Preview

Medical Immunology (Russia)

Advanced search

Functional exhaustion of CD4+T cells in HIV/HCV coinfected HAART-treated patients

https://doi.org/10.15789/1563-0625-FEO-2734

Abstract

Infection with hepatitis C virus (HCV) is common among HIV-positive patients, with up to 50% of them being coinfected in Russia. While highly active antiretroviral therapy (HAART) suppresses HIV replication and restores the immune system of HIV-infected subjects, HCV coinfection interferes with CD4+T cell regeneration and increases the risk of patients’ morbidity and mortality. During HAART, HIVinfection progression and the immune system restoration efficiency largely depend on immune activation and CD4+T cell exhaustion. This study determined the level of activation, exhaustion, and cytokine production in CD4+T cells obtained from the peripheral blood of HAART-treated HIV/HCV coinfected and HIV monoinfected subjects. The study comprised 11 HIV/HCV coinfected individuals and 10 HIV monoinfected patients receiving HAART for more than two years, with a control group of 10 volunteers without the signs of HIV or HCV infections. Compared with healthy controls, HIV/HCV coinfected patients had an increased frequency of activated CD38+HLA-DR+ CD4+T lymphocytes (p < 0.05), a higher level of CD4+T cell exhaustion determined according to the TIGIT expression density per cell (p < 0.05), and a greater proportion of interferon-gamma (IFNγ)-producing CD4+T lymphocytes following activation (p < 0.05). The frequency of IFNγ-producing CD4+T cells in the donors’ blood positively correlated with the proportion of activated CD4+T cells (R = 0.514, p < 0.01). Despite having a large number of IFNγ-producing CD4+T lymphocytes, the HIV/HCV coinfected patients’ average production of IFNγ by CD4+T cells was significantly lower than that in healthy controls (p < 0.05). The IFNγ production in CD4+T lymphocytes did not depend on activation (p > 0.05). However, a negative correlation was established between the IFNγ production and the level of CD4+T cell exhaustion (R = -0.400, p < 0.05). The letter was also found to inversely correlate with the CD4+T cell counts in the donors’ peripheral blood (R = -0.598, p < 0.01). These data suggest that HCV coinfection leads to pronounced functional exhaustion of CD4+T cells and may aggravate the course of HIVinfection in patients receiving HAART.

About the Authors

V. V. Vlasova
Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center, Ural Branch, Russian Academy of Sciences
Russian Federation

Vlasova V.V., Junior Research Associate, Laboratory of Molecular Immunology 

Perm



L. B. Korolevskaya
Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center, Ural Branch, Russian Academy of Sciences
Russian Federation

Korolevskaya L.B., PhD (Medicine), Research Associate, Laboratory of Ecological Immunology 

Perm



O. A. Loginova
Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center, Ural Branch, Russian Academy of Sciences
Russian Federation

Loginova O.A., PhD (Biology), Research Associate, Laboratory of Molecular Immunology 

Perm



N. G. Shmagel
Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center, Ural Branch, Russian Academy of Sciences
Russian Federation

Shmagel N.G., PhD, MD (Medicine), Senior Research Associate, Laboratory of Ecological Immunology 

Perm



E. V. Saidakova
Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center, Ural Branch, Russian Academy of Sciences
Russian Federation

Saidakova E.V., PhD, MD (Biology), Head, Laboratory of Molecular Immunology 

Perm



References

1. Chen T.Y., Ding E.L., Seage III G.R., Kim A.Y. Meta-analysis: increased mortality associated with hepatitis C in HIV-infected persons is unrelated to HIV disease progression. Clin Infect Dis, 2009, Vol. 49, no. 10, pp. 1605-1615.

2. Chew G.M., Fujita T., Webb G.M., Burwitz B.J., Wu H.L., Reed J.S., Hammond K.B., Clayton, K.L., Ishii N., Abdel-Mohsen M., Liegler T., Mitchell B.I., Hecht F.M., Ostrowski M., Shikuma C.M., Hansen S.G., Maurer M., Korman A.J., Deeks S.G., Sacha J.B., Ndhlovu L.C. TIGIT marks exhausted T Cells, correlates with disease progression, and serves as a target for immune restoration in HIV and SIV infection. PLoS Pathog., 2016, Vol. 12, no. 1, e1005349. doi: 10.1371/journal.ppat.1005349.

3. d’Arminio Monforte A., Cozzi-Lepri A., Castagna A., Antinori A., de Luca A., Mussini C., Caputo S.L., Arlotti M., Magnani G., Pellizzer G., Maggiolo F., Puoti M., Icona Foundation Study Group. Risk of developing specific AIDS-defining illnesses in patients coinfected with HIV and hepatitis C virus with or without liver cirrhosis. Clin. Infect. Dis., 2009, Vol. 49, no. 4, pp. 612-622.

4. Feuth T., Arends J.E., Fransen J.H., Nanlohy N.M., van Erpecum K.J., Siersema P.D., Hoepelman A.I.M., van Baarle D. Complementary role of HCV and HIV in T-cell activation and exhaustion in HIV/HCV coinfection. PLoS One, 2013, Vol. 8, no. 3, e59302. doi: 10.1371/journal.pone.0059302.

5. Freeman G.J., Wherry E.J., Ahmed R., Sharpe A.H. Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J. Exp. Med., 2006, Vol. 203, no. 10, pp. 2223-2227.

6. Guihot A., Tubiana R., Breton G., Marcelin A.G., Samri A., Assoumou L., Goncalves E., Bricaire F., Costagliola D., Calvez V., Rouzioux С., Autran B., Katlama C., Carcelain G., ALT-ANRS CO-15 study group, DECAMUNE study group. Immune and virological benefits of 10 years of permanent viral control with antiretroviral therapy. AIDS, 2010, Vol. 24, no.4, pp. 614-617.

7. Hernandez M.D., Sherman K.E. HIV/hepatitis C coinfection natural history and disease progression. Curr. Opin. HIV AIDS, 2011, Vol. 6, no. 6, pp. 478-482.

8. Joller N., Kuchroo V.K. Tim-3, Lag-3, and TIGIT. Curr. Top. Microbiol. Immunol., 2017, Vol. 410, pp. 127-156.

9. Okoye A.A., Picker L.J. CD4(+) T-cell depletion in HIV infection: mechanisms of immunological failure. Immunol. Rev., 2013, Vol. 254, no. 1, pp. 54-64.

10. Operskalski E.A., Kovacs A. HIV/HCV co-infection: pathogenesis, clinical complications, treatment, and new therapeutic technologies. Curr. HIV/AIDS Rep., 2011, Vol. 8, no. 1, pp. 12-22.

11. Rallón N., García M., García-Samaniego J., Cabello A., Álvarez B., Restrepo C., Nistal S., Górgolas M., Benito J.M. Expression of PD-1 and Tim-3 markers of T-cell exhaustion is associated with CD4 dynamics during the course of untreated and treated HIV infection. PLoS One, 2018, Vol. 13, no. 3, 0193829. DOI:10.1371/journal.pone.0193829

12. Shmagel K.V., Saidakova E.V., Shmagel N.G., Korolevskaya L.B., Chereshnev V.A., Robinson J., Grivel J-C., Douek D.C., Margolis L., Anthony D.D., Lederman M.M. Systemic inflammation and liver damage in HIV/hepatitis C virus coinfection. HIV Med., 2016, Vol. 17, no. 8, pp. 581-589.

13. Simon S., Labarriere N. PD-1 expression on tumor-specific T cells: Friend or foe for immunotherapy? Oncoimmunology, 2017, Vol. 7, no. 1, e1364828. doi: 10.1080/2162402X.2017.1364828.

14. Taye S., Lakew M. Impact of hepatitis C virus co-infection on HIV patients before and after highly active antiretroviral therapy: an immunological and clinical chemistry observation, Addis Ababa, Ethiopia. BMC Immunol., 2013, Vol. 14, 23. doi: 10.1186/1471-2172-14-23.

15. Zatoloka P.A. Prevalence of concomitant pathology in HIVinfected individuals. Medical Journal, 2017, Vol. 3, no. 61, pp. 95-100. (In Russ.)


Supplementary files

Review

For citations:


Vlasova V.V., Korolevskaya L.B., Loginova O.A., Shmagel N.G., Saidakova E.V. Functional exhaustion of CD4+T cells in HIV/HCV coinfected HAART-treated patients. Medical Immunology (Russia). 2023;25(4):837-844. https://doi.org/10.15789/1563-0625-FEO-2734

Views: 325


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.


ISSN 1563-0625 (Print)
ISSN 2313-741X (Online)