The effect of leflunomide on cycling and activation of T-cells in HIV-1-infected participants
Sarah W Read, Mary DeGrezia, Emily J Ciccone, Rebecca DerSimonian, Jeanette Higgins, Joseph W Adelsberger, Judith M Starling, Catherine Rehm, Irini Sereti, Sarah W Read, Mary DeGrezia, Emily J Ciccone, Rebecca DerSimonian, Jeanette Higgins, Joseph W Adelsberger, Judith M Starling, Catherine Rehm, Irini Sereti
Abstract
Background: The pathogenesis of immunodeficiency due to human immunodeficiency virus (HIV)-1 is incompletely understood, but immune activation is believed to play a central role. Immunomodulatory agents that decrease immune activation may be useful in the treatment of HIV-1 infection.
Methodology: A randomized, double blind, placebo-controlled pilot study of leflunomide for 28 days was performed in participants with HIV-1 infection who were not receiving antiretroviral therapy. Participants randomized to leflunomide were subsequently treated with cholestyramine until leflunomide levels were below detection limit.
Findings: Treatment with leflunomide was well tolerated with mostly low-grade adverse events. Leflunomide administration reduced cycling of CD4 T cells (by ex vivo bromodeoxyuridine uptake and Ki67 expression) and decreased expression of activation markers (HLA-DR/CD38 co-expression) on CD8 T cells in peripheral blood. In addition, decreased expression of HIV-1 co-receptors was observed in both CD4 and CD8 T cells in the leflunomide group. There were no significant changes in naïve and memory T cell subsets, apoptosis of T cells or markers of microbial translocation.
Conclusions: Leflunomide was effective in reducing immune activation in the setting of chronic HIV-1 infection suggesting that targeting immune activation with immunomodulatory agents may be a feasible strategy.
Trial registration: ClinicalTrials.gov NCT00101374.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
Figures
![Figure 1. Flow chart of clinical study.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2914784/bin/pone.0011937.g001.jpg)
![Figure 2. Changes in T cell counts…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2914784/bin/pone.0011937.g002.jpg)
Figure 3. Changes in markers of CD4…
Figure 3. Changes in markers of CD4 T cell cycling and CD8 T cell activation.
Figure 4. Changes in HIV coreceptor expression.
Figure 4. Changes in HIV coreceptor expression.
A) Change from baseline in percent of CD4…
- Rapid restoration of CD4 T cell subsets in subjects receiving antiretroviral therapy during primary HIV-1 infection.Kaufmann GR, Zaunders JJ, Cunningham P, Kelleher AD, Grey P, Smith D, Carr A, Cooper DA. Kaufmann GR, et al. AIDS. 2000 Dec 1;14(17):2643-51. doi: 10.1097/00002030-200012010-00003. AIDS. 2000. PMID: 11125882 Clinical Trial.
- [T-lymphocyte immune in HIV-infected people and AIDS patients in China].Li T, Qiu Z, Wang A, Sheng R. Li T, et al. Zhonghua Yi Xue Za Zhi. 2002 Oct 25;82(20):1391-5. Zhonghua Yi Xue Za Zhi. 2002. PMID: 12509921 Chinese.
- Changes in CD4+ and CD8+ T cell subsets in response to highly active antiretroviral therapy in HIV type 1-infected patients with prior protease inhibitor experience.Gray CM, Schapiro JM, Winters MA, Merigan TC. Gray CM, et al. AIDS Res Hum Retroviruses. 1998 May 1;14(7):561-9. doi: 10.1089/aid.1998.14.561. AIDS Res Hum Retroviruses. 1998. PMID: 9591710
- Combined Env- and Gag-specific T cell responses in relation to programmed death-1 receptor and CD4 T cell loss rates in human immunodeficiency virus-1 infection.Pettersen FO, Taskén K, Kvale D. Pettersen FO, et al. Clin Exp Immunol. 2010 Aug;161(2):315-23. doi: 10.1111/j.1365-2249.2010.04179.x. Epub 2010 May 10. Clin Exp Immunol. 2010. PMID: 20491784 Free PMC article.
- Maraviroc Intensification of cART in Patients with Suboptimal Immunological Recovery: A 48-Week, Placebo-Controlled Randomized Trial.van Lelyveld SF, Drylewicz J, Krikke M, Veel EM, Otto SA, Richter C, Soetekouw R, Prins JM, Brinkman K, Mulder JW, Kroon F, Middel A, Symons J, Wensing AM, Nijhuis M, Borghans JA, Tesselaar K, Hoepelman AI; MIRS study group. van Lelyveld SF, et al. PLoS One. 2015 Jul 24;10(7):e0132430. doi: 10.1371/journal.pone.0132430. eCollection 2015. PLoS One. 2015. PMID: 26208341 Free PMC article. Clinical Trial.
- The Many Faces of Immune Activation in HIV-1 Infection: A Multifactorial Interconnection.Mazzuti L, Turriziani O, Mezzaroma I. Mazzuti L, et al. Biomedicines. 2023 Jan 8;11(1):159. doi: 10.3390/biomedicines11010159. Biomedicines. 2023. PMID: 36672667 Free PMC article. Review.
- Effects of metabolic cancer therapy on tumor microenvironment.Hyroššová P, Milošević M, Škoda J, Vachtenheim J Jr, Rohlena J, Rohlenová K. Hyroššová P, et al. Front Oncol. 2022 Dec 13;12:1046630. doi: 10.3389/fonc.2022.1046630. eCollection 2022. Front Oncol. 2022. PMID: 36582801 Free PMC article. Review.
- Neuropathogenesis of HIV-1: insights from across the spectrum of acute through long-term treated infection.Killingsworth L, Spudich S. Killingsworth L, et al. Semin Immunopathol. 2022 Sep;44(5):709-724. doi: 10.1007/s00281-022-00953-5. Epub 2022 Jul 26. Semin Immunopathol. 2022. PMID: 35882661 Review.
- HIV-Related Immune Activation and Inflammation: Current Understanding and Strategies.Lv T, Cao W, Li T. Lv T, et al. J Immunol Res. 2021 Sep 29;2021:7316456. doi: 10.1155/2021/7316456. eCollection 2021. J Immunol Res. 2021. PMID: 34631899 Free PMC article. Review.
- Efficacy and safety of dihydroorotate dehydrogenase (DHODH) inhibitors "leflunomide" and "teriflunomide" in Covid-19: A narrative review.Kaur H, Sarma P, Bhattacharyya A, Sharma S, Chhimpa N, Prajapat M, Prakash A, Kumar S, Singh A, Singh R, Avti P, Thota P, Medhi B. Kaur H, et al. Eur J Pharmacol. 2021 Sep 5;906:174233. doi: 10.1016/j.ejphar.2021.174233. Epub 2021 Jun 7. Eur J Pharmacol. 2021. PMID: 34111397 Free PMC article. Review.
-
- Liu Z, Cumberland WG, Hultin LE, Kaplan AH, Detels R, et al. CD8+ T-lymphocyte activation in HIV-1 disease reflects an aspect of pathogenesis distinct from viral burden and immunodeficiency. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;18:332–340. - PubMed
-
- Liu Z, Cumberland WG, Hultin LE, Prince HE, Detels R, et al. Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;16:83–92. - PubMed
-
- Hazenberg MD, Otto SA, van Benthem BH, Roos MT, Coutinho RA, et al. Persistent immune activation in HIV-1 infection is associated with progression to AIDS. Aids. 2003;17:1881–1888. - PubMed
-
- Anthony KB, Yoder C, Metcalf JA, DerSimonian R, Orenstein JM, et al. Incomplete CD4 T cell recovery in HIV-1 infection after 12 months of highly active antiretroviral therapy is associated with ongoing increased CD4 T cell activation and turnover. J Acquir Immune Defic Syndr. 2003;33:125–133. - PubMed
-
- Silvestri G, Sodora DL, Koup RA, Paiardini M, O'Neil SP, et al. Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Immunity. 2003;18:441–452. - PubMed
- Randomized Controlled Trial
- Research Support, N.I.H., Extramural
- Research Support, N.I.H., Intramural
- Adult
- CD4-Positive T-Lymphocytes / cytology
- CD4-Positive T-Lymphocytes / drug effects
- CD4-Positive T-Lymphocytes / immunology
- CD8-Positive T-Lymphocytes / cytology
- CD8-Positive T-Lymphocytes / drug effects
- CD8-Positive T-Lymphocytes / immunology
- Drug-Related Side Effects and Adverse Reactions
- Female
- HIV Infections / immunology*
- HIV-1 / physiology*
- Humans
- Immunologic Factors / adverse effects
- Immunologic Factors / metabolism
- Immunologic Factors / pharmacology*
- Isoxazoles / adverse effects
- Isoxazoles / immunology*
- Isoxazoles / metabolism
- Leflunomide
- Lymphocyte Count
- Male
- Phenotype
- RNA, Viral / blood
- T-Lymphocytes / cytology*
- T-Lymphocytes / drug effects
- T-Lymphocytes / immunology*
- Immunologic Factors
- Isoxazoles
- RNA, Viral
- Leflunomide
- ClinicalTrials.gov/NCT00101374
- Full Text Sources
- Medical
- Research Materials
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![Figure 3. Changes in markers of CD4…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2914784/bin/pone.0011937.g003.jpg)
Figure 4. Changes in HIV coreceptor expression.
Figure 4. Changes in HIV coreceptor expression.
A) Change from baseline in percent of CD4…
- Rapid restoration of CD4 T cell subsets in subjects receiving antiretroviral therapy during primary HIV-1 infection.Kaufmann GR, Zaunders JJ, Cunningham P, Kelleher AD, Grey P, Smith D, Carr A, Cooper DA. Kaufmann GR, et al. AIDS. 2000 Dec 1;14(17):2643-51. doi: 10.1097/00002030-200012010-00003. AIDS. 2000. PMID: 11125882 Clinical Trial.
- [T-lymphocyte immune in HIV-infected people and AIDS patients in China].Li T, Qiu Z, Wang A, Sheng R. Li T, et al. Zhonghua Yi Xue Za Zhi. 2002 Oct 25;82(20):1391-5. Zhonghua Yi Xue Za Zhi. 2002. PMID: 12509921 Chinese.
- Changes in CD4+ and CD8+ T cell subsets in response to highly active antiretroviral therapy in HIV type 1-infected patients with prior protease inhibitor experience.Gray CM, Schapiro JM, Winters MA, Merigan TC. Gray CM, et al. AIDS Res Hum Retroviruses. 1998 May 1;14(7):561-9. doi: 10.1089/aid.1998.14.561. AIDS Res Hum Retroviruses. 1998. PMID: 9591710
- Combined Env- and Gag-specific T cell responses in relation to programmed death-1 receptor and CD4 T cell loss rates in human immunodeficiency virus-1 infection.Pettersen FO, Taskén K, Kvale D. Pettersen FO, et al. Clin Exp Immunol. 2010 Aug;161(2):315-23. doi: 10.1111/j.1365-2249.2010.04179.x. Epub 2010 May 10. Clin Exp Immunol. 2010. PMID: 20491784 Free PMC article.
- Maraviroc Intensification of cART in Patients with Suboptimal Immunological Recovery: A 48-Week, Placebo-Controlled Randomized Trial.van Lelyveld SF, Drylewicz J, Krikke M, Veel EM, Otto SA, Richter C, Soetekouw R, Prins JM, Brinkman K, Mulder JW, Kroon F, Middel A, Symons J, Wensing AM, Nijhuis M, Borghans JA, Tesselaar K, Hoepelman AI; MIRS study group. van Lelyveld SF, et al. PLoS One. 2015 Jul 24;10(7):e0132430. doi: 10.1371/journal.pone.0132430. eCollection 2015. PLoS One. 2015. PMID: 26208341 Free PMC article. Clinical Trial.
- The Many Faces of Immune Activation in HIV-1 Infection: A Multifactorial Interconnection.Mazzuti L, Turriziani O, Mezzaroma I. Mazzuti L, et al. Biomedicines. 2023 Jan 8;11(1):159. doi: 10.3390/biomedicines11010159. Biomedicines. 2023. PMID: 36672667 Free PMC article. Review.
- Effects of metabolic cancer therapy on tumor microenvironment.Hyroššová P, Milošević M, Škoda J, Vachtenheim J Jr, Rohlena J, Rohlenová K. Hyroššová P, et al. Front Oncol. 2022 Dec 13;12:1046630. doi: 10.3389/fonc.2022.1046630. eCollection 2022. Front Oncol. 2022. PMID: 36582801 Free PMC article. Review.
- Neuropathogenesis of HIV-1: insights from across the spectrum of acute through long-term treated infection.Killingsworth L, Spudich S. Killingsworth L, et al. Semin Immunopathol. 2022 Sep;44(5):709-724. doi: 10.1007/s00281-022-00953-5. Epub 2022 Jul 26. Semin Immunopathol. 2022. PMID: 35882661 Review.
- HIV-Related Immune Activation and Inflammation: Current Understanding and Strategies.Lv T, Cao W, Li T. Lv T, et al. J Immunol Res. 2021 Sep 29;2021:7316456. doi: 10.1155/2021/7316456. eCollection 2021. J Immunol Res. 2021. PMID: 34631899 Free PMC article. Review.
- Efficacy and safety of dihydroorotate dehydrogenase (DHODH) inhibitors "leflunomide" and "teriflunomide" in Covid-19: A narrative review.Kaur H, Sarma P, Bhattacharyya A, Sharma S, Chhimpa N, Prajapat M, Prakash A, Kumar S, Singh A, Singh R, Avti P, Thota P, Medhi B. Kaur H, et al. Eur J Pharmacol. 2021 Sep 5;906:174233. doi: 10.1016/j.ejphar.2021.174233. Epub 2021 Jun 7. Eur J Pharmacol. 2021. PMID: 34111397 Free PMC article. Review.
-
- Liu Z, Cumberland WG, Hultin LE, Kaplan AH, Detels R, et al. CD8+ T-lymphocyte activation in HIV-1 disease reflects an aspect of pathogenesis distinct from viral burden and immunodeficiency. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;18:332–340. - PubMed
-
- Liu Z, Cumberland WG, Hultin LE, Prince HE, Detels R, et al. Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;16:83–92. - PubMed
-
- Hazenberg MD, Otto SA, van Benthem BH, Roos MT, Coutinho RA, et al. Persistent immune activation in HIV-1 infection is associated with progression to AIDS. Aids. 2003;17:1881–1888. - PubMed
-
- Anthony KB, Yoder C, Metcalf JA, DerSimonian R, Orenstein JM, et al. Incomplete CD4 T cell recovery in HIV-1 infection after 12 months of highly active antiretroviral therapy is associated with ongoing increased CD4 T cell activation and turnover. J Acquir Immune Defic Syndr. 2003;33:125–133. - PubMed
-
- Silvestri G, Sodora DL, Koup RA, Paiardini M, O'Neil SP, et al. Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Immunity. 2003;18:441–452. - PubMed
- Randomized Controlled Trial
- Research Support, N.I.H., Extramural
- Research Support, N.I.H., Intramural
- Adult
- CD4-Positive T-Lymphocytes / cytology
- CD4-Positive T-Lymphocytes / drug effects
- CD4-Positive T-Lymphocytes / immunology
- CD8-Positive T-Lymphocytes / cytology
- CD8-Positive T-Lymphocytes / drug effects
- CD8-Positive T-Lymphocytes / immunology
- Drug-Related Side Effects and Adverse Reactions
- Female
- HIV Infections / immunology*
- HIV-1 / physiology*
- Humans
- Immunologic Factors / adverse effects
- Immunologic Factors / metabolism
- Immunologic Factors / pharmacology*
- Isoxazoles / adverse effects
- Isoxazoles / immunology*
- Isoxazoles / metabolism
- Leflunomide
- Lymphocyte Count
- Male
- Phenotype
- RNA, Viral / blood
- T-Lymphocytes / cytology*
- T-Lymphocytes / drug effects
- T-Lymphocytes / immunology*
- Immunologic Factors
- Isoxazoles
- RNA, Viral
- Leflunomide
- ClinicalTrials.gov/NCT00101374
- Full Text Sources
- Medical
- Research Materials
![Figure 4. Changes in HIV coreceptor expression.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2914784/bin/pone.0011937.g004.jpg)
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- Liu Z, Cumberland WG, Hultin LE, Prince HE, Detels R, et al. Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;16:83–92.
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