Cytomegalovirus-specific T cells persist at very high levels during long-term antiretroviral treatment of HIV disease

Abstract

Background: In healthy, HIV seronegative, CMV seropositive adults, a large proportion of T cells are CMV-specific. High-level CMV-specific T cell responses are associated with accelerated immunologic aging ("immunosenesence") in the elderly population. The impact of untreated and treated HIV infection on the frequency of these cells remains undefined.

Methodology/principal findings: We measured the proportion of CD4+ and CD8+ T cells responding to CMV pp65 and IE proteins was measured using flow cytometry in 685 unique HIV seronegative and seropositive individuals. The proportion of CMV-specific CD8+ T cells was consistently higher in the HIV-seropositive subjects compared to the HIV-seronegative subjects. This HIV effect was observed even in patients who lacked measurable immunodeficiency. Among the HIV-seropositive subjects, CMV-specific CD8+ T cell responses were proportionately lower during recent infection, higher during chronic untreated infection and higher still during long-term antiretroviral treated infection. The CD8+ T cell response to just two CMV proteins (pp65 and IE) was approximately 6% during long-term therapy, which was over twice that seen in HIV-seronegative persons. CMV-specific CD4+ T cell responses followed the same trends, but the magnitude of the effect was smaller.

Conclusions/significance: Long-term successfully treated HIV infected patients have remarkably high levels of CMV-specific effector cells. These levels are similar to that observed in the elderly, but occur at much younger ages. Future studies should focus on defining the potential role of the CMV-specific inflammatory response in non-AIDS morbidity and mortality, including immunosenescence.

Figure 1. The distribution of percent of CMV-specific T cells in CMV-seronegative and CMV-seropositive, HIV-uninfected subjects.

Figure 2. The distribution of pp65 IFN-γ-bright CD4+ and CD8+ T cell responses (background corrected) in four unique groups: (1) HIV-seronegative, CMV-seropositive, (2) acute and recent untreated HIV infection, (3) established chronic untreated HIV infection, and (4) antiretroviral-treated infection with undetectable plasma HIV RNA levels.

Figure 3. The distribution of the CMV-specific CD4+ and CD8+ T cell responses (background corrected) in three unique groups: (1) HIV-seronegative, CMV-seropositive, (2) established chronic untreated HIV infection, and (3) antiretroviral-treated infection with undetectable plasma HIV RNA levels.

The IE IFN-γ-bright levels are shown in panel A (CD4+ T cells) and panel B (CD8+ T cells). The combined pp65 and IE IFN-γ/IL2 data are shown in panels C (CD4+ T cells) and panel D (CD8+ T cells). The data in panels C and D reflect the sum of all possible response (IFN-γ alone, IL2 alone, or IFN-γ/IL2) to each of the CMV proteins. Standard gating was used for dual cytokine data.