Main Article Content
Abstract
ABSTRACT
Background. Although plasma viral load is the main indicator of viral progression amongst HIV-infected patients on antiretroviral therapy, immune reconstitution remains a major challenge. Our study aimed to evaluate the potential of interleukin 7 (IL-7) and CD4/CD8 ratio as markers of immune reconstitution amongst HIV patients on antiretroviral therapy (ART) in Yaoundé, Cameroon. Methods. A cross-sectional study was conducted from July to December 2017, at the Yaoundé University Teaching Hospital. T-lymphocyte profile, IL-7 level and plasma viral load were determined using standard methods. GraphPad Prism 5.0 software was used for statistical analysis. Comparison between variables was performed using the non-parametric Kruskal Wallis test. Results. Enrolled participants were divided into ART success 110(54%), ART failure 58(30%) and Uninfected 32(16%). The mean age of treatment was 3±0.76 years. The plasma level of IL7 and CD4/CD8 ratio were statistically different amongst groups (p<0.0001). There was a direct correlation between IL-7 and viral load (r =0, 6, p =0.03, 95%CI =[0.02005 - 0.8952]). It was inverse between IL-7 and CD4 lymphocytes (r =-0.7, p =0.03, 95%CI =[-0.93 - 0.26]). There was an inverse correlation between CD4/CD8 ratio and IL-7 (r =-0.7, p =0.01, 95%CI =[-0.9255 – (-0.1961)]). Conclusion. The variation in CD4/CD8 ratio and the IL-7 level was statistically significant amongst ART failure and success patients. IL-7 and CD4/CD8 ratio were influenced by ART in both groups. They might be predictive of immunological dysfunction associated to disease progression and might be used as immunological markers in the immunological monitoring of HIV infected patients.
RÉSUMÉ
Contexte. Bien que la charge virale plasmatique soit le principal indicateur de la progression virale chez les patients VIH positifs sous traitement antirétroviral, la reconstitution immunitaire reste un défi majeur. Notre étude visait à évaluer le potentiel de l'interleukine-7 (IL-7) et du ratio CD4/CD8 comme marqueurs de l’immuno-reconstitution chez les patients VIH sous traitement antirétroviral à Yaoundé, au Cameroun. Méthodes. Une étude transversale a été menée de juillet à décembre 2017 au Centre Hospitalier Universitaire, Yaoundé. Le profil lymphocytaire T, la concentration d'IL-7 et la charge virale plasmatique ont été déterminés par des méthodes standards. GraphPad Prism 5.0 a été utilisé pour l'analyse statistique. Le test non paramétrique de Kruskal Wallis a été utilisé pour comparer les variables. Résultats. Les participants étaient regroupés en succès thérapeutique 110 (54%), échecs thérapeutique 58 (30%) et non infectés 32 (16%). L'âge moyen du traitement était 3±0,76 ans. L’IL7 et ratio CD4/CD8 étaient différents entre les groupes (p<0,0001). Il y’avait une corrélation positive entre l'IL-7 et la charge virale (r =0,6, p =0,03, IC=[0,02005 - 0,8952]). Elle était inverse entre le ratio CD4/CD8 et IL-7 (r =-0,7, p =0,01, IC = [-0,9255 – (-0,1911)]). Conclusion. La variation du ratio CD4/CD8 et de l'IL-7 était statistiquement significative. Le ratio CD4/CD8 et IL-7 était influencé par le traitement antirétroviral dans les deux groupes. Ils pourraient prédire les dysfonctionnements immunologiques associés à la progression de la maladie et pourraient être utilisés comme marqueurs immunologiques dans la surveillance immunologique de patients infectés par le VIH.
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References
- Bruce W, Andrew M. The T-Cell Response to HIV. Perspectives in medicine. 2012, 2(11): a007054. doi: 10.1101/cshperspect.a007054
- Okoye AA, Picker LJ. CD4+ T cell depletion in HIV infection: mechanisms of immunological failure. Immunol Rev. 2013, 254(11): 54–64. doi: 10.1111/imr.12066.
- Evan SJ, Sheila MK, Mohamed AM, Stuart L, John WH, Heather C, et al. Cytokines Elevated in HIV Elite Controllers Reduce HIV Replication in vitro and Modulate HIV Restriction Factor Expression. Journal of Virology. 2017, 91(6): e02051-16. doi: 10.1128/JVI.02051-16
- Guy A. Quelle valeur accorder à l’élévation du ratio lymphocytaire T CD4/CD8 dans le phénotypage lymphocytaire du sang : analyse d’une étude préliminaire et rétrospective au CHU de Bordeaux. Medecine humaine et pathologie. 2015 , (13071). https://dumas.ccsd.cnrs.fr/dumas-01223858/document
- Rafael S, Ruizhu H, Bruno L, Manuel B, Enos B, Matthias C, et al. CD4/CD8 ratio and CD8 counts predict CD4 response in HIV-1-infected drug naive and in patients on cART. Journal of Medecine. 2016, 95(42): e5094. doi: 10.1097/MD.0000000000005094
- Napolitano LA, Grant RM, Deeks SG, Schmidt D, De Rosa SC, Herzenberg LA, et al. Increased production of IL-7 accompanies HIV-1–mediated T-cell depletion: implications for T-cell homeostasis. Nature Medicine. 2001, 7:73 - 79. DOI:10.1038/83381
- Rethi B, Vivar N, Sammicheli S, Chiodi F. Limited efciency of endogenous interleukin-7 levels in T cell reconstitution during HIV-1 infection: will exogenous interleukin-7 therapy work? AIDS. 2009, 23(7):745-55. doi: 10.1097/QAD.0b013e3283298572.
- Chiodi F, Bekele Y, Lantto GR, Nasi A. IL-7 and CD4 T Follicular Helper Cells in HIV-1 Infection. Frontiers in Immunology. 2017, 8:451. doi: 10.3389/fimmu.2017.00451.
- Jack L, Ziwen Z, Huaping X, Mark RW, Vivi AD, Qian B, et al. The role of IL-7 in Immunity and Cancer. Anticancer Research. 2017, 37:963-968.
- Corbeau P, Reynes J. Immune reconstitution under antiretroviral therapy: the new challenge in HIV-1 infection. American Society of Hematology. 2011, 117(1 21):5582-5590.
- WHO. WHO definitions of clinical, immunological and virological failure for the decision to switch ART regimens. [Cited 2016]. Available from https://www.who.int/hiv/pub/guidelines/arv2013/art/WHO_CG_table_7.15.pdf.
- Katherine K, Suzanne C. Cytokines and HIV-1: interactions and clinical implications. Antiviral Chemistry & Chemotherapy. 2001, 12:133–150.
- Boulassel M, Smith G, Gilmore N, Klein M, Murphy T, MacLeod J, et al. Interleukin-7 levels may predict virological response in advanced HIV-1-infected patients receiving lopinavir/ritonavir-based therapy. British HIV Association. 2003, 4:315–320.
- Terry J, Elizabeth C, Judith F, Michael M, David JL, John S, et al. A potential role for interleukin-7 in T-cell homeostasis. BLOOD. 2001 , 97(110):2983-2990.
- Lindi R, Jo-Ann P, Carolyn W, Francesca L, Lisa B, Koleka M, et al. Plasma cytokine levels during acute HIV-1 infection predict HIV disease progression. AIDS. 2010, 24(16):819–831.
- Jan S, Bengt-Olof N, Sture L, Jan E, Graham P, Boo J, et al. No Immune Risk Profile among individuals who reach 100 years of age: Findings from the Swedish NONA Immune Longitudinal Study, Experimental Gerontology. 2007, 42:753.
- Marta C, Michele D, Zonghui H, Sharat S, Vishakha T, Joseph A. HIV infection-associated immune activation occurs by two distinct pathways that differentially affect CD4 and CD8 T cells. PNAS. 2009 , 105:19851–19856.
- Sergio SV, María JP, Fernando D, José L, Ana M, Ana R, et al. Increased Risk of Serious Non-AIDS-Related Events in HIV-Infected Subjects on Antiretroviral Therapy Associated with a Low CD4/CD8 Ratio. PLoS ONE. 2014, 9:e85798.
- Xiuqiong B, Azumi I, Lam VN, Kazunori M, Hung VP, Chung TT, et al. Impact of HIV Infection and Anti-Retroviral Therapy on the Immune Profile of and Microbial Translocation in HIV-Infected Children in Vietnam. Int. J. Mol. Sci. 2016, 17:1245.
- Jay AL. The importance of the innate immune system in controlling HIV infection and disease. Trends in Immunology. 2001 , 22(16):312-316.
- Meira DA, Souza LR, Calvi SA, Lima CR, Henriques R, Pardini MI, et al. Correlation between cytokine serum levels, number of CD4+ T cells/mm³ and viral load in HIV-1 infected individuals with or without antiretroviral therapy. J. Venom. Anim. Toxins incl. Trop. Diseases. 2004, 10(13) 1678-9199.
- Kitahata M, Gange S, Abraham A, Merriman B, Saag M, Justice A, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009, 360(118):1815-26.
- Carey S, Brian C, Marie M, Joseph M, Nicholas F, Michael F, et al. Inflammation perturbs the IL-7 axis, promoting senescence and exhaustion that broadly characterize immune failure in treated HIV infection. J Acquir Immune Defic Syndr. 2016, 71(15):483–492.
- Yves L, Christine L, Laurence W, Cecile G, François B, Christine R et al. Enhanced T cell recovery in HIV-1–infected adults through IL-7 treatment. J Clin Invest. 2009, 119(14): 997–1007.
- Lundtoft C, Afum-Adjei Awuah A, Rimpler J, Harling K, Nausch N, Kohns M, et al. Aberrant plasma IL-7 and solubleIL-7 receptor levels indicate impaired T-cell response to IL-7 in human tuberculosis. PLoSPathog. 2017, 13(6):e1006425. https://doi.org/10.1371/journal.ppat.1006425
- Steele A K, Carrasco-Medina L, Sodora DL, Crawley AM. Increased soluble IL-7 receptor concentrations associate with improvedIL-7 therapy outcomes in SIV-infected ART-treated Rhesus macaques. PLoSONE. 2017, 12(12):e0188427. https://doi.org/10.1371/journal.pone.0188427
- Tanaskovic S, Fernandez S, Price P, French M. Interleukin-7 signalling defects in naive CD4+ T cells of HIV patients with CD4+ T-cell deficiency on antiretroviral therapy are associated with T-cell activation and senescence. AIDS. 2014, 28(6):821-830. https://doi.org/10.1097/QAD.0000000000000213
References
Bruce W, Andrew M. The T-Cell Response to HIV. Perspectives in medicine. 2012, 2(11): a007054. doi: 10.1101/cshperspect.a007054
Okoye AA, Picker LJ. CD4+ T cell depletion in HIV infection: mechanisms of immunological failure. Immunol Rev. 2013, 254(11): 54–64. doi: 10.1111/imr.12066.
Evan SJ, Sheila MK, Mohamed AM, Stuart L, John WH, Heather C, et al. Cytokines Elevated in HIV Elite Controllers Reduce HIV Replication in vitro and Modulate HIV Restriction Factor Expression. Journal of Virology. 2017, 91(6): e02051-16. doi: 10.1128/JVI.02051-16
Guy A. Quelle valeur accorder à l’élévation du ratio lymphocytaire T CD4/CD8 dans le phénotypage lymphocytaire du sang : analyse d’une étude préliminaire et rétrospective au CHU de Bordeaux. Medecine humaine et pathologie. 2015 , (13071). https://dumas.ccsd.cnrs.fr/dumas-01223858/document
Rafael S, Ruizhu H, Bruno L, Manuel B, Enos B, Matthias C, et al. CD4/CD8 ratio and CD8 counts predict CD4 response in HIV-1-infected drug naive and in patients on cART. Journal of Medecine. 2016, 95(42): e5094. doi: 10.1097/MD.0000000000005094
Napolitano LA, Grant RM, Deeks SG, Schmidt D, De Rosa SC, Herzenberg LA, et al. Increased production of IL-7 accompanies HIV-1–mediated T-cell depletion: implications for T-cell homeostasis. Nature Medicine. 2001, 7:73 - 79. DOI:10.1038/83381
Rethi B, Vivar N, Sammicheli S, Chiodi F. Limited efciency of endogenous interleukin-7 levels in T cell reconstitution during HIV-1 infection: will exogenous interleukin-7 therapy work? AIDS. 2009, 23(7):745-55. doi: 10.1097/QAD.0b013e3283298572.
Chiodi F, Bekele Y, Lantto GR, Nasi A. IL-7 and CD4 T Follicular Helper Cells in HIV-1 Infection. Frontiers in Immunology. 2017, 8:451. doi: 10.3389/fimmu.2017.00451.
Jack L, Ziwen Z, Huaping X, Mark RW, Vivi AD, Qian B, et al. The role of IL-7 in Immunity and Cancer. Anticancer Research. 2017, 37:963-968.
Corbeau P, Reynes J. Immune reconstitution under antiretroviral therapy: the new challenge in HIV-1 infection. American Society of Hematology. 2011, 117(1 21):5582-5590.
WHO. WHO definitions of clinical, immunological and virological failure for the decision to switch ART regimens. [Cited 2016]. Available from https://www.who.int/hiv/pub/guidelines/arv2013/art/WHO_CG_table_7.15.pdf.
Katherine K, Suzanne C. Cytokines and HIV-1: interactions and clinical implications. Antiviral Chemistry & Chemotherapy. 2001, 12:133–150.
Boulassel M, Smith G, Gilmore N, Klein M, Murphy T, MacLeod J, et al. Interleukin-7 levels may predict virological response in advanced HIV-1-infected patients receiving lopinavir/ritonavir-based therapy. British HIV Association. 2003, 4:315–320.
Terry J, Elizabeth C, Judith F, Michael M, David JL, John S, et al. A potential role for interleukin-7 in T-cell homeostasis. BLOOD. 2001 , 97(110):2983-2990.
Lindi R, Jo-Ann P, Carolyn W, Francesca L, Lisa B, Koleka M, et al. Plasma cytokine levels during acute HIV-1 infection predict HIV disease progression. AIDS. 2010, 24(16):819–831.
Jan S, Bengt-Olof N, Sture L, Jan E, Graham P, Boo J, et al. No Immune Risk Profile among individuals who reach 100 years of age: Findings from the Swedish NONA Immune Longitudinal Study, Experimental Gerontology. 2007, 42:753.
Marta C, Michele D, Zonghui H, Sharat S, Vishakha T, Joseph A. HIV infection-associated immune activation occurs by two distinct pathways that differentially affect CD4 and CD8 T cells. PNAS. 2009 , 105:19851–19856.
Sergio SV, María JP, Fernando D, José L, Ana M, Ana R, et al. Increased Risk of Serious Non-AIDS-Related Events in HIV-Infected Subjects on Antiretroviral Therapy Associated with a Low CD4/CD8 Ratio. PLoS ONE. 2014, 9:e85798.
Xiuqiong B, Azumi I, Lam VN, Kazunori M, Hung VP, Chung TT, et al. Impact of HIV Infection and Anti-Retroviral Therapy on the Immune Profile of and Microbial Translocation in HIV-Infected Children in Vietnam. Int. J. Mol. Sci. 2016, 17:1245.
Jay AL. The importance of the innate immune system in controlling HIV infection and disease. Trends in Immunology. 2001 , 22(16):312-316.
Meira DA, Souza LR, Calvi SA, Lima CR, Henriques R, Pardini MI, et al. Correlation between cytokine serum levels, number of CD4+ T cells/mm³ and viral load in HIV-1 infected individuals with or without antiretroviral therapy. J. Venom. Anim. Toxins incl. Trop. Diseases. 2004, 10(13) 1678-9199.
Kitahata M, Gange S, Abraham A, Merriman B, Saag M, Justice A, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009, 360(118):1815-26.
Carey S, Brian C, Marie M, Joseph M, Nicholas F, Michael F, et al. Inflammation perturbs the IL-7 axis, promoting senescence and exhaustion that broadly characterize immune failure in treated HIV infection. J Acquir Immune Defic Syndr. 2016, 71(15):483–492.
Yves L, Christine L, Laurence W, Cecile G, François B, Christine R et al. Enhanced T cell recovery in HIV-1–infected adults through IL-7 treatment. J Clin Invest. 2009, 119(14): 997–1007.
Lundtoft C, Afum-Adjei Awuah A, Rimpler J, Harling K, Nausch N, Kohns M, et al. Aberrant plasma IL-7 and solubleIL-7 receptor levels indicate impaired T-cell response to IL-7 in human tuberculosis. PLoSPathog. 2017, 13(6):e1006425. https://doi.org/10.1371/journal.ppat.1006425
Steele A K, Carrasco-Medina L, Sodora DL, Crawley AM. Increased soluble IL-7 receptor concentrations associate with improvedIL-7 therapy outcomes in SIV-infected ART-treated Rhesus macaques. PLoSONE. 2017, 12(12):e0188427. https://doi.org/10.1371/journal.pone.0188427
Tanaskovic S, Fernandez S, Price P, French M. Interleukin-7 signalling defects in naive CD4+ T cells of HIV patients with CD4+ T-cell deficiency on antiretroviral therapy are associated with T-cell activation and senescence. AIDS. 2014, 28(6):821-830. https://doi.org/10.1097/QAD.0000000000000213