AEGiS-15IAC: Diminished in vitro proliferation of HIV-specific CD4+ T cells during viremia is due to reduced positive factors not the presence of dominant negative factors.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

DIMINISHED IN VITRO PROLIFERATION OF HIV-SPECIFIC CD4+ T CELLS DURING VIREMIA IS DUE TO REDUCED POSITIVE FACTORS NOT THE PRESENCE OF DOMINANT NEGATIVE FACTORS

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. MoOrA1002)

J C Tilton, A J Johnson, C A Iyasere, S A Migueles, M Connors
National Institutes of Allergy and Infectious Diseases, Bethesda, United States

BACKGROUND: CD4+ T cell function is critical for the induction and maintenance of antiviral CD8+ T cell responses in chronic viral infections in humans and experimental animals. In vitro proliferation of HIV-specific CD4+ T cells is diminished during HIV viremia, however the mechanism of this effect remains poorly understood. It remains unclear whether this decrease is caused by diminished positive signals during viremia such as diminished IL-2 production, or dominant negative effects such as increases in suppressive cytokines, viral gene products, or regulatory T cells.

METHODS: CD4+ T cell proliferation and cytokine production were measured in response to HIV Gag, Nef, Pol, and Env peptide pools, p24 antigen, CMV lysate, CMV pp65 peptide pools, and tetanus toxoid In a separate cohort of 15 patients with progressive infection with strong HIV-specific CD4+ T cell proliferative responses, CFSE labeled cells from an on-therapy timepoint were mixed with unlabeled cells from the off-therapy timepoint, or the reverse, and the effects on antigen-specific proliferation were analyzed.

RESULTS: The mean frequency of HIV-specific IFN-g producing CD4+ T cells in response to individual gene products were: gag 0.24, env 0.015, nef 0.04, and pol 0.04% of CD4+ T cells. The percent of HIV-specific CD4+ T cells that produce IL-2 was significantly diminished in patients with high level viremia (38% in in patients with<1000 copies/ml plasma vs 14% in patients with >1000 copies/ml plasma; p=0.01). Proliferation of on-therapy HIV-specific CD4+ T cells was not impaired by mixing with cells from the viremic time-point. However, addition of cells from the on-therapy time-point was able to completely recover proliferation of HIV-specific CD4+ T cells from the viremic timepoint.

CONCLUSIONS: These results suggest that diminished in vitro proliferation of HIV-specific CD4+ T cells during viremia is not due to dominant host or viral negative factors, but rather due to decreases in positive factors such as diminished IL-2 production or other proinflammatory cytokines.

Keywords: AEGIS, HIV, Acquired Immunodeficiency Syndrome, Viremia, Antigens, CD4, HIV Seropositivity, CD4-Positive T-Lymphocytes, Lymphocyte Activation, HIV Infections, CD8-Positive T-Lymphocytes, Interleukin-2, HIV Core Protein p24, HIV Long-Term Survivors, Interferon Type II, HIV Antigens, Anti-HIV Agents, Humans, In Vitro, immunology

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MoOrA1002