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.
Figure 1. Flow chart of clinical study.
Figure 2. Changes in T cell counts…
Figure 2. Changes in T cell counts and HIV viral load.
A) Changes from baseline in CD4 T cell counts, and B) CD8 T cell counts throughout the study duration; median values and interquartile ranges; C) Change from baseline in HIV plasma viral load; median values and interquartile ranges. There was a significant decrease in HIV-1 RNA at Day 15 in the leflunomide group (*p-value

Figure 3. Changes in markers of CD4…

Figure 3. Changes in markers of CD4 T cell cycling and CD8 T cell activation.

Figure 3. Changes in markers of CD4 T cell cycling and CD8 T cell activation.
A) Change from baseline in percent Ki67 expression in CD4 T cells; median values and interquartile ranges. There was a significant decrease in Ki67 expression by CD4 T cells at Day 29 in the leflunomide group (*p-value

Figure 4. Changes in HIV coreceptor expression.

Figure 4. Changes in HIV coreceptor expression.

A) Change from baseline in percent of CD4…

Figure 4. Changes in HIV coreceptor expression.
A) Change from baseline in percent of CD4 T cells, and B) CD8 T cells expressing CCR5, median values and interquartile ranges. In the leflunomide group, there were significant decreases in CCR5 expression by CD4 and CD8 T cells at Day 15 and Day 29 (*p-value
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References
    1. 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
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Figure 3. Changes in markers of CD4…
Figure 3. Changes in markers of CD4 T cell cycling and CD8 T cell activation.
A) Change from baseline in percent Ki67 expression in CD4 T cells; median values and interquartile ranges. There was a significant decrease in Ki67 expression by CD4 T cells at Day 29 in the leflunomide group (*p-value

Figure 4. Changes in HIV coreceptor expression.

Figure 4. Changes in HIV coreceptor expression.

A) Change from baseline in percent of CD4…

Figure 4. Changes in HIV coreceptor expression.
A) Change from baseline in percent of CD4 T cells, and B) CD8 T cells expressing CCR5, median values and interquartile ranges. In the leflunomide group, there were significant decreases in CCR5 expression by CD4 and CD8 T cells at Day 15 and Day 29 (*p-value
Similar articles
Cited by
References
    1. 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
    1. 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
    1. 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
    1. 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
    1. 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
Show all 36 references
Publication types
MeSH terms
Associated data
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Figure 4. Changes in HIV coreceptor expression.
Figure 4. Changes in HIV coreceptor expression.
A) Change from baseline in percent of CD4 T cells, and B) CD8 T cells expressing CCR5, median values and interquartile ranges. In the leflunomide group, there were significant decreases in CCR5 expression by CD4 and CD8 T cells at Day 15 and Day 29 (*p-value

References

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