Cytomegalovirus Immunity and Exhaustive CD8⁺T Cell Proliferation in Treated Human Immunodeficiency Virus Infection

To the Editor—We read with great interest the recent article by Freeman et al describing a link between cytomegalovirus (CMV) infection, CD8+ T-cell expansion, and inflammation in treated human immunodeficiency virus (HIV) infection [1]. A large longitudinal study establishing CMV infection as a risk factor for severe, non-AIDS adverse clinical events in HIV infection highlights the relevance of this research [2]. Although multiple factors acting across a broad pathophysiological landscape bring age-related morbidities early to prominence in HIV infection, the potential influence of CMV crystallizes around inflammation and immune senescence [1, 3]. Despite highly prevalent CMV coinfection throughout most HIV-infected cohorts, overt effects on inflammation and immune senescence concentrate within subsets heretofore not distinguished by either immunological or virological aspects of CMV infection. There could be significant benefit to identifying those at greatest risk for adverse outcomes and intervening against immunological or virological factors at play. To this end, several studies detected CMV in saliva or semen of a substantial fraction of HIV-infected men having sex with men [4, 5]. Thus, there is potential for CMV replication to directly drive immune activation in this setting, a prospect supported by reduction in T-cell activation in HIV-infected individuals following valganciclovir treatment [6]. From an immunological perspective, some middle aged and even younger HIV-infected individuals have T-cell responses against CMV inflated to a degree that has been associated with immunological deterioration and increased risk for all cause mortality in old elderly individuals [7]. Because CMV memory inflation has an established relationship with immune senescence in the aging general population, its development may also relate to immunological deterioration in the antiretroviral treated HIV-infected population, a group often characterized as undergoing accelerated aging. Rapid inflation of CMV-specific T-cell responses in HIV infection may relate to the higher likelihood of detectable CMV in semen or saliva and, therefore, increased CMV replication overall, but there is no conclusive evidence for this relationship [8]. Given the propensity for CMV infection to induce exceptionally strong specific T-cell responses, drive general CD8+ T-cell expansion, and increase phenotypic evidence of senescence in HIV infection [3, 9], we measured T-cell receptor excision circle (TREC) frequency in CD8+ T cells from HIV-infected individuals, as previously described [10], to assess the impact of CMV infection on cumulative proliferation of the CD8+ T-cell population. Proliferation of T cells reduces TREC frequency, and we found a lower median TREC frequency in HIV-infected individuals coinfected with CMV vs age matched HIV-infected individuals not coinfected with CMV (Figure 1A). Furthermore, TREC frequency inversely correlated with size of the CD8+ T-cell response against CMV pp65 and immediate early 1 (IE-1) proteins (Figure 1B). These data support links between inflation of the CD8+ T-cell response against CMV, exhaustive CD8+ T-cell proliferation, immune senescence, and downstream sequelae related to inflammation. Studies to determine whether this could be mitigated either by enhanced suppression of CMV or by selectively promoting naive T-cell proliferation with interleukin-7 are warranted. Influence of cytomegalovirus (CMV)-specific immunity on CD8+ T-cell T-cell receptor excision circle (TREC) frequency in human immunodeficiency virus (HIV) infection. A, CD8+ T cells were separated from peripheral blood mononuclear cells (PBMCs) of 150 HIV-infected subjects, nucleic acids isolated, and TREC frequency measured by quantitative polymerase chain reaction as in [10]. CMV infection status was assessed as in [3]. Horizontal lines through group data represent medians with interquartile range shown above and below. Difference between medians was evaluated by 2-tailed Mann–Whitney test and the probability of significant difference shown over a line spanning the groups. B, Spearman correlation (r) between CD8+ T-cell TREC frequency and percentage of CD8+ T cells specific for CMV IE-1 and pp65 proteins was calculated and together with significance of the correlation is shown within the graph. Intracellular flow cytometry to detect interferon-gamma production following incubation of PBMC with overlapping peptides from CMV IE-1 and pp65 proteins was carried out to enumerate the percentage of CD8+ T cells specific for CMV. Acknowledgments. This study received ethical approval from the Newfoundland and Labrador Health Ethics Research Authority and all subjects provided informed consent for blood collection and immunological testing. The authors are thankful for their participation. Financial support. This study was supported by research grants from the Canadian Institutes for Health Research (FRN# RNL-134530) and Newfoundland and Labrador Research Development Corporation (Project #5404.1758.101). Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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