Markers of CD4⁺ AND CD8⁺ T-cell exhaustion in hiv/hcv coinfected immunological non-responders to antiretroviral therapy
- Authors: Saidakova E.V.1, Korolevskaya L.B.1, Vlasova V.V.1, Shmagel N.G.1, Shmagel K.V.1
-
Affiliations:
- Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center of the Ural Branch of the Russian Academy of Sciences
- Issue: Vol 14, No 3 (2024)
- Pages: 586-592
- Section: SHORT COMMUNICATIONS
- URL: https://journals.rcsi.science/2220-7619/article/view/262085
- DOI: https://doi.org/10.15789/2220-7619-MIC-16641
- ID: 262085
Cite item
Full Text
Abstract
Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is a risk factor for immunological non-response to antiretroviral therapy. In cases of immunological non-response, HIV viral load suppression occurs without an increase in CD4⁺ T-cell counts, heightening the risk of morbidity and mortality in infected individuals. T-cell exhaustion may hinder their regeneration in immunological non-responders. This study aimed to identify markers of CD4⁺ and CD8⁺ T-cell exhaustion in HIV/HCV coinfected immunological non-responders. The study examined three clinical groups: 1) HIV/HCV coinfected immunological non-responders (CD4⁺ T-cells < 350/µl blood; n = 9), 2) HIV/HCV coinfected individuals with a standard response to therapy (CD4⁺ T-cells > 500/µl blood; n = 9), and 3) relatively healthy volunteers without HIV and HCV infections (n = 9). Ex vivo, the number of CD4⁺ and CD8⁺ T-cells expressing the inhibitory receptor PD-1 was determined using multi-color flow cytometry. In the 7-day in vitro experiment, cell cultures were stimulated with phytohemagglutinin. The number of dying proliferated CD4⁺ and CD8⁺ T-cells (CFSElowZombieUV+) was determined using multi-color flow cytometry. The amount of interleukin-2 in the culture supernatants was measured using an enzyme-linked immunosorbent assay. It was found that in HIV/HCV coinfected immunological non-responders, there was a higher number of CD4⁺ and CD8⁺ T-cells expressing PD-1, a phenotypic marker of exhaustion, compared to the other two groups. Furthermore, the frequency of dying dividing T-cells was higher in immunological non-responders, with an increase in CD4⁺ T-cells but not CD8⁺ T-lymphocytes. Similarly, a decrease in interleukin-2 production was found in stimulated T-cells of HIV/HCV coinfected immunological non-responders in the CD4⁺ T-cell pool, but not in CD8⁺ T-lymphocytes. Thus, in HIV/HCV coinfected immunological non-responders, CD4⁺ T-cells appear exhausted both phenotypically and functionally. While CD8⁺ T-cells express inhibitory receptors, they do not show functional impairments. It appears that the specialized therapy for HIV/HCV coinfected immunological non-responders should aim to improve CD4⁺ T-cell function.
Full Text
##article.viewOnOriginalSite##About the authors
Evgeniya V. Saidakova
Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center of the Ural Branch of the Russian Academy of Sciences
Author for correspondence.
Email: radimira@list.ru
DSc (Biology), Associate Professor, Head of the Laboratory of Molecular Immunology
Russian Federation, 614081, Perm, Goleva str., 13L. B. Korolevskaya
Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center of the Ural Branch of the Russian Academy of Sciences
Email: radimira@list.ru
PhD (Medicine), Researcher, Laboratory of Ecological Immunology
Russian Federation, 614081, Perm, Goleva str., 13V. V. Vlasova
Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center of the Ural Branch of the Russian Academy of Sciences
Email: radimira@list.ru
Junior Researcher, Laboratory of Molecular Immunology
Russian Federation, 614081, Perm, Goleva str., 13N. G. Shmagel
Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center of the Ural Branch of the Russian Academy of Sciences
Email: radimira@list.ru
DSc (Medicine), Senior Researcher, Laboratory of Ecological Immunology
Russian Federation, 614081, Perm, Goleva str., 13K. V. Shmagel
Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center of the Ural Branch of the Russian Academy of Sciences
Email: radimira@list.ru
DSc (Medicine), Head of the Laboratory of Ecological Immunology
Russian Federation, 614081, Perm, Goleva str., 13References
- Королевская Л.Б., Сайдакова Е.В. Нарушение функции CD4⁺ Т-лимфоцитов у ВИЧ-инфицированных пациентов с дискордантным ответом на антиретровирусную терапию // Российский иммунологический журнал. 2019. Т. 13, № 2. С. 329–331. [Korolevskaya L.B., Saidakova E.V. CD4⁺ T-lymphocyte function is violated in HIV-infected patients with discordant response to antiretroviral therapy. Rossiiskii immunologicheskii zhurnal = Russian Journal of Immunology (Russia), 2019, vol. 13, no. 2, pp. 329–331. (In Russ.)] doi: 10.31857/S102872210006617-3
- Черешнев В.А., Шмагель К.В., Королевская Л.Б., Сайдакова Е.В., Шмагель Н.Г., Слободчикова С.В., Зверев С.Я., Тара нин А.В. Влияние коинфекции вирусом гепатита С на активацию и апоптоз Т-лимфоцитов у ВИЧ-инфицированных пациентов, получающих антиретровирусную терапию // Иммунология. 2013. Т. 34, № 5. С. 236–241. [Chereshnev V.A., Shmagel K.V., Korolevskaya L.B., Saidakova E.V., Shmagel N.G., Slobodchikova S.V., Zverev S.Ya., Taranin A.V. The impact of hepatitis C virus coinfection on immune recovery in HIV-infected patients during antiretroviral therapy. Immunologiya = Immunologiya, 2013, vol. 34, no. 5, pp. 236–241. (In Russ.)]
- Ando S., Perkins C.M., Sajiki Y., Chastain C., Valanparambil R.M., Wieland A., Hudson W.H., Hashimoto M., Ramalingam S.S., Freeman G.J., Ahmed R., Araki K. mTOR regulates T cell exhaustion and PD-1-targeted immunotherapy response during chronic viral infection. J. Clin. Invest., 2023, vol. 133, no. 2: e160025. doi: 10.1172/JCI160025
- Benito J.M., Restrepo C., Garcia-Foncillas J., Rallon N. Immune checkpoint inhibitors as potential therapy for reverting T-cell exhaustion and reverting HIV latency in people living with HIV. Front. Immunol., 2023, vol. 14: 1270881. doi: 10.3389/fimmu.2023.1270881
- Chikuma S., Terawaki S., Hayashi T., Nabeshima R., Yoshida T., Shibayama S., Okazaki T., Honjo T. PD-1-mediated suppression of IL-2 production induces CD8⁺ T cell anergy in vivo. J. Immunol., 2009, vol. 182, no. 11, pp. 6682–6689. doi: 10.4049/jimmunol.0900080
- Grabmeier-Pfistershammer K., Steinberger P., Rieger A., Leitner J., Kohrgruber N. Identification of PD-1 as a unique marker for failing immune reconstitution in HIV-1-infected patients on treatment. J. Acquir. Immune Defic. Syndr., 2011, vol. 56, no. 2, pp. 118–124. doi: 10.1097/QAI.0b013e3181fbab9f
- Macias J., Pineda J.A., Lozano F., Corzo J.E., Ramos A., Leon E., García-García J.A., Fernández-Rivera J., Mira J.A., Gómez-Mateos J. Impaired recovery of CD4⁺ cell counts following highly active antiretroviral therapy in drug-naive patients coinfected with human immunodeficiency virus and hepatitis C virus. Eur. J. Clin. Microbiol. Infect. Dis., 2003, vol. 22, no. 11, pp. 675–680. doi: 10.1007/s10096-003-1015-2
- Noiman A., Esber A., Wang X., Bahemana E., Adamu Y., Iroezindu M., Kiweewa F., Maswai J., Owuoth J., Maganga L., Ganesan A., Maves R.C., Lalani T., Colombo R.E., Okulicz J.F., Polyak C., Crowell T.A., Ake J.A., Agan B.K. Clinical factors and outcomes associated with immune non-response among virally suppressed adults with HIV from Africa and the United States. Sci. Rep., 2022, vol. 12, no. 1: 1196. doi: 10.1038/s41598-022-04866-z
- Saidakova E.V., Korolevskaya L.B., Shmagel N.G., Shmagel K.V., Chereshnev V.A. T cell apoptosis in HIV-infected patients with incomplete immune recovery after antiretroviral therapy. Dokl. Biol. Sci., 2013, vol. 450, pp. 189–191. doi: 10.1134/S0012496613030010
- 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, vol. 25, no. 4, pp. 837–844. doi: 10.15789/1563-0625-feo-2734
- Wherry E.J., Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol., 2015, vol. 15, no. 8, pp. 486–499. doi: 10.1038/nri3862
- Yang X., Su B., Zhang X., Liu Y., Wu H., Zhang T. Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders. J. Leukoc. Biol., 2020, vol. 107, no. 4, pp. 597–612. doi: 10.1002/JLB.4MR1019-189R
- Younes S.A., Talla A., Pereira Ribeiro S., Saidakova E.V., Korolevskaya L.B., Shmagel K.V., Shive C.L., Freeman M.L., Panigrahi S., Zweig S., Balderas R., Margolis L., Douek D.C., Anthony D.D., Pandiyan P., Cameron M., Sieg S.F., Calabrese L.H., Rodriguez B., Lederman M.M. Cycling CD4⁺ T cells in HIV-infected immune nonresponders have mitochondrial dysfunction. J. Clin. Invest., 2018, vol. 128, no. 11, pp. 5083–5094. doi: 10.1172/JCI120245
- Youngblood B., Oestreich K.J., Ha S.J., Duraiswamy J., Akondy R.S., West E.E., Wei Z., Lu P., Austin J.W., Riley J.L., Boss J.M., Ahmed R. Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8(+) T cells. Immunity, 2011, vol. 35, no. 3, pp. 400–412. doi: 10.1016/j.immuni.2011.06.015
Supplementary files
