatically enhanced H3K27me3 levels at the HIV LTR and was associated with increased DNA methylation. In latently infected cells from patients, GSK-J4, which is a potent dual inhibitor of the H3K27me3/me2-demethylases JMJD3/KDM6B and UTX/KDM6A, effectively suppressed the reactivation of latent HIV-1 and also induced DNA methylation at specific sites in the 5'LTR of latent HIV-1 by the enhanced recruitment of DNMT3A to HIV-1. Nonetheless, suppression of HIV-1 through epigenetic silencing required the continued treatment with GSK-J4 and was rapidly reversed after removal of the drug. DNA methylation was also rapidly lost after removal of drug, suggesting active and rapid DNA-demethylation of the HIV LTR. Thus, induction of epigenetic silencing by histone and DNA methylation appears to be insufficient to permanently silence HIV-1 proviral transcription.

Decreased Activated CD4+ T Cell Repertoire Diversity After Antiretroviral Therapy in HIV-1/HCV Coinfection Correlates with CD4+ T Cell Recovery.

Dysfunctional immune activation accumulates during chronic viral infection and contributes to disease pathogenesis. In HIV-1, immune activation is exacerbated by concurrent infection with hepatitis C virus (HCV), accelerating depletion of CD4+ T cells. HIV-1 suppression with antiretroviral therapy (ART) generally reconstitutes CD4+ T cell counts, while also reducing the proportion that is activated. Whether this immune reconstitution also reduces the complexity of the CD4+ T cell population is unknown. We sought to characterize the relationship between activated CD4+ T cell repertoire diversity and immune reconstitution following ART in HIV-1/HCV coinfection. We extracted T cell receptor (TCR) sequences from RNA sequencing data obtained from activated CD4+ T cells of HIV-1/HCV coinfected individuals before and after treatment with ART (clinical trial NCT01285050). There was notable heterogeneity in both the extent of CD4+ T cell reconstitution and in the change in activated CD4+ TCR repertoire diversity following ART. Decreases in activated CD4+ TCR repertoire diversity following ART were predictive of the degree of CD4+ T cell reconstitution. The association of decreased activated CD4+ TCR repertoire diversity and improved CD4+ T cell reconstitution may represent loss of nonspecifically activated TCR clonotypes, and possibly selective expansion of specifically activated CD4+ clones. These results provide insight into the dynamic relationship between activated CD4+ TCR diversity and CD4+ T cell recovery of HIV-1/HCV coinfected individuals after suppression of HIV-1 viremia.

Long-acting cabotegravir and rilpivirine for HIV-1 suppression: switch to 2-monthly dosing after 5 years of daily oral therapy.

Objectives:Long-acting formulations of cabotegravir (CAB) and rilpivirine (RPV) have demonstrated efficacy in Phase 3 studies. POLAR (NCT03639311) assessed antiviral activity and safety of CAB+RPV long-acting administered every 2 months (Q2M) in adults living with HIV-1 who previously received daily oral CAB+RPV in LATTE (NCT01641809).Design:A Phase 2b, multicenter, open-label, rollover study.Methods:LATTE participants with plasma HIV-1 RNA less than 50 copies/ml who completed at least 300 weeks on study were eligible. Participants elected to switch to either CAB+RPV long-acting Q2M or daily oral dolutegravir/RPV for maintenance of virologic suppression. The primary endpoint was the proportion of participants with HIV-1 RNA greater than or equal to 50 copies/ml at Month 12 (M12) per the Food and Drug Administration Snapshot algorithm. The incidence of confirmed virologic failure (CVF, two consecutive HIV-1 RNA measurements greater than or equal to 200 copies/ml), as well as safety, laboratory, and patient-reported outcomes (HIV Treatment Satisfaction and preference questionnaires) were also assessed.Results:Of 97 participants enrolled, 90 chose to receive CAB+RPV long-acting and seven chose dolutegravir/RPV. At M12, no participant had HIV-1 RNA greater than or equal to 50 copies/ml or met the CVF criterion in either treatment group. No new safety signals were identified. Total treatment satisfaction was high at Baseline and remained stable through M12 across both treatment groups. Overall, 88% (n = 77/88) of long-acting arm participants preferred CAB+RPV long-acting to oral CAB+RPV.Conclusion:CAB+RPV long-acting maintained virologic suppression in participants who had previously received daily oral CAB+RPV for at least 5 years in LATTE, with a favorable safety profile. Most participants preferred CAB+RPV long-acting to their prior oral CAB+RPV regimen at M12.

Hepatitis B screening practices and viral control among persons living with HIV in urban Senegal.

Chronic hepatitis B virus (HBV) infection affects >10% of the general population and is the leading cause of liver cirrhosis and cancer in West Africa. Despite current recommendations, HBV is often not tested for in clinical routine in the region. We included all people living with HIV (PLWH) in care between March and July 2019 at Fann University Hospital in Dakar (Senegal) and proposed hepatitis B surface antigen (HBsAg) test to those never tested. All HBsAg‐positive underwent HIV and HBV viral load (VL) and liver stiffness measurement. We evaluated, using logistic regression, potential associations between patient characteristics and (a) HBV testing uptake; (b) HIV/HBV co‐infection among individual HBsAg tested. We determined the proportion of co‐infected who had HBV DNA >20 IU/ml on ART and sequenced HBV polymerase in those with HBV replication.of 1076 PLWH in care, 689 (64.0%) had never had an HBsAg test prior to our HBV testing intervention. Women and individuals >40 years old were less likely to have been previously tested. After HBV testing intervention,107/884 (12.1%) PLWH were HBsAg‐positive. Seven of 58 (12.1%) individuals newly diagnosed with HIV/HBV co‐infection had a detectable HBV VL, of whom five were HIV‐suppressed. Two patients on ART including 3TC and AZT as backbone showed the presence of the triple resistance mutation 180M/204I/80V. In this Senegalese urban HIV clinic, the majority of patients on ART had never been tested for HBV infection. One in ten co‐infected individuals had a detectable HBV VL despite HIV suppression, and 8% were not receiving a TDF‐containing regimen.

HIV Viral Suppression and Pre-exposure Prophylaxis in HIV and Syphilis Contact Tracing Networks: An Analysis of Disease Surveillance and Prescription Claims Data.

HIV and syphilis contact tracing networks offer efficient platforms for HIV treatment and prevention interventions, but intervention coverage within these networks has not been characterized. HIV and syphilis sexual contact tracing networks among men who have sex with men (MSM) in North Carolina (NC). Using surveillance data, we identified 2 types of "network events" that occurred between January 2013 and June 2017 among MSM in NC: being diagnosed with early syphilis or being named as a recent sexual contact of a person diagnosed with HIV or early syphilis. We estimated prevalent and incident HIV viral suppression among persons diagnosed with HIV before the network event, and we assessed the effect of contact tracing services on a 6-month cumulative incidence of viral suppression among previously HIV-diagnosed, virally unsuppressed persons. Using linked prescription claims data, we also evaluated prevalent and incident pre-exposure prophylaxis (PrEP) use in an insured subset of HIV-negative network members. Viral suppression prevalence among previously HIV-diagnosed persons was 52.6%. The 6-month cumulative incidence of viral suppression was 35.4% overall and 13.1 (95% confidence interval: 8.8 to 17.4) percentage points higher among persons reached than among those not reached by contact tracing services. Few HIV-negative persons had prevalent (5.4%) or incident (4.1%) PrEP use in the 6 months before or after network events, respectively. Suboptimal viral suppression and PrEP use among MSM in NC in HIV/syphilis contact tracing networks indicate a need for intensified intervention efforts. In particular, expanded services for previously HIV-diagnosed persons could improve viral suppression and reduce HIV transmission within these networks.

Undisclosed HIV Status to Sex Partners and Its Unintended Consequences in the Era of Undetectable = Untransmittable.

Adherence to antiretroviral therapy (ART) and sustained HIV suppression virtually eliminate HIV transmission, eg, having an undetectable viral load renders HIV untransmittable (U=U). Owing to the greatly reduced likelihood of HIV transmission when viral load is undetectable, we studied one behavioral ramification of adopting a U=U prevention strategy-not disclosing HIV status to sex partners. Cisgender men recruited through community outreach in the state of Georgia, USA. We examined HIV status disclosure to sex partners among 345 young (median age = 29 years) men receiving ART. Data were collected using computerized interviews, daily sexual behavior surveys over 28 days, unannounced pill counts for ART adherence, urine tests for drug use and urogenital health, and blood samples for HIV viral load. One in 3 participants (34%) engaged in condomless anal/vaginal intercourse with an HIV-negative/unknown HIV status partner over 28 days. Average ART adherence was 76%, and one in 5 men had detectable HIV viral loads. Men who engaged in condomless sex with undisclosed partners demonstrated significantly less HIV disclosure to family and friends and had fewer enacted stigma experiences. Hierarchical regression models showed that endorsing U=U as a personal HIV prevention strategy predicted undisclosed condomless sex over and above substance use, HIV stigma experiences, disclosure to family and friends, ART adherence, and HIV viral load. Interventions are needed to improve ART adherence and assist men living with HIV in their decisions to disclose HIV status to sex partners.

Efficient Inhibition of HIV Using CRISPR/Cas13d Nuclease System.

Recently discovered Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas13 proteins are programmable RNA-guided ribonucleases that target single-stranded RNA (ssRNA). CRISPR/Cas13-mediated RNA targeting has emerged as a powerful tool for detecting and eliminating RNA viruses. Here, we demonstrate the effectiveness of CRISPR/Cas13d to inhibit HIV-1 replication. We designed guide RNAs (gRNAs) targeting highly conserved regions of HIV-1. RfxCas13d (CasRx) in combination with HIV-specific gRNAs efficiently inhibited HIV-1 replication in cell line models. Furthermore, simultaneous targeting of four distinct, non-overlapping sites in the HIV-1 transcript resulted in robust inhibition of HIV-1 replication. We also show the effective HIV-1 inhibition in primary CD4+ T-cells and suppression of HIV-1 reactivated from latently infected cells using the CRISPR/Cas13d system. Our study demonstrates the utility of the CRISPR/Cas13d nuclease system to target acute and latent HIV infection and provides an alternative treatment modality against HIV.