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Effects of Brief Adjunctive Metformin Therapy in Virologically Suppressed HIV-Infected Adults on Polyfunctional HIV-Specific CD8 T Cell Responses to PD-L1 Blockade.

ABSTRACT: Targeting inhibitory immune checkpoint receptor pathways has shown remarkable success in improving anticancer T cell responses for the elimination of tumors. Such immunotherapeutic strategies are being pursued for HIV remission. Metformin has shown favorable clinical outcomes in enhancing the efficacy of programmed cell death-1 (PD-1) blockade and restoring antitumor T cell immunity. Furthermore, monocytes are known to be a strong predictor of progression-free survival in response to anti-PD-1 immunotherapy. In a single-arm clinical trial, we evaluated the immunological effects over an 8-week course of metformin therapy in seven euglycemic, virally suppressed HIV-infected participants on combination antiretroviral therapy (cART). We assessed changes in peripheral HIV-Gag-specific T cell responses to immune checkpoint blockade (ICB) with anti-PD-L1 and anti-T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) monoclonal antibodies (mAbs) and changes in CD8 T cell and monocyte subsets using flow cytometry. Study participants were all male, 71% (5/7) Caucasian, with a median age of 61 years, CD4 count of 739 cells/μL, and plasma HIV RNA of <50 copies/mL on stable cART for >1 year. Ex vivo polyfunctional HIV-Gag-specific CD8 T cell responses to anti-PD-L1 mAb significantly improved (p < .05) over the 8-week course of metformin therapy. Moreover, frequencies of both intermediate (CD14⁺CD16⁺; r = 0.89, p = .01) and nonclassical (CD14^lowCD16⁺; r = 0.92, p = .01) monocytes at entry were predictive of the magnitude of the anti-HIV CD8 T cell responses to PD-L1 blockade. Collectively, these findings highlight that 8-week course of metformin increases the polyfunctionality of CD8 T cells and that baseline monocyte subset frequencies may be a potential determinant of PD-L1 blockade efficacy. These data provide valuable information for HIV remission trials that utilize ICB strategies to enhance anti-HIV CD8 T cell immunity.

SUBMITTER: Chew GM

PROVIDER: S-EPMC7864091 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIron metabolism plays an essential role in cellular functions. Since virologically suppressed chronic HIV-infected subjects under effective antiretroviral treatment (ART) exhibit a persistent immune dysfunction that leads to comorbidities, iron homeostasis may be relevant in this context. We aimed to explore iron metabolism in virologically suppressed chronic HIV infected subjects under a successful ART.MethodsIn this retrospective study, traditional iron metabolism biomarkers (total iron, ferritin, transferrin, and transferrin saturation index), as well as soluble transferrin receptor (sTfR), hepcidin, and inflammatory markers were determined in virologically suppressed chronic HIV-infected subjects under at least 2 years of ART (HIV) who also had >350 CD4-T-cells/mm3 (N=92) from Spain. As controls, we collected non-HIV age-matched healthy donors (Young, N=25) and elderly subjects (>65 years old; Elderly; N=25). Additionally, an external group of non-HIV patients with ferritin<50 ng/mL diagnosed with absolute iron deficiency (Ferropenic group; N=84) was included. Comparisons between groups were performed using Kruskal-Wallis or Mann-Whitney U-tests, while associations between variables were explored by Spearman's rho correlation coefficient.ResultsWe selected samples from HIV-infected subjects (aged 42[34-47], 95% males), young age-matched (aged 40[30-58], 60% males), and elderly controls (aged 82[78-88], 100% males). Compared to both healthy (Young and Elderly) groups, HIV exhibited decreased iron, transferrin saturation, and sTfR, and increased ferritin, but similar hepcidin levels. Notably, associations between sTfR and iron (Young, r=-0.587, p=0.002; Elderly, r=-0.496, p=0.012) or transferrin saturation index (Young, r=-0.581, p=0.002; Elderly, r=-0.489, p=0.013) were negative in both controls while positive in HIV (r=0.464, p<0.0001 and r=0.421, p<0.0001, respectively). Moreover, the expected negative correlation between hepcidin and sTfR, observed in controls (Young, r=-0.533, p=0.006; Elderly, r=-0.473, p=0.017), was absent in HIV (r=0.082; p=0.438). Interestingly, the HIV inflammatory profile differed from the Elderly one, who despite their inflammaging-related profile, succeed in maintaining these associations. Furthermore, subjects from the ferropenic group (aged 42[32-51], 5% males), showing significantly lower levels of hepcidin and higher sTfR, as expected, reflected similar correlations as those Young and Elderly, in contrast to HIV.ConclusionsVirologically suppressed chronic HIV-infected patients under successful ART exhibit altered levels of iron metabolism modulators suggesting a complex functional iron deficiency.

Project description:BACKGROUND:Immune restoration is often incomplete after ART in HIV patients, both quantitatively and qualitatively. We studied the incidence and probability of CD4/CD8 normalization in an adult Thai HIV cohort and explored the predictive value of the ratio for developing of non-AIDS defining events (NAEs). METHODS:We analyzed data from HIV-infected Thai adults between 1996 and 2017 in the HIV-NAT 006 prospective long-term cohort in Bangkok, Thailand. Normalization was defined as CD4/CD8 ratio ??1 on two consecutive visits, and normalization probability was calculated using the Kaplan-Meier method. NAEs were a composite endpoint including cardiovascular or cerebrovascular diseases, chronic kidney diseases, non-AIDS defining malignancies and death. Multivariate Cox regression was used to evaluate demographic, disease and treatment characteristics associated with CD4/CD8 ratio normalization and NAEs. RESULTS:A total of 800 ART-naïve patients with baseline CD4/CD8 ratio of <?0.8 who started combination ART, and had sustained virological suppression were enrolled. Participants were on ART for a median of 8.9 years and virologically suppressed for 6.1 years. The probabilities of CD4/CD8 normalization at 2, 5 and 10 years after virological suppression were 5.1%, 18.6% and 39.1%, respectively. Factors associated with normalization in multivariate analysis were female sex (hazard ratio [HR]: 2.47, 95% CI 1.71-3.56, p?<?0.001) and baseline CD4 counts ??350 cells/mm3 (HR: 3.62, 95% CI 2.36-5.55), p?<?0.001) vs. <?200 cells/mm3 as reference. The second analysis explored the predictive value of CD4/CD8 ratio for NAEs. Older age (HR: 1.09, 95% CI 1.05-1.13, p?<?0.01) and current CD4/CD8 ratio <?0.3 (HR: 3.02, 95% CI 1.27-7.21, p?=?0.01) or between 0.3 and 0.45 (HR: 2.03, 95% CI 1.03-3.98, p?=?0.04) vs. >?0.45 were independently associated with higher risk of progression to NAEs in the multivariate analysis. CONCLUSIONS:Our findings showed that complete immune recovery is uncommon in an Asian setting and earlier ART initiation at higher CD4 counts may have increased the ratio sooner. The findings demonstrate the use of CD4/CD8 ratio as a prognostic marker for clinical progression of NAEs. Trial registration HIV-NAT 006 cohort, clinical trial number: NCT00411983.

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Effects of Brief Adjunctive Metformin Therapy in Virologically Suppressed HIV-Infected Adults on Polyfunctional HIV-Specific CD8 T Cell Responses to PD-L1 Blockade.

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