Chronic alcohol increases CD8+ T-cell immunosenescence in simian immunodeficiency virus-infected rhesus macaques

doi:10.1016/j.alcohol.2015.09.003

. 2015 Dec;49(8):759-65.

doi: 10.1016/j.alcohol.2015.09.003. Epub 2015 Oct 27.

Chronic alcohol increases CD8+ T-cell immunosenescence in simian immunodeficiency virus-infected rhesus macaques

Affiliations

¹ Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
² Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Comprehensive Alcohol Research Center, Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
³ Comprehensive Alcohol Research Center, Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Medicine, Section of Pulmonary/Critical Care & Allergy/Immunology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
⁴ Comprehensive Alcohol Research Center, Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Medicine, Section of Pulmonary/Critical Care & Allergy/Immunology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
⁵ School of Public Health, Biostatistics Program, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
⁶ Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; New Orleans Louisiana Cancer Research Center, New Orleans, LA 70112, USA.
⁷ Comprehensive Alcohol Research Center, Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Tulane National Primate Research Center, Tulane University, Covington, LA 70433, USA.
⁸ Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Comprehensive Alcohol Research Center, Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Medicine, Section of Pulmonary/Critical Care & Allergy/Immunology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
⁹ Comprehensive Alcohol Research Center, Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Medicine, Section of Pulmonary/Critical Care & Allergy/Immunology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA. Electronic address: dwelsh@lsuhsc.edu.

PMID: 26603633
PMCID: PMC4691397
DOI: 10.1016/j.alcohol.2015.09.003

Chronic alcohol increases CD8+ T-cell immunosenescence in simian immunodeficiency virus-infected rhesus macaques

Paige S Katz et al. Alcohol. 2015 Dec.

. 2015 Dec;49(8):759-65.

doi: 10.1016/j.alcohol.2015.09.003. Epub 2015 Oct 27.

Authors

Affiliations

¹ Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
² Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Comprehensive Alcohol Research Center, Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
³ Comprehensive Alcohol Research Center, Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Medicine, Section of Pulmonary/Critical Care & Allergy/Immunology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
⁴ Comprehensive Alcohol Research Center, Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Medicine, Section of Pulmonary/Critical Care & Allergy/Immunology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
⁵ School of Public Health, Biostatistics Program, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
⁶ Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; New Orleans Louisiana Cancer Research Center, New Orleans, LA 70112, USA.
⁷ Comprehensive Alcohol Research Center, Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Tulane National Primate Research Center, Tulane University, Covington, LA 70433, USA.
⁸ Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Comprehensive Alcohol Research Center, Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Medicine, Section of Pulmonary/Critical Care & Allergy/Immunology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
⁹ Comprehensive Alcohol Research Center, Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Medicine, Section of Pulmonary/Critical Care & Allergy/Immunology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA. Electronic address: dwelsh@lsuhsc.edu.

PMID: 26603633
PMCID: PMC4691397
DOI: 10.1016/j.alcohol.2015.09.003

Abstract

Activated CD8+ T-cells correlate with viral load and may foretell antiretroviral therapy (ART) failure. HIV infection has been suggested to accelerate immunosenescence through chronic persistent inflammation. Alcohol-use disorders (AUD) are prevalent in persons living with HIV/AIDS (PLWHA). We tested the hypothesis that hazardous alcohol consumption accelerates immune activation and immunosenescence. Immune activation and immunosenescence were examined in CD8+ T lymphocytes (CD3+CD4-CD8+) isolated from intestinal biopsies, axillary lymph nodes, and peripheral blood mononuclear cells (PBMCs) of chronic binge alcohol (CBA)-consuming simian immunodeficiency virus (SIV)-infected male rhesus macaques with and without antiretroviral therapy (ART; CBA/ART+, CBA/ART-) and in PBMCs isolated from a cohort of PLWHA. Polychromatic flow cytometry was used to phenotype cells isolated from intestinal biopsies, lymph nodes, and peripheral blood from rhesus macaques and PLWHA. The Alcohol Use Disorders Identification Test (AUDIT) identified hazardous alcohol drinking in PLWHA. Viral load was determined by RT-qPCR and telomere length was measured using qPCR. PBMC CD8+ T-cell activation (CD38+HLA-DR+) and immunosenescence (CD28-) were increased over baseline levels (857% ± 334, p < 0.05; 398% ± 80, p < 0.05, respectively) only in CBA animals not receiving ART. Viral load correlated with CD8+ T-cell immunosenescence in macaque PBMCs (r(s) = 0.49, p = 0.02). Activated immunosenescent T-cell (CD8+CD38+CD28-) frequencies in PBMCs from PLWHA significantly correlated with AUDIT scores (r(s) = 0.75, p = 0.001), while no correlation was observed with CD4+ T-cell and AUDIT scores (r(s) = -0.24, p = 0.38). Activated immunosenescent T-cells had shorter telomeres than CD8+ T-cells (CD8+CD28+) from PLWHA. Our results suggest that CBA and AUD augment immune activation and immunosenescence in SIV-infected macaques and PLWHA.

Keywords: Alcohol; Anti-retroviral therapy; Immune activation; Immunosenescence; SIV.

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Figures

**Fig. 1**
CD8+ T-cell activation (CD3+CD4−CD8+CD38+HLA-DR+) expressed as a percent of baseline in **(a)** PBMCs, **(b)** intestinal MCs, and **(c)** lymph node MCs isolated from SIV-infected macaques. Two-way ANOVA was performed to determine statistically significant differences from baseline and Bonferroni *post hoc* to compare between groups. * indicates p < 0.05 from baseline values; n = 5–6/group.

**Fig. 2**
CD8+ T and immunosenescence (CD3+CD4−CD8+CD28−) expressed as a percent of baseline in **(a)** PBMCs, **(b)** intestinal MCs, and **(c)** lymph node MCs isolated from SIV-infected macaques. Two-way ANOVA was performed to determine statistically significant differences from baseline and Bonferroni *post hoc* to compare between groups. * indicates p < 0.05 from baseline values, # indicates p < 0.05 compared to CBA/ART+; n = 5–6/group.

**Fig. 3**
**(a)** Viral load measured in plasma after 12–14 months of SIV infection from SIV-infected macaques. **(b)** Viral load correlated with CD8+ T-cell senescence in PBMCs from SIV-infected macaques. Two-way ANOVA with Bonferroni *post hoc* was performed to determine statistically significant differences between groups (a), and association was tested using Spearman’s correlation **(b)**. # indicates p < 0.05 compared to ART− groups; n = 5–6/group.

**Fig. 4**
**(a)** Percentage of activated immunosenescent (CD3+CD4−CD8+CD38+CD28−) T-cell human PBMCs isolated from HIV-positive patients with either a low or high AUDIT score. **(b)** Correlation of AUDIT score and activated immunosenescent T-cells human PBMCs isolated from HIV-positive patients. (c) Telomere length of CD8+CD28+, CD8+CD38−CD28− and activated immunosenescent T-cells. Student’s t test **(a and c)** was performed to determine statistically significant differences between groups, and association was tested using Spearman’s correlation **(b)**. * indicates p < 0.05 compared to AUDIT < 8 (a), * indicates p < 0.05 compared to CD8+CD28+ T-cells (c); n = 6–9/group.

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References

1. Bagby GJ, Stoltz DA, Zhang P, Kolls JK, Brown J, Bohm RP, Jr, et al. The effect of chronic binge ethanol consumption on the primary stage of SIV infection in rhesus macaques. Alcoholism: Clinical and Experimental Research. 2003;27:495–502. - PubMed
1. Bagby GJ, Zhang P, Purcell JE, Didier PJ, Nelson S. Chronic binge ethanol consumption accelerates progression of simian immunodeficiency virus disease. Alcoholism: Clinical and Experimental Research. 2006;30:1781–1790. - PubMed
1. Boucher N, Dufeu-Duchesne T, Vicaut E, Farge D, Effros RB, Schächter F. CD28 expression in T cell aging and human longevity. Experimental Gerontology. 1998;33:267–282. - PubMed
1. Caruso A, Licenziati S, Corulli M, Canaris AD, De Francesco MA, Fiorentini S, et al. Flow cytometric analysis of activation markers on stimulated T cells and their correlation with cell proliferation. Cytometry. 1997;27:71–76. - PubMed
1. Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Research. 2002;30:e47. - PMC - PubMed

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[1] Bagby GJ, Stoltz DA, Zhang P, Kolls JK, Brown J, Bohm RP, Jr, et al. The effect of chronic binge ethanol consumption on the primary stage of SIV infection in rhesus macaques. Alcoholism: Clinical and Experimental Research. 2003;27:495–502. - PubMed

[2] Bagby GJ, Stoltz DA, Zhang P, Kolls JK, Brown J, Bohm RP, Jr, et al. The effect of chronic binge ethanol consumption on the primary stage of SIV infection in rhesus macaques. Alcoholism: Clinical and Experimental Research. 2003;27:495–502. - PubMed

[3] Bagby GJ, Zhang P, Purcell JE, Didier PJ, Nelson S. Chronic binge ethanol consumption accelerates progression of simian immunodeficiency virus disease. Alcoholism: Clinical and Experimental Research. 2006;30:1781–1790. - PubMed

[4] Bagby GJ, Zhang P, Purcell JE, Didier PJ, Nelson S. Chronic binge ethanol consumption accelerates progression of simian immunodeficiency virus disease. Alcoholism: Clinical and Experimental Research. 2006;30:1781–1790. - PubMed

[5] Boucher N, Dufeu-Duchesne T, Vicaut E, Farge D, Effros RB, Schächter F. CD28 expression in T cell aging and human longevity. Experimental Gerontology. 1998;33:267–282. - PubMed

[6] Boucher N, Dufeu-Duchesne T, Vicaut E, Farge D, Effros RB, Schächter F. CD28 expression in T cell aging and human longevity. Experimental Gerontology. 1998;33:267–282. - PubMed

[7] Caruso A, Licenziati S, Corulli M, Canaris AD, De Francesco MA, Fiorentini S, et al. Flow cytometric analysis of activation markers on stimulated T cells and their correlation with cell proliferation. Cytometry. 1997;27:71–76. - PubMed

[8] Caruso A, Licenziati S, Corulli M, Canaris AD, De Francesco MA, Fiorentini S, et al. Flow cytometric analysis of activation markers on stimulated T cells and their correlation with cell proliferation. Cytometry. 1997;27:71–76. - PubMed

[9] Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Research. 2002;30:e47. - PMC - PubMed

[10] Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Research. 2002;30:e47. - PMC - PubMed

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Chronic alcohol increases CD8+ T-cell immunosenescence in simian immunodeficiency virus-infected rhesus macaques

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Chronic alcohol increases CD8+ T-cell immunosenescence in simian immunodeficiency virus-infected rhesus macaques

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