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Short Communication: Metformin Reduces CD4 T Cell Exhaustion in HIV-Infected Adults on Suppressive Antiretroviral Therapy.

ABSTRACT: Increased negative immune checkpoint receptors (NCR) on T cells are linked to T cell exhaustion, dysfunctional effector responses, and HIV viral persistence. Metformin, an oral hypoglycemic agent used for diabetes, may have previously unrecognized beneficial immunologic effects. Using cryopreserved blood from a 24-week pilot study involving 12 virally suppressed HIV-infected individuals randomized 1:1 to metformin versus observation (OBS), we assessed change in the frequencies of T cell activation (CD38⁺HLA-DR⁺) and NCR [programmed cell death protein 1 (PD1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and T cell mucin-domain containing-3 (TIM3)]. No differences in 24-week change were seen between arms in CD4 or CD8 T cells, in the CD4/CD8 ratio, or in activated (CD38⁺HLA-DR⁺) CD4 or CD8 T cells. However, metformin over 24 weeks led to decreases compared with OBS in single PD1⁺ (percent decrease: -9.6% vs. 7.5%, p = .015), in dual PD1⁺TIGIT⁺ (-15.0% vs. 10.4%, p = .002), and in triple PD1⁺TIGIT⁺TIM3⁺ (-24.0% vs. 8.1%, p = .041) CD4 T cells. Metformin led to no changes in CD8 T cell NCR frequencies. Metformin decreases the frequency of PD1⁺, PD1⁺TIGIT⁺, and PD1⁺TIGIT⁺TIM3⁺ expressing CD4 T cells. This may have relevance to HIV cure strategies and to efforts to mitigate the risk of chronic complications of HIV.

SUBMITTER: Shikuma CM

PROVIDER: S-EPMC7185314 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Short communication: CD4 T cell declines occurring during suppressive antiretroviral therapy reflect continued production of Casp8p41.

Project description:Most patients on suppressive antiretroviral therapy (ART) experience improvements in CD4 T cell count. However, some patients with undetectable viral load continue to lose CD4 T cells for unknown reasons. Casp8p41 is a host-derived protein fragment that is present only in productively infected cells and that causes the death of HIV-infected cells. We questioned whether ongoing CD4(+) T cell losses while on suppressive ART were associated with subclinical HIV replication causing production of Casp8p41. We analyzed the association of Casp8p41 content with subsequent CD4 losses in patients on continuous suppressive ART and in patients who discontinued ART after Casp8p41 content was determined, adjusting for age, baseline CD4(+) T cell count, and baseline HIV RNA level. Casp8p41 expression in memory CD4(+) T cells was measured by intracellular flow cytometry and was correlated with viral load and CD4(+) T cell change over time. In patients who stopped therapy after Casp8p41 content was determined, baseline Casp8p41 content did not predict CD4(+) T cell change. However, in patients on continuous ART, higher baseline Casp8p41 content was associated with a greater odds of a CD4(+) T cell decline at 6 months (p=0.01). Therefore, patients on suppressive ART, who have ongoing production of Casp8p41, have an increased risk of CD4 T cell losses, suggesting that subclinical HIV replication is driving both Casp8p41, which in turn causes a CD4(+) T cell decline.

| S-EPMC4010171 | biostudies-literature

Short Communication: Effect of Antiretroviral Therapy on Circulating Damage-Associated Molecular Pattern Molecules and CD4 Immune Reconstitution in HIV-Infected Individuals.

Project description:We examined levels of the damage-associated molecular pattern molecules, HMGB1 and S100A9, in individuals for whom stored samples were available before and after antiretroviral therapy (ART) initiation, to determine their association with CD4 reconstitution. Mean HMGB1 levels (1.95?ng/ml vs. 3.02?ng/ml) and the proportion of individuals with detectable S100A9 (19.6% vs. 43.1%) significantly increased after ART. Detectable post-ART S100A9 was independently associated with impaired immune reconstitution.

| S-EPMC5028901 | biostudies-other

Pathological Role of Anti-CD4 Antibodies in HIV-Infected Immunologic Nonresponders Receiving Virus-Suppressive Antiretroviral Therapy.

Project description:Increased mortality and morbidity occur among human immunodeficiency virus (HIV)-infected patients in whom CD4+ T-cell counts do not increase despite viral suppression with antiretroviral therapy (ART). Here we identified an underlying mechanism. Significantly elevated plasma levels of anti-CD4 immunoglobulin G (IgG) were found in HIV-positive immunologic nonresponders (ie, HIV-positive individuals with CD4+ T-cell counts of ≤350 cells/μL), compared with levels in HIV-positive immunologic responders (ie, HIV-positive individuals with CD4+ T-cell counts of ≥500 cells/μL) and healthy controls. Higher plasma level of anti-CD4 IgG correlated with blunted CD4+ T-cell recovery. Furthermore, purified anti-CD4 IgG from HIV-positive immunologic nonresponders induced natural killer (NK) cell-dependent CD4+ T-cell cytolysis and apoptosis through antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro. We also found that anti-CD4 IgG-mediated ADCC exerts greater apoptosis of naive CD4+ T cells relative to memory CD4+ T cells. Consistently, increased frequencies of CD107a+ NK cells and profound decreases of naive CD4+ T cells were observed in immunologic nonresponders as compared to responders and healthy controls ex vivo. These data indicate that autoreactive anti-CD4 IgG may play an important role in blunted CD4+ T-cell reconstitution despite effective ART.

| S-EPMC5853506 | biostudies-literature

Activation of HIV transcription with short-course vorinostat in HIV-infected patients on suppressive antiretroviral therapy.

Project description:UnlabelledHuman immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells.Trial registrationClinicalTrials.gov NCT01365065.

| S-EPMC4231123 | biostudies-literature

Short Communication: Preferential Killing of HIV Latently Infected CD4(+) T Cells by MALT1 Inhibitor.

Project description:We report that the addition of an host paracaspase MALT1 inhibitor, MI-2, to HIV latently infected ACH-2, Jurkat E4, and J-LAT cells accelerated cell death in the presence of cell stimuli or the protein kinase C agonist, bryostatin 1. MI-2-mediated cell death correlated with the induction of the cellular RNase MCPIP1 and requires the presence of viral component(s). Altogether, the combination of MI-2 and bryostatin 1 displays selective killing of HIV latently infected CD4(+) T cells.

| S-EPMC4761853 | biostudies-literature

Short Communication: Expression of Host Restriction Factors by Memory CD4+ T Cells Differs Between Healthy Donors and HIV-1-Infected Individuals with Effective Antiretroviral Therapy.

Project description:Much has been learnt from the functions of host restriction factors during acute and chronic HIV-1 infection, but far less is known about their role in HIV-1-infected individuals in which viral load is stably suppressed with antiretroviral therapy (ART). In this study transcriptional expression of 42 host restriction factors was determined for memory CD4+ T cells sorted from 10 uninfected and 21 HIV-1-infected individuals, treated with suppressive ART and for which the viral reservoir was quantified. No significant associations were observed between restriction factor expression and HIV-1 reservoir size, quantified by measurement of HIV-1 Gag DNA using droplet digital polymerase chain reaction, and by measurement of replication-competent inducible virus using quantitative viral outgrowth assays. Expression of eight of the restriction factors differed significantly, and with a false discovery rate of <10%, between ART-suppressed and uninfected individuals. APOBEC3G, ISG15, LGALS3BP, RNASEL, and MX2 were upregulated in the ART-suppressed individuals, likely because of increased levels of immune activation observed in virally suppressed compared with uninfected individuals. In contrast CDKN1A, TRIM11, and BRD4 were expressed at lower levels in ART-suppressed than uninfected individuals. This suggests perturbation of the CD4+ memory T cell compartment, in which a viral reservoir persists in HIV-1-infected individuals with effective ART. Modulation of restriction factor expression, or overrepresentation of cell subsets that intrinsically express these restriction factors at lower levels could result in the distinct expression of restriction factors observed in treated infected individuals.

| S-EPMC6343196 | biostudies-literature

CD4-specific mortality rates among HIV-infected adults with high CD4 counts and no antiretroviral treatment in West Africa.

Project description:CD4-specific rates of mortality in sub-Saharan African adults with high CD4 counts have rarely been estimated. This estimation is useful to the when to start antiretroviral treatment (ART) debate.We pooled data from National Agency for Research on AIDS and Viral Hepatitis (ANRS)-funded research cohorts or associated partners in West Africa. All HIV-infected adults (?18 years) with available follow-up time off ART were eligible. We used a joint model to estimate CD4 count evolution. We estimated CD4-specific rates of mortality, loss-to-follow-up (LTFU) and ART initiation by dividing the number of first event by the follow-up time off ART within each CD4 category.Between 1996 and 2009, 2588 adults (80% women) from 5 cohorts in Cote d'Ivoire and Burkina Faso were followed off ART during 6862 person-years. In the 201-350, 351-500, 501-650, and >650 cells per cubic millimeter CD4 categories, mortality rates were: 3.0, 1.5, 0.4, 0.2 per 100 person-years; LTFU rates: 6.0, 4.6, 6.1, 6.0 per 100 person-years; and ART initiation rates: 18.1, 2.7, 0.5, 0.5 per 100 person-years, respectively. All estimates varied across cohorts; mortality rates were higher when rates of LFTU and ART initiation were lower; LTFU rates were 2-40 times higher than mortality rates.Among untreated West African adults with high CD4 counts, mortality and LTFU rates were substantial. Even when data are collected under research conditions, informative censoring due to ART initiation and LTFU could lead to significantly underestimate mortality figures.

| S-EPMC3921663 | biostudies-other

Short communication: Late refills during the first year of antiretroviral therapy predict mortality and program failure among HIV-infected adults in urban Zambia.

Project description:We evaluated the association of the number of late antiretroviral therapy (ART) refills with patient outcomes in a large public-sector human immunodeficiency virus treatment program in Lusaka, Zambia. Using pharmacy data routinely collected during 2004-2010, we calculated the number of late refills during the initial year of ART. We used multivariable Cox proportional hazard regression to examine the association between the number of late refills and death or program failure (i.e., death, loss to follow-up, or program withdrawal) >12 months after ART initiation, with and without stratification by the medication possession ratio (MPR) during the initial year of ART. Of 53,015 adults who received ART for ?12 months (median follow-up duration, 86.1 months; interquartile range, 53.2-128.2 months), 26,847 (50.6%) had 0 late refills, 16,762 (31.6%) had 1, 6,505 (12.3%) had 2, and 2,901 (5.5%) had ?3. Kaplan-Meier analysis revealed that ?3 late refills was associated with a greater mortality risk than 1 and 2 late refills (p<0.001, by the log-rank test). The mortality risk was greater for patients with 2 late refills [adjusted hazard ratio (HR), 1.17; 95% confidence interval (CI), 0.99-1.38] or ?3 late refills (adjusted HR, 1.51; 95% CI, 1.23-1.87), compared with that for patients with 0-1 late refills. Program failure was associated with ?2 late refills. An MPR of <80% was associated with similar increases in mortality risk across late-refill strata. Monitoring late refills during the initial period of ART may help resource- and time-constrained clinics identify patients at risk for program failure.

| S-EPMC3887398 | biostudies-literature

CD4+ gain percentile curves for monitoring response to antiretroviral therapy in HIV-infected adults.

Project description:We constructed CD4 cell count gain percentile distributions standardized by baseline CD4 cell count and assessed the association between poor CD4 cell count gain and subsequent death and virological failure on antiretroviral therapy (ART).Secondary analysis of 10 years of clinical data from a cohort of adults initiated on ART at the Themba Lethu clinic in Johannesburg, South Africa.The generalized additive model for location, scale and shape was used to construct percentile curves for CD4 cell count gain standardized by baseline CD4 cell count in the first 28 months of ART. Cox proportional models were used to assess the association between lower percentiles (<50th) of CD4 cell count gain, and subsequent death and virological failure.Among 9640 nonpregnant adults 7406, with available CD4 cell count results for CD4 gain calculation at 4 months of ART, 843 (8.7%) died subsequently and 1101 (11.4%) experienced virologic failure, respectively. For CD4 gains below the third percentile, the adjusted hazard ratios at different time points ranged between 2.72 and 5.73 for death, and between 1.48 and 6.93 for virologic failure. The CD4 percentile curves revealed a gradient of increasing risk of subsequent death and virological failure, with lower CD4 gain percentiles and increasing time on ART, and were more informative than the WHO criteria for immunological failure or current CD4 cell count.Percentile curves of CD4 cell count gain provide a simple tool for healthcare workers in low-resource settings to monitor response to ART with improved information regarding risk of death and virological failure compared to current WHO criteria for immunological failure.

| S-EPMC4487417 | biostudies-literature

HIV persistence in mucosal CD4+ T cells within the lungs of adults receiving long-term suppressive antiretroviral therapy.

Project description:BackgroundThe lungs were historically identified as one of the major anatomic sites for HIV replication in the pre-antiretroviral therapy (ART) era. However, their contribution to HIV persistence in individuals under suppressive ART remains understudied.DesignWe assessed HIV persistence and comprehensively characterized pulmonary mucosal CD4 T cells in HIV-infected (HIV) individuals receiving long-term suppressive ART versus uninfected participants.MethodsBronchoalveolar lavage (BAL), bronchial biopsies, and matched peripheral blood were obtained from n?=?24 HIV-infected adults receiving long-term suppressive ART (median: 9 years) and n?=?8 healthy volunteers without respiratory symptoms. HIV-DNA and cell-associated HIV-RNA were quantified by ultra-sensitive PCR, and lung mucosal CD4 T-cell subsets were characterized by multiparameter flow cytometry.ResultsThe levels of HIV-DNA were 13-fold higher in total BAL cells compared to blood. Importantly, FACS-sorted CD4 T cells from BAL contained greater levels of HIV-DNA compared to peripheral CD4 T cells. BAL CD4 T cells in HIV individuals were characterized mostly by an effector memory phenotype, whereas naive and terminally differentiated cells were underrepresented compared to blood. Furthermore, BAL CD4 T cells expressed higher levels of immune activation (HLA-DR/CD38) and senescence (CD57) markers. Importantly, BAL was enriched in T-cell subsets proposed to be preferential cellular HIV reservoirs, including memory CD4CCR6, Th1Th17 (CD4CCR6CCR4CXCR3), CD4CCR6CXCR3CCR4, and CD4CD32a T cells.ConclusionThe pulmonary mucosa represents an important immunological effector site highly enriched in activated and preferential CD4 T-cell subsets for HIV persistence during long-term ART in individuals without respiratory symptoms. Our findings raise new challenges for the design of novel HIV eradication strategies in mucosal tissues.

| S-EPMC6200382 | biostudies-literature

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