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. 2017 Sep;33(9):905-918.
doi: 10.1089/AID.2016.0303. Epub 2017 May 10.

Restoring Cytokine Balance in HIV-Positive Individuals With Low CD4 T Cell Counts

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Free PMC article

Restoring Cytokine Balance in HIV-Positive Individuals With Low CD4 T Cell Counts

Anddre Valdivia et al. AIDS Res Hum Retroviruses. .
Free PMC article

Abstract

HIV infects and destroys CD4+ T cells leading to a compromised immune system. In a double-blinded study, a group of HIV-infected individuals with CD4+ T cell counts below 350 cells/mm3 were given either an empty liposomal supplement or a liposomal glutathione (L-GSH) supplement to take over a 3-month period. Baseline measurements in HIV-positive subjects show a significant decrease in levels of interleukin (IL)-12, IL-2, and interferon (IFN)-γ, along with a substantial increase in the levels of IL-6, IL-10, transforming growth factor (TGF)-β, and free radicals, compared to healthy individuals. Supplementation of HIV-positive subjects with L-GSH for 3 months resulted in a notable increase in the levels of IL-12, IL-2, and IFN-γ, with a concomitant decrease in the levels of IL-6, IL-10, and free radicals, and stabilization in the levels of TGF-β, IL-1, and IL-17, compared to their placebo counterparts. Levels of free radicals in CD4+ T cells stabilized, while GSH levels increased in the treatment group. Those in the placebo group showed no significant difference throughout the study. In summary, supplementation with L-GSH in HIV-infected individuals with CD4+ T cell counts below 350 cells/mm3 can help restore redox homeostasis and cytokine balance, therefore aiding the immune system to control opportunistic infections.

Keywords: AIDS; HIV; cytokines; glutathione; redox homeostasis.

Conflict of interest statement

No competing financial interests exist.

Figures

<b>FIG. 1.</b>
FIG. 1.
Measurement of total GSH and rGSH. (A) Baseline levels of total GSH in plasma samples of Healthy Baseline, and HIV-positive subjects with CD4+ T cell counts below 350 cells/mm3. Total GSH in plasma samples from HIV patients was significantly lower compared to the healthy individuals. GSH assay was performed using a colorimetric assay kit from Arbor Assays. Data represent mean ± SE from 16 healthy individuals and 30 individuals with HIV. (B) Baseline levels of rGSH in plasma samples of Healthy Baseline and HIV-positive subjects with CD4+ T cell counts below 350 cells/mm3. rGSH in plasma samples from HIV-positive subjects was significantly lower compared to the healthy individuals. Data represent mean ± SE from 16 healthy individuals and 30 individuals with HIV. (C) Baseline levels of total GSH in CD4+ T cells of Healthy Baseline and HIV-positive subjects with CD4+ T cell counts below 350 cells/mm3. CD4+ T cells were isolated using the EasySep Human CD4 Positive Selection Kit from nonadherent PBMCs isolated from whole blood of healthy participants and HIV patients. Total GSH in CD4 T cells from HIV patients was significantly lower compared to the healthy individuals. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV with placebo supplementation. (D) Baseline levels of rGSH in CD4+ T cells of Healthy Baseline and HIV-positive subjects with CD4 T cells below 350 cells/mm3. Levels of rGSH in CD4 T cells from HIV patients were significantly lower compared to the healthy individuals. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV with placebo supplementation. (E) Total GSH in CD4+ T cells from the HIV placebo group with CD4+ T cell counts below 350 cells/mm3. There were no significant changes in the levels of total GSH in the CD4 T cells at 3 months postsupplementation with empty liposomes. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV placebo. (F) Total GSH in CD4+ T cells from the HIV-L-GSH treatment group with CD4 T cells below 350 cells/mm3. There was a significant increase in the levels of total GSH in the CD4 T cells from the HIV-positive subjects at 3 months post-L-GSH treatment. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV-L-GSH. (G) rGSH in CD4+ T cells from the HIV-L-GSH treatment group with CD4+ T cell counts below 350 cells/mm3. There was a significant increase in the levels of rGSH in the CD4 T cells from the HIV-positive subjects at 3 months post-L-GSH treatment. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV-L-GSH. (H) Total GSH in CD4+ T cells from the HIV placebo group with CD4+ T cell counts below 200 cells/mm3 and between 200 and 350 cells/mm3. There were no changes in the levels of total GSH in the CD4 T cells from the HIV subgroups such as those with CD4 T cell counts below 200 cells/mm3 and participants with CD4 T cell counts between 200 and 350 cells/mm3 at 3 months post-treatment with empty liposomes. Data represent mean ± SE from 16 healthy individuals and seven individuals with HIV below 200 cells/mm3 and eight individuals with HIV 200–350 cells/mm3 with placebo supplementation. (I) Total GSH in CD4+ T cells from the HIV-L-GSH treatment group with CD4+ T cell counts below 200 cells/mm3 and between 200 and 350 cells/mm3. There was a significant increase in the levels of total GSH in the CD4 T cells from the HIV-positive subjects with CD4 T cell counts between 200 and 350 cells/mm3 at 3 months post-L-GSH treatment. Data represent mean ± SE from 16 healthy individuals and seven individuals with HIV below 200 cells/mm3 and eight individuals with HIV 200–350 cells/mm3 with L-GSH supplementation. (J) rGSH levels in CD4+ T cells from the HIV-L-GSH treatment group with CD4+ T cell counts below 200 cells/mm3 and between 200 and 350 cells/mm3. There was a significant increase in the levels of rGSH in the CD4 T cells from the HIV-positive subjects with CD4 T cell counts between 200 and 350 cells/mm3 at 3 months post-L-GSH treatment. Data represent mean ± SE from 16 healthy individuals and seven individuals with HIV CD4 T cell counts below 200 cells/mm3 and eight individuals with HIV 200–350 cells/mm3 with L-GSH supplementation, *p ≤ 0.05; **p ≤ 0.01. GSH, glutathione; rGSH, reduced glutathione; SE, standard error; PBMC, peripheral blood mononuclear cell; L-GSH, liposomal glutathione.
<b>FIG. 2.</b>
FIG. 2.
Measurement of MDA. (A) Baseline levels of MDA in plasma samples of Healthy Baseline and HIV-positive subjects with CD4 T cell counts below 350 cells/mm3. MDA levels in the plasma samples from HIV patients were significantly elevated compared to healthy individuals. MDA assay was performed using the TBARS assay kit from Cayman Chemical. Data represent mean ± SE from 16 healthy individuals and 30 individuals with HIV. (B) Baseline levels of MDA in RBCs of Healthy Baseline and HIV-positive subjects with CD4+ T cell counts below 350 cells/mm3. MDA levels in the RBCs from HIV patients were significantly enhanced compared to healthy individuals. Data represent mean ± SE from 16 healthy individuals and 30 individuals with HIV. (C) Baseline levels of MDA in CD4+ T cells of Healthy Baseline and HIV-positive subjects with CD4+ T cell counts below 350 cells/mm3. MDA levels in the CD4+ T cells from HIV patients were significantly higher compared to healthy individuals. Data represent mean ± SE from 16 healthy individuals and 30 individuals with HIV. (D) MDA levels in the plasma samples from the HIV placebo group with CD4+ T cell counts below 350 cells/mm3. There were no significant changes in the levels of MDA in the samples collected at 3 months postsupplementation with empty liposomes. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV placebo. (E) MDA levels in the plasma samples from the HIV-L-GSH treatment group with CD4+ T cell counts below 350 cells/mm3. There was a significant decrease in the levels of MDA in the plasma samples from the HIV-positive subjects at 3 months post-L-GSH treatment. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV-L-GSH. (F) MDA levels in the RBCs from the HIV-L-GSH treatment group with CD4+ T cell counts below 350 cells/mm3. There was a significant decrease in the levels of MDA in the RBCs from the HIV-positive subjects at 3 months post-L-GSH treatment. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV-L-GSH. (G) MDA levels in RBCs from the HIV-L-GSH treatment group with CD4+ T cell counts below 200 cells/mm3 and between 200 and 350 cells/mm3. L-GSH treatment resulted in a significant reduction in the levels of MDA in the RBCs isolated from HIV-positive subjects with CD4 T cells below 200 cells/mm3 and in CD4 T cells between 200 and 350 cells/mm3 at 3 months postsupplementation. Data represent mean ± SE from 16 healthy individuals and seven individuals with HIV below 200 cells/mm3 and eight individuals with HIV 200–350 cells/mm3 with L-GSH supplementation. (H) MDA levels in the CD4+ T cells from the HIV placebo group with CD4+ T cell counts below 350 cells/mm3. There was a significant increase in the levels of MDA in the CD4+ T cells isolated from the HIV-positive subjects at 3 months post-treatment with empty liposomes. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV placebo. (I) MDA levels in the CD4+ T cells from the HIV-L-GSH treatment group with CD4 T cell counts below 350 cells/mm3. There was stabilization in the levels of MDA in the CD4+ T cells isolated from the HIV-positive subjects at 3 months post-L-GSH treatment. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV-L-GSH, *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.005; ****p ≤ 0.0005. MDA, malondialdehyde; RBC, red blood cell.
<b>FIG. 3.</b>
FIG. 3.
Assay of IL-6, IL-10, and TGF-β. (A) Baseline levels of IL-6 in plasma samples of Healthy Baseline and HIV-positive subjects with CD4+ T cell counts below 350 cells/mm3. IL-6 levels were significantly elevated in the plasma samples from HIV patients compared to the healthy individuals. IL-6 was assayed in the plasma samples by sandwich ELISA using assay kits procured from eBioscience. Data represent mean ± SE from 16 healthy individuals and 30 individuals with HIV. (B) IL-6 levels in the plasma from the HIV placebo group with CD4+ T cell counts below 350 cells/mm3. There were no changes in the levels of IL-6 in the plasma samples isolated from the HIV-positive subjects at 3 months post-treatment with empty liposomes. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV placebo. (C) IL-6 levels in the plasma from the HIV-L-GSH group with CD4+ T cell counts below 350 cells/mm3. There was a significant decrease in the levels of IL-6 in the plasma samples isolated from the HIV-positive subjects at 3 months post-treatment with L-GSH. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV-L-GSH. (D) Baseline levels of IL-10 in plasma samples of Healthy Baseline and HIV-positive subjects with CD4+ T cell counts below 350 cells/mm3. IL-10 levels were significantly increased in the plasma samples from HIV patients compared to the healthy individuals. IL-10 was assayed in the plasma samples by sandwich ELISA using assay kits procured from eBioscience. Data represent mean ± SE from 16 healthy individuals and 30 individuals with HIV. (E) IL-10 levels in the plasma from the HIV placebo group with CD4+ T cell counts below 350 cells/mm3. There were no changes in the levels of IL-10 in the plasma samples isolated from the HIV-positive subjects at 3 months post-treatment with empty liposomes. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV placebo. (F) IL-10 levels in the plasma from the HIV-L-GSH group with CD4+ T cell counts below 350 cells/mm3. There was a significant decrease in the levels of IL-10 in the plasma samples isolated from the HIV-positive subjects at 3 months post-treatment with L-GSH. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV-L-GSH. (G) Baseline levels of TGF-β in plasma samples of Healthy Baseline and HIV-positive subjects with CD4+ T cell counts below 350 cells/mm3. TGF-β levels were significantly increased in the plasma samples from HIV patients compared to the healthy individuals. TGF-β was assayed in the plasma samples by sandwich ELISA using assay kits procured from eBioscience. Data represent mean ± SE from 16 healthy individuals and 30 individuals with HIV. (H) TGF-β levels in the plasma from the HIV placebo group with CD4+ T cell counts below 350 cells/mm3. There was a significant increase in the levels of TGF-β in the plasma samples isolated from the HIV-positive subjects at 3 months post-treatment with empty liposomes. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV placebo. (I) TGF-β levels in the plasma from the HIV-L-GSH group with CD4+ T cell counts below 350 cells/mm3. There was a stabilization in the levels of TGF-β in the plasma samples isolated from the HIV-positive subjects at 3 months post-treatment with L-GSH. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV-L-GSH, *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.005; ****p ≤ 0.0005. IL, interleukin; TGF, transforming growth factor; ELISA, enzyme-linked immunosorbent assay.
<b>FIG. 4.</b>
FIG. 4.
Assay of IL-12, IL-2, and IFN-γ. (A) Baseline levels of IL-12 in plasma samples of Healthy Baseline and HIV-positive subjects with CD4+ T cell counts below 350 cells/mm3. IL-12 levels were significantly decreased in the plasma samples from HIV patients compared to the healthy individuals. IL-12 was assayed in the plasma samples by sandwich ELISA using assay kits procured from eBioscience. Data represent mean ± SE from 16 healthy individuals and 30 individuals with HIV. (B) IL-12 levels in the plasma samples from the HIV placebo group with CD4+ T cell counts below 350 cells/mm3. There were no significant changes in the levels of IL-12 in the plasma samples isolated from the HIV-positive subjects at 3 months post-treatment with empty liposomes. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV placebo. (C) IL-12 levels in the plasma samples from the HIV-L-GSH group with CD4+ T cell counts below 350 cells/mm3. There was a significant increase in the levels of IL-12 in the plasma samples isolated from the HIV-positive subjects at 3 months post-treatment with L-GSH. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV-L-GSH. (D) IL-12 levels in the plasma samples from the HIV placebo group with CD4+ T cell counts below 200 cells/mm3 and between 200 and 350 cells/mm3. There were no changes in the levels of IL-12 in the plasma samples from the HIV subgroups such as those with CD4 T cell counts below 200 cells/mm3 and participants with CD4 T cell counts between 200 and 350 cells/mm3 at 3 months post-treatment with empty liposomes. Data represent mean ± SE from 16 healthy individuals and seven individuals with HIV below 200 cells/mm3 and eight individuals with HIV 200–350 cells/mm3 with placebo supplementation. (E) IL-12 levels in the plasma samples from the HIV-L-GSH treatment group with CD4+ T cell counts below 200 cells/mm3 and between 200 and 350 cells/mm3. There was a significant increase in the levels of IL-12 in the plasma samples from the HIV-positive subjects with CD4 T cell counts between 200 and 350 cells/mm3 at 3 months post-L-GSH treatment. Data represent mean ± SE from 16 healthy individuals and seven individuals with HIV below 200 cells/mm3 and eight individuals with HIV 200–350 cells/mm3 with L-GSH supplementation. (F) Baseline levels of IL-2 in plasma samples of Healthy Baseline and HIV-positive subjects with CD4+ T cell counts below 350 cells/mm3. IL-2 levels were significantly compromised in the plasma samples from HIV patients compared to the healthy individuals. IL-2 was assayed in the plasma samples by sandwich ELISA using assay kits procured from eBioscience. Data represent mean ± SE from 16 healthy individuals and 30 individuals with HIV. (G) IL-2 levels in the plasma samples from the HIV placebo group with CD4+ T cell counts below 350 cells/mm3. There was a further significant decrease in the levels of IL-2 in the plasma samples isolated from the HIV-positive subjects at 3 months post-treatment with empty liposomes. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV placebo. (H) IL-2 levels in the plasma samples from the HIV-L-GSH group with CD4+ T cell counts below 350 cells/mm3. The levels of IL-2 stabilized in the plasma samples isolated from the HIV-positive subjects at 3 months post-treatment with L-GSH. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV-L-GSH. (I) Baseline levels of IFN-γ in plasma samples of Healthy Baseline and HIV-positive subjects with CD4+ T cell counts below 350 cells/mm3. IFN-γ levels were diminished in the plasma samples from HIV patients compared to the healthy individuals. IFN-γ was assayed in the plasma samples by sandwich ELISA using assay kits procured from eBioscience. Data represent mean ± SE from 16 healthy individuals and 30 individuals with HIV. (J) IFN-γ levels in the plasma samples from the HIV placebo group with CD4+ T cell counts below 350 cells/mm3. There were no significant changes in the levels of IFN-γ in the plasma samples isolated from the HIV-positive subjects at 3 months post-treatment with empty liposomes. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV placebo. (K) IFN-γ levels in the plasma samples from the HIV-L-GSH group with CD4+ T cell counts below 350 cells/mm3. There was a significant increase in the levels of IFN-γ in the plasma samples isolated from the HIV-positive subjects at 3 months post-treatment with L-GSH. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV-L-GSH. (L) IFN-γ levels in the plasma samples from the HIV-L-GSH treatment group with CD4+ T cell counts below 200 cells/mm3 and between 200 and 350 cells/mm3. L-GSH treatment resulted in a significant increase in the levels of IFN-γ in the plasma samples isolated from HIV-positive subjects with CD4 T cells below 200 cells/mm3 and in CD4 T cells between 200 and 350 cells/mm3 at 3 months postsupplementation. Data represent mean ± SE from 16 healthy individuals and seven individuals with HIV below 200 cells/mm3 and eight individuals with HIV 200–350 cells/mm3 with L-GSH supplementation, *p ≤ 0.05; **p ≤ 0.01. IFN, interferon.
<b>FIG. 5.</b>
FIG. 5.
Assay of IL-17 and IL-1. (A) Baseline levels of IL-17 in plasma samples of Healthy Baseline and HIV-positive subjects with CD4+ T cell counts below 350 cells/mm3. IL-17 levels were significantly compromised in the plasma samples from HIV patients compared to the healthy individuals. IL-17 was assayed in the plasma samples by sandwich ELISA using assay kits procured from eBioscience. Data represent mean ± SE from 16 healthy individuals and 30 individuals with HIV. (B) IL-17 levels in the plasma samples from the HIV placebo group with CD4+ T cell counts below 350 cells/mm3. There was a further significant decrease in the levels of IL-17 in the plasma samples isolated from the HIV-positive subjects at 3 months post-treatment with empty liposomes. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV placebo. (C) IL-17 levels in the plasma samples from the HIV-L-GSH group with CD4+ T cell counts below 350 cells/mm3. The levels of IL-17 stabilized in the plasma samples isolated from the HIV-positive subjects at 3 months post-treatment with L-GSH. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV-L-GSH. (D) Baseline levels of IL-1 in plasma samples of Healthy Baseline and HIV-positive subjects with CD4+ T cell counts below 350 cells/mm3. IL-1 levels were significantly compromised in the plasma samples from HIV patients compared to the healthy individuals. IL-1 was assayed in the plasma samples by sandwich ELISA using assay kits procured from eBioscience. Data represent mean ± SE from 16 healthy individuals and 30 individuals with HIV. (E) IL-1 levels in the plasma samples from the HIV placebo group with CD4+ T cell counts below 350 cells/mm3. There was a further significant decrease in the levels of IL-1 in the plasma samples isolated from the HIV-positive subjects at 3 months post-treatment with empty liposomes. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV placebo. (F) IL-1 levels in the plasma samples from the HIV-L-GSH group with CD4+ T cell counts below 350 cells/mm3. The levels of IL-1 stabilized in the plasma samples isolated from the HIV-positive subjects at 3 months post-treatment with L-GSH. Data represent mean ± SE from 16 healthy individuals and 15 individuals with HIV-L-GSH, *p ≤ 0.05; **p ≤ 0.01.

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