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-b 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-b-producing cells had a lower content of Gag DNA than MIP1-b-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-b-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.