Partners in Crime: The Role of CMV in Immune Dysregulation and Clinical Outcome During HIV Infection

Abstract

In the current era of combination antiretroviral therapy (ART), human immunodeficiency virus (HIV)-infected individuals are living longer and healthier lives. Nevertheless, HIV-infected persons are at greater risk for age-related disorders, which have been linked to residual immune dysfunction and inflammation. HIV-infected individuals are almost universally co-infected with cytomegalovirus (CMV) and both viruses are associated with inflammation-related morbidities. Therefore, a detailed investigation of the relationship between CMV and aging-related morbidities emerging during chronic HIV infection is warranted. Here, we review the literature on how CMV co-infection affects HIV infection and host immunity and we discuss the gaps in our knowledge that need elucidation.

Keywords: Aging; CMV infection; HIV infection; Immune response; Inflammation.

Fig. 1

Proposed model connecting CMV, HIV, CD4 T cell dysfunction, and CD8 T cell expansion. We propose a model where HIV infection itself drives inflammation and cytokine production (for example IL-15) promoting CD8⁺ T cell expansion. HIV infection also induces CD4⁺ T cell loss and dysfunction, thereby failing to provide help to CD8⁺ T cells and permitting more CMV replication, which contributes to inflammation and further promotes the expansion of CD8⁺ T cells. Signals from CMV infection may also promote HIV persistence in CD4⁺ T cells (dotted line). Expanded CD8⁺ T cells are unable to control CMV replication, contributing to the vicious cycle. In addition, CD8⁺ T cell expansion, coupled with a loss of CD4⁺ T cells (leading to a lower CD4/CD8 T cell ratio) are linked to morbid outcomes of CMV and HIV infections, including cardiovascular risk (and other non AIDS events)