Alveolar Macrophages Isolated Directly From Human Cytomegalovirus (HCMV)–Seropositive Individuals Are Sites of HCMV Reactivation In Vivo

Poole, Emma; Juss, Jatinder K.; Krishna, Benjamin A.; Herre, Jürgen; Chilvers, Edwin R.; Sinclair, John

doi:10.1093/infdis/jiu837

Cited by 50 publications

(53 citation statements)

References 26 publications

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“…However, the other arm of the conundrum is the exit from latency and reactivation of the lytic lifecycle. A key trigger of this event is the cellular differentiation to a differentiated macrophage or dendritic cell [19,40,64,[77][78][79][80] suggesting that changes in the cellular environment are promoting the reactivation event (Figure 1). At the most simplistic level, the first event that must likely occur is that the MIEP must transition from a repressed to an active promoter state for robust lytic IE gene expression to occur.…”

Section: Viral Reactivation-has Human Cytomegalovirus Perfected An Exmentioning

confidence: 99%

Cytomegalovirus latency and reactivation: recent insights into an age old problem

Dupont

Reeves

2015

Reviews in Medical Virology

152

150

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Human cytomegalovirus (HCMV) infection remains a major cause of morbidity in patient populations. In certain clinical settings, it is the reactivation of the pre-existing latent infection in the host that poses the health risk. The prevailing view of HCMV latency was that the virus was essentially quiescent in myeloid progenitor cells and that terminal differentiation resulted in the initiation of the lytic lifecycle and reactivation of infectious virus. However, our understanding of HCMV latency and reactivation at the molecular level has been greatly enhanced through recent advancements in systems biology approaches to perform global analyses of both experimental and natural latency. These approaches, in concert with more classical reductionist experimentation, are furnishing researchers with new concepts in cytomegalovirus latency and suggest that latent infection is far more active than first thought. In this review, we will focus on new studies that suggest that distinct sites of cellular latency could exist in the human host, which, when coupled with recent observations that report different transcriptional programmes within cells of the myeloid lineage, argues for multiple latent phenotypes that could impact differently on the biology of this virus in vivo. Finally, we will also consider how the biology of the host cell where the latent infection persists further contributes to the concept of a spectrum of latent phenotypes in multiple cell types that can be exploited by the virus.

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Section: Viral Reactivation-has Human Cytomegalovirus Perfected An Exmentioning

confidence: 99%

Cytomegalovirus latency and reactivation: recent insights into an age old problem

Dupont

Reeves

2015

Reviews in Medical Virology

152

150

View full text Add to dashboard Cite

show abstract

“…In contrast, latent infection was so far characterized only in cells of the early myeloid lineage, including CD34+ hematopoietic progenitor cells (HPCs) and CD14+ monocytes (8). It was further established that terminal differentiation of HPCs and CD14+ monocytes to dendritic cells or macrophages triggers virus reactivation from latency (9)(10)(11)(12)(13). This differentiationdependent reactivation of latent virus is thought to be mediated by changes in posttranslational modification of histones around the viral major immediate-early promoter (MIEP).…”

Section: Introductionmentioning

confidence: 99%

Defining the Transcriptional Landscape during Cytomegalovirus Latency with Single-Cell RNA Sequencing

Shnayder

Nachshon

Krishna

et al. 2017

Preprint

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Primary infection with human cytomegalovirus (HCMV) results in a lifelong infection due to its ability to establish latent infection, one characterized viral reservoir being hematopoietic cells. Although reactivation from latency causes serious disease in immunocompromised individuals, our molecular understanding of latency is limited. Here, we delineate viral gene expression during natural HCMV persistent infection by analyzing the massive RNA-seq atlas generated by the Genotype-Tissue Expression (GTEx) project. This systematic analysis reveals that HCMV persistence in-vivo is prevalent in diverse tissues. Unexpectedly, we find only viral transcripts that resemble gene expression during stages of lytic infection with no evidence of any highly restricted latency-associated viral gene expression program. To further define the transcriptional landscape during HCMV latent infection, we also used single cell RNA-seq and a tractable experimental latency model. In contrast to current views on latency, we also find no evidence for a specific restricted latency-associated viral gene expression program. Instead, we reveal that latency-associated gene expression largely mirrors a late lytic viral program albeit at much lower levels of expression. Overall, our work has the potential to revolutionize our understanding of HCMV persistence and suggests that latency is governed mainly by quantitative changes, with a limited number of qualitative changes, in viral gene expression.peer-reviewed)

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“…Human cytomegalovirus (HCMV) causes interstitial pneumonitis in immunocompromised patients (5). While HCMV could potentially reach the lungs via circulating monocytes (6), viral lytic antigen expression in alveolar epithelial cells (AECs) (7)(8)(9) and alveolar macrophage (AM) infection (10) suggest entry by inhalation.…”

mentioning

confidence: 99%

Alveolar Macrophages Are a Prominent but Nonessential Target for Murine Cytomegalovirus Infecting the Lungs

Farrell

Lawler

Oliveira

et al. 2016

J Virol

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H erpesviruses are among the most prevalent of all mammalian pathogens. Many cause lung disease (1-5), making the lung an important site of infection. Human cytomegalovirus (HCMV) causes interstitial pneumonitis in immunocompromised patients (5). While HCMV could potentially reach the lungs via circulating monocytes (6), viral lytic antigen expression in alveolar epithelial cells (AECs) (7-9) and alveolar macrophage (AM) infection (10) suggest entry by inhalation.Sporadic transmission and late clinical presentation make early HCMV infection hard to analyze. However, the relatedness between cytomegaloviruses (CMVs) and their hosts implies that CMV parasitism preceded the speciation of most mammals (11), and peaks of viral diversity in genes engaging the immune functions of diverse hosts suggest that coevolution has operated since to conserve a parasitic status quo. Therefore, nonhuman CMVs can help us to understand how HCMV works. The preeminence of mice as experimental models of mammalian cell biology gives murine CMV (MCMV) particular value in this regard. It causes an interstitial pneumonitis after intranasal (i.n.) inoculation, infecting epithelial and mononuclear cells (12). Thus, it reproduces at least some features of HCMV lung infection.Which lung cells CMVs infect first is unknown. The ciliated upper airways capture large inhaled particles (diameter, Ͼ5 m), but submicron-sized particles, such as viruses, can reach the lung alveoli (13). Here, type 1 alveolar epithelial cells (AEC1s) provide Ͼ90% of the accessible surface, their abundant type 2 progenitors (AEC2s) produce surfactant, and AMs patrol the airspaces for inhaled pathogens. In neonatal mice, i.n. inoculated MCMV infects AMs and AEC2s (14). Infection was reduced when AMs were depleted with liposomal clodronate or when MCMV lacked m129 (15). The m131/m129 MCMV chemokine homolog (designated MCK2) attracts macrophages (16) and alters viral tropism to promote macrophage infection (17). Thus, it was concluded that AMs provide an acutely productive gateway into the lungs. However, MCK2-negative (MCK2 Ϫ ) MCMV given intra-

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Alveolar Macrophages Isolated Directly From Human Cytomegalovirus (HCMV)–Seropositive Individuals Are Sites of HCMV Reactivation In Vivo

Cited by 50 publications

References 26 publications

Cytomegalovirus latency and reactivation: recent insights into an age old problem

Cytomegalovirus latency and reactivation: recent insights into an age old problem

Defining the Transcriptional Landscape during Cytomegalovirus Latency with Single-Cell RNA Sequencing

Alveolar Macrophages Are a Prominent but Nonessential Target for Murine Cytomegalovirus Infecting the Lungs

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