Nelson Vergel
Founder, ExcelMale.com
METFORMIN REDUCES T-CELL EXHAUSTION IN A CLINICAL TRIAL OF HIV-INFECTED ADULTS ON ART
Author(s):
Glen Chew1, Dominic Chow1, Scott A. Souza1, Lindsay Kohorn1, Richard M. Watanabe2, Ivo Sah Bandar1, Eun-Young Park1, Mary Margaret Byron1, Lishomwa C. Ndhlovu1, Cecilia Shikuma1
1Univ of Hawaii, Honolulu, HI, USA,2Univ of Southern California, Los Angeles, CA, USA
Abstract Body:
Chronic HIV infection is associated with persistent inflammation and increased expression of negative checkpoint receptors (NCRs; eg: PD-1, TIM-3, TIGIT) on T cells that result in immune dysfunction (Chew et al 2016 PLoS Pathog) and viral persistence (Fromentin et al 2016 PLoS Pathog). Current scientific literature suggests that Metformin, an oral hypoglycemic agent used for diabetes, may have additional, previously unrecognized therapeutic effects against age-related conditions including anti-inflammatory properties. We assessed NCR in banked blood specimens from a small clinical trial of Metformin conducted in individuals with chronic HIV.
An open label, 24 week pilot study in 12 individuals on antiretroviral therapy (ART) stable for >1year with plasma HIV RNA < 50 copies/ml, median age of 58 years and majority male (11/12) randomized 1:1 to Metformin (500 mg increasing to 1000 mg at week 4) vs Observation (OBS). We assessed surface expression of T cell exhaustion receptors (PD-1,TIM-3, TIGIT) and activation (CD38+HLA-DR+) by flow cytometry on cryopreserved peripheral blood mononuclear cells collected at enrollment and study end. Statistical analyses include nonparametric Mann-Whitney Statistical T tests.
Compared to OBS, Metformin led to significant 24 week decrease changes of single expressing PD-1+ CD4 T cells [Metformin -1.6 (-4.7,0.2), OBS 2.0 (0.4,3.7) p=0.026]; in dual expressing PD-1+TIGIT+ CD4 T cells [Metformin -0.9 (-2.9,-0.1), OBS 0.8 (0.2,1.2) p=0.002], and in triple expressing PD-1+TIM-3+TIGIT+ CD4 T cells [Metformin -0.9 (-1.3, -0.1), OBS (0.3 (0.07,0.6) p=0.041]. No difference in 24 week changes between the Metformin and OBS arms were observed in CD8 T cell exhaustion and CD4 or CD8 T cell activation.
A 24 week course of Metformin reduced CD4 T cell expression of multiple NCR among virally suppressed HIV infected adults. The data suggests the unexpected benefit of Metformin in potentially improving anti-viral T cell function or impacting the persistence of CD4 T cell viral reservoirs. Metformin may have value as an adjunctive therapy to ART in chronic HIV infection.
Author(s):
Glen Chew1, Dominic Chow1, Scott A. Souza1, Lindsay Kohorn1, Richard M. Watanabe2, Ivo Sah Bandar1, Eun-Young Park1, Mary Margaret Byron1, Lishomwa C. Ndhlovu1, Cecilia Shikuma1
1Univ of Hawaii, Honolulu, HI, USA,2Univ of Southern California, Los Angeles, CA, USA
Abstract Body:
Chronic HIV infection is associated with persistent inflammation and increased expression of negative checkpoint receptors (NCRs; eg: PD-1, TIM-3, TIGIT) on T cells that result in immune dysfunction (Chew et al 2016 PLoS Pathog) and viral persistence (Fromentin et al 2016 PLoS Pathog). Current scientific literature suggests that Metformin, an oral hypoglycemic agent used for diabetes, may have additional, previously unrecognized therapeutic effects against age-related conditions including anti-inflammatory properties. We assessed NCR in banked blood specimens from a small clinical trial of Metformin conducted in individuals with chronic HIV.
An open label, 24 week pilot study in 12 individuals on antiretroviral therapy (ART) stable for >1year with plasma HIV RNA < 50 copies/ml, median age of 58 years and majority male (11/12) randomized 1:1 to Metformin (500 mg increasing to 1000 mg at week 4) vs Observation (OBS). We assessed surface expression of T cell exhaustion receptors (PD-1,TIM-3, TIGIT) and activation (CD38+HLA-DR+) by flow cytometry on cryopreserved peripheral blood mononuclear cells collected at enrollment and study end. Statistical analyses include nonparametric Mann-Whitney Statistical T tests.
Compared to OBS, Metformin led to significant 24 week decrease changes of single expressing PD-1+ CD4 T cells [Metformin -1.6 (-4.7,0.2), OBS 2.0 (0.4,3.7) p=0.026]; in dual expressing PD-1+TIGIT+ CD4 T cells [Metformin -0.9 (-2.9,-0.1), OBS 0.8 (0.2,1.2) p=0.002], and in triple expressing PD-1+TIM-3+TIGIT+ CD4 T cells [Metformin -0.9 (-1.3, -0.1), OBS (0.3 (0.07,0.6) p=0.041]. No difference in 24 week changes between the Metformin and OBS arms were observed in CD8 T cell exhaustion and CD4 or CD8 T cell activation.
A 24 week course of Metformin reduced CD4 T cell expression of multiple NCR among virally suppressed HIV infected adults. The data suggests the unexpected benefit of Metformin in potentially improving anti-viral T cell function or impacting the persistence of CD4 T cell viral reservoirs. Metformin may have value as an adjunctive therapy to ART in chronic HIV infection.
