14th Conference on Retroviruses and Opportunistic Infections Los Angeles, California - February 25-28, 2007

Conf Retrovir Opportunistic Infect 2007 Feb 25-28;14: (abstract no. 27)

Joseph Casazza¹, J Brenchley¹, R Ayana¹, M Roederer¹, D Douek¹, M Betts², and R Koup^1
1Vaccine Res Ctr, NIAID, NIH, Bethesda, MD, US and ²Univ of Pennsylvannia, Philadelphia, US

BACKGROUND: Unlike HIV-specific CD4+ T cells, cytomegalovirus (CMV)-specific CD4+, T cells are easily detected in patients with HIV infection. The reason for the persistence of these CMV-specific CD4+ T cells, even in patients with AIDS, is not known.

METHODS: We used polychromatic flow cytometry to characterize functional and maturational phenotypes of pp65-specific CD4+ T cells from HIV-uninfected and HIV-infected subjects, and HIV Gag-specific CD4+ T cells from HIV-infected individuals. After stimulation with CMV pp65 or HIV Gag peptides, we simultaneously measured CD3, CD4, CD8, CD27, CD57, CD45RO, interferon-gamma (IFN-γ), interleukin-2 (IL-2), macrophage inhibitory protein-1beta (MIP-1β), CD107a, and TNF-α. In addition, we sorted cells based on differential cytokine/chemokine responses and measured cell associated Gag DNA in pp65-specific CD4+ T cells from HIV-infected individuals to determine infection frequency in vivo.

RESULTS: Gag-specific CD4+ T cells showed a markedly different functional and maturational profile than that seen in pp65-specific CD4+ T cells from HIV-infected individuals. When responses were compared in CMV and HIV co-infected individuals, Gag-specific responses were less polyfunctional, with a lower frequency of surface mobilization of CD107a and MIP-1β-producing cells than CMV pp65-specific CD4+ T cells (p <0.05). In addition, in HIV Gag-specific CD4+ T cells CD27 expression was more frequent, and CD57 expression was less frequent (p <0.05). No difference in functional response was found between pp65 responses in HIV-infected and -uninfected individuals. To test whether MIP1-β production in response to antigenic stimulation could prevent infection with HIV, we sorted pp65-specific CD4+ T cells and used cell associated Gag DNA as a marker of previous HIV infection. We consistently found that MIP1-β-producing cells had a lower content of Gag DNA than MIP1-β-non-producing cells.

CONCLUSIONS: These data show a marked difference in cytokine/chemokine production and surface mobilization of CD107a between pp65-specific and gag-specific CD4+ T cells. In addition, our data show that MIP1-β-producing pp65-specific CD4+ T cells consistently showed a lower level of cell-associated Gag DNA than MIP1-β-non-producing pp65-specific CD4+ T cells. These data suggest an explanation for the persistence of CMV-specific CD4+ T cells in patients with AIDS.

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2007-02-25
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