Advances in Model Systems for Human Cytomegalovirus Latency and Reactivation, 2022, Crawford et al

[Hutan]

Lindsey B. Crawford, a ,* Nicole L. Diggins, a Patrizia Caposio, a and Meaghan H. Hancock

a

Abstract
Human cytomegalovirus (HCMV) is a highly prevalent beta-herpesvirus and a significant cause of morbidity and mortality following hematopoietic and solid organ transplant, as well as the leading viral cause of congenital abnormalities. A key feature of the pathogenesis of HCMV is the ability of the virus to establish a latent infection in hematopoietic progenitor and myeloid lineage cells.

The study of HCMV latency has been hampered by difficulties in obtaining and culturing primary cells, as well as an inability to quantitatively measure reactivating virus, but recent advances in both in vitro and in vivo models of HCMV latency and reactivation have led to a greater understanding of the interplay between host and virus. Key differences in established model systems have also led to controversy surrounding the role of viral gene products in latency establishment, maintenance, and reactivation.

This review will discuss the details and challenges of various models including hematopoietic progenitor cells, monocytes, cell lines, and humanized mice. We highlight the utility and functional differences between these models and the necessary experimental design required to define latency and reactivation, which will help to generate a more complete picture of HCMV infection of myeloid-lineage cells.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8749418/

 

[Hutan]

This paper has some of the same authors as for this recently posted paper:Viral miRNA regulation of host gene expression, 2023, Diggins and Hancock

In patients, CD34+ hematopoietic progenitor cells (HPCs) are a critical reservoir of latent HCMV (7,–9) and infection of HPCs contributes to the hematopoietic abnormalities observed following transplantation (10,–13). Reactivation in vivo is initiated when infected HPCs exit the bone marrow in response to cytokine/growth factor signaling, traffic to the periphery, and differentiate first into monocytes and ultimately into tissue macrophages that support lytic replication

So, we know there could be viruses hanging out in bone marrow producing infected cells. Perhaps either the progenitor cells or the infected cells they produce could be resulting in the body reacting to that latent infection in ways that result in ME/CFS. I think this is a topic worth looking at more.

This paper discusses some of the issues with working with cells with latent infections. It sounds as though there is plenty that can go wrong, and lead to faulty conclusions. For example:

The experimental design and controls outlined above are critical to producing high quality data for studying mechanisms of HCMV latency and reactivation. Both the source of CD34+ HPCs and their culture conditions are important contributors to the outcome of HCMV latency assays. Therefore, it is unsurprising that differences in experimental outcomes have been documented using different latency systems. As one example, conflicting data about the role of the HCMV-encoded G protein-coupled receptor US28 in latency and reactivation has been reported. US28 is expressed in naturally infected peripheral blood cells (47) and in CD34+ HPC and monocyte models during latency (17, 48,–51). Using the latency and reactivation model described above and a variety of US28 mutants, we previously demonstrated that US28 ligand binding activity is required for latency in both CD34+ HPCs and humanized mice (see below) (21). These results are in contrast to other published data suggesting that in CD34+ HPCs US28 constitutive signaling is required for latency establishment and virus-mediated reprogramming of infected cells (38, 51). These discrepancies directly highlight the different possible outcomes of HCMV latency and reactivation from different experimental conditions and underscore the importance of clearly defining and describing the source, identity, and purity of CD34+ HPCs, the conditions for culture, and the need for appropriate controls, especially when comparing results across different studies.