Cytomegalovirus and HIV Persistence: Pouring Gas on the Fire

Abstract

The inherent stability of a small population of T cells that are latently infected with HIV despite antiretroviral therapy (ART) remains a stubborn obstacle to an HIV cure. By exploiting the memory compartment of our immune system, HIV maintains persistence in a small subset of quiescent cells with varying phenotypes, thus evading immune surveillance and clinical detection. Understanding the molecular and immunological mechanisms that maintain the latent reservoir will be critical to the success of HIV eradication strategies. Human cytomegalovirus (CMV), another chronic viral infection, frequently co-occurs with HIV and occupies an oversized proportion of memory T cell responses. CMV and HIV have both evolved complex strategies to manipulate our immune system for their own advantage. Given the increasingly clear links between CMV replication, chronic immune activation, and increased HIV reservoirs, we present a closer examination of the interplay between these two chronic coinfections. Here we review the effects of CMV on the immune system and show how they may affect persistence of the latent HIV reservoir during ART. The studies described herein suggest that hijacking of cytokine and chemokine signaling, manipulation of cell development pathways, and transactivation of HIV expression by CMV might be pouring gas on the fire of HIV persistence. Future interventional studies are required to formally determine the extent to which CMV is causally associated with inflammation and HIV reservoir expansion.

Keywords: CMV; HIV; inflammation; persistence; reservoir.

FIG. 1.

Putative mechanisms by which CMV might promote HIV persistence. Cells harboring latent HIV could become more numerous through CMV-associated inflammation, inhibitory signaling, proliferation, or inhibition of apoptosis. CMV can also directly transactivate latent HIV, which could lead to more target cells becoming infected. Blue circles with nucleus represent CD4 T cells with and without integrated HIV DNA; purple dots represent inhibitory cytokines; orange circles represent HIV. Gray circles represent CMV. Squared cells represent epithelial cells with signs of inflammation. CMV, cytomegalovirus.