11th Conference on Retroviruses and Opportunistic Infections San Francisco, California - February 8 - 11, 2004

Conf Retrovir Opportunistic Infect 2004 Feb 8-11; 11:(abstract no. 14)

A Kinter¹, M Hennessey¹, A Bell¹, Y Lin¹, R Jackson¹, M Planta¹, M McLaughlin¹, S Zeigler², and A S Fauci^1
1NIH, DHHS, Bethesda, MD, USA and ²Virginia Mason, Seattle, WA, USA

BACKGROUND: CD4⁺CD25⁺ regulatory T cells (Treg) have been demonstrated to inhibit antigen-specific CD4+ and CD8+ T-cell responses in the context of pathogenic infections in mice; an effect that can contribute to the persistence of infection. A virtually identical cellular population has been identified in humans. To date the effect of CD4⁺ CD25⁺ Treg cells in the context of HIV disease has not been investigated.

METHODS: PBMC subsets were isolated from HIV-infected donors (n=25; on or off anti-retroviral therapy) using immunomagnetic beads. CD25⁺CD4⁺ (±CD45RA-) T cells were phenotyped (FACS/Western blot) and tested for their effects on HIV-specific proliferation (LPA or CFSE) and cytokine (secreted or intracellular (ICC)) production by CD25^-CD4⁺ or CD8⁺ T cells.

RESULTS: CD25⁺CD4⁺ T cells isolated from HIV-infected donors exhibited surface and nuclear (FoxP3 transcription factor) markers consistent with regulatory T cells. A modest elevation in the frequency of the CD25^+hi CD4⁺ subset was seen in HIV-infected versus uninfected donor PBMC. HIV p24-induced proliferation and cytokine (IL-2, IFN-γ) production by memory CD4⁺ T cells were enhanced following depletion, and suppressed by re-addition, of CD25⁺ CD45RA-CD4⁺ T cells in a subset of donors (15/25); this effect was independent of TGF-b and IL-10. Depletion of CD25⁺ CD4⁺ T cells resulted in increased frequencies HIV Gag peptide-induced IFN-γ⁺ CD8⁺ T cells from most donors and increased spontaneous IFN-γ production by CD8⁺ cells from donors with high viral loads. Furthermore, CD25⁺, but not CD25^-, CD4⁺ T cells suppressed the ability of effector (perforin⁺) CD8⁺ T cells to proliferate in response to autologous HIV super-infected target cells.

CONCLUSIONS: These data demonstrate that a subset of CD25⁺CD4⁺ T cells isolated from HIV-infected donors exhibit a CD25⁺CD4⁺ Treg-like phenotype and suppress HIV-specific immune responses in vitro. These findings suggest that CD25⁺CD4⁺ Treg-mediated immunosuppression may restrict the ability of both CD4⁺ and CD8⁺ T cells to effectively control HIV replication in vivo.

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