Elsevier

Clinical Immunology

Volume 187, February 2018, Pages 107-112
Clinical Immunology

Review Article
HIV patients, healthy aging and transplant recipients can reveal the hidden footprints of CMV

https://doi.org/10.1016/j.clim.2017.11.001Get rights and content

Highlights

  • Cytomegalovirus (CMV) is a persistent infection with repeated reactivations and periods of viral replication.

  • The “clinical footprint” of CMV includes several diseases of aging - notably vasculopathy and neurocognitive impairment.

  • CMV drives accumulation of multifunctional terminally-differentiated αβ T-cells and a novel population of Vδ2- γδ T-cells.

  • CMV also drives accumulation of a population of CD56lo NK cells lacking a key regulatory molecule.

  • An understanding of “immunological footprints” of CMV will reveal how they promote the varied “clinical footprints” of the virus.

Abstract

Cytomegalovirus (CMV) is a β-herpesvirus. Latent infections are common in all populations. However age-associated increases in levels of CMV-reactive antibody are testament to repeated reactivations and periods of viral replication. CMV has been associated with several diseases of aging, including vasculopathy and neurocognitive impairment. These conditions occur at a younger age in persons with particularly high burdens of CMV - transplant recipients and people living with HIV. Here we define the “clinical footprints” as immunopathologies triggered by CMV that develop over many years.

A high burden of CMV also drives accumulation of multifunctional terminally-differentiated αβ T-cells, a novel population of Vδ2  γδ T-cells, and a population of CD56lo NK cells lacking a key regulatory molecule. An understanding of these “immunological footprints” of CMV may reveal how they collectively promote the “clinical footprints” of the virus. This is explored here in transplant recipients, HIV patients and healthy aging.

Introduction

Cytomegalovirus (CMV) is a β-herpesvirus able to replicate in fibroblasts, endothelial cells, salivary acinar cells and monocytes [1]. It induces distinct end-organ diseases in patients with HIV/AIDS, transplant recipients and premature infants, but acute symptoms are rare in immunocompetent adults. This is remarkable as 35–95% of adults tested anywhere in the world are CMV seropositive, so it is possible that everyone has been exposed to virus shed in saliva [2]. During infection CMV becomes latent and can be reactivated by “stress” such as that exerted by infections, but the “when” and “how” remain unclear [3]. Many studies of the pathogenesis of CMV disease have been based on laboratory mice infected with murine CMV. This shares homology with human CMV and is endemic in wild mice so it is studied in its natural host. Inbred strains of mice that differ in their susceptibility to infection and disease have been used to show how NK and T-cells affect primary infections [4]. However the timescale of a human lifetime and the impacts of everyday stresses and co-infections are not well modeled in mice.

To better understand human CMV, it would be beneficial to study people resident in the community who retain a high burden of the virus over time, as mounting evidence links CMV with age-associated changes to the immune system and with diverse age-related diseases. A lesson from murine CMV is its effects on multiple organs, including the eyes, adrenals, pancreas and salivary glands. Our experience with this virus highlights the reality that the number of cells infected with CMV is small relative to the inflammatory response and that replication is in tissues rather than blood leukocytes [5]. These features make it difficult to prove that CMV is the primary cause of any chronic condition [6]. In a more holistic approach, we now propose a “footprint of CMV” as a tool to investigate the short- and long-term effects of CMV infection.

Section snippets

Assessing the burden of CMV

The clinical or immunological footprints of CMV are likely to depend on the susceptibility of the host to the immunological/inflammatory change, and on the individual's burden of CMV (i.e.: the amount of replicating virus). Metrics of the burden of CMV include CMV DNA amplified in blood or saliva, and immune responses to components of the virus – usually assessed as CD8+ T-cells and antibody.

The immunological footprint of CMV

The effects of CMV on αβ T-cells, γδ T-cells and NK-cells are evident without selection for CMV-reactive cells. Such large changes have potential to affect long-term health.

The clinical footprint of CMV

CMV has been linked with several diseases of aging. In addition to cardiovascular disease (CVD), we demonstrated higher titres of antibodies reactive with CMV in patients with chronic obstructive pulmonary disease or pulmonary non-tuberculous mycobacterial (NTM) infections [49], [50]. However T-cell and antibody responses to CMV rise with age [20], [51], so immune activation that is associated with age and other infections must be considered.

Conclusions

We propose characterization of the immunological and clinical footprints of CMV as a tool to elucidate the mechanisms invoked by this most unusual virus, as outlined in Fig. 1. Our understanding of the footprint can be advanced through studies of people with high burdens of CMV, notably HIV patients, transplant recipients and during healthy aging. The immunological footprint can be assessed in individuals of any age by linking phenotypic assessments of αβ T-cell, γδ T-cells and NK cells with

Competing interests

No authors have competing interests in relation to this manuscript.

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