Work

Reply to Barrett, et al

Year: 2016

Type: letter

Abstract: To the Editor—We thank Barrett and colleagues for their comments on our recent report [1, 2]. Nearly all individuals infected with human immunodeficiency virus (HIV) are also coinfected with cytomegalovirus (CMV) infection, and asymptomatic replication of CMV is highly prevalent in antiretroviral therapy (ART)-treated HIV infection [3, 4]; yet the role CMV coinfection plays in the persistent inflammatory state, CD8 T cell expansion, and comorbidities observed in treated HIV infection remains unclear. It is likely that a substantial proportion of the expanded CD8 T cells we observe in HIV/CMV coinfected persons are demonstrably specific for CMV antigens. CMV-specific cells can comprise up to 50% of all circulating CD8 T cells in HIV-uninfected donors [5], and the percentage of CMV-reactive CD8 T cells are further increased during HIV infection [6]. Most CMV-specific CD8 T cells have a senescent-like phenotype, including low expression of CD28 and high expression of CD57 [7, 8]. In HIV infection, CD57+ CD8 T cells retain cytotoxic and cytokine-producing abilities and predict subclinical cardiovascular disease [9, 10]. Barrett, et al [1] provide intriguing data consistent with an antigen-driven expansion of CD8 T cells in HIV/CMV coinfection. However, it is not clear whether CMV antigens directly drive CD8 T cell expansion in vivo, or if expanded CMV-specific CD8 T cells contribute to the comorbidities that are associated with a low CD4/CD8 T cell ratio in treated HIV infection [11]. Our group has recently identified an increase in CD8 T cells in the aortas of rhesus macaques following simian immunodeficiency virus/simian-human immunodeficiency virus infection [12]. These cells were in close proximity to CD68+ macrophages, suggesting common trafficking signals, and the aortic endothelium in infected monkeys exhibited evidence of inflammation and dysfunction. Notably, CD8 T cells and macrophages can express the vascular endothelium homing receptor CX3CR1 [13], and CX3CR1+ CD8 T cells are increased in treated HIV infection [14]. Thus, if CMV coinfection drives an expansion of cytokine-producing CD8 T cells that can traffic to sites of vascular inflammation, those cells could potentially contribute to the development of cardiovascular disease. CD8 T cells in the vasculature would be susceptible to activating stimuli, whether from CMV peptide antigens directly presented by vascular endothelial cells or by soluble “bystander” mechanisms, such as proinflammatory cytokines [15]. Indeed, nonspecific activation signals might prime the expanded CD8 T cells to potentiate multiple adverse clinical events, regardless of their antigen specificity. We should note that congenital CMV infection is another condition that requires further study, particularly in light of the recent Zika virus outbreak in South and Central America. CMV shedding is increased in the immunocompromised [16], and congenital CMV infection is linked to maternal HIV infection in sub-Saharan Africa [17]. For both CMV and Zika, primary infections are usually mild or even asymptomatic, but mother-to-fetus transmission may lead to neurological abnormalities [18, 19]. Because of these concerns and others, we think a stronger focus on mitigating the adverse effects of CMV infection in the HIV infected and uninfected is warranted. Financial support. The authors are supported by the Case Western Reserve University (CWRU) Center for AIDS Research (AI036219), the CWRU AIDS Clinical Trials Unit (AI069501), and funding by the Richard J. Fasenmyer Foundation. 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.

Source: Clinical Infectious Diseases

DOI: 10.1093/cid/ciw152