Latently KSHV-Infected Cells Promote Further Establishment of Latency upon Superinfection with KSHV.

Chen Gam Ze Letova,Meir Shamay,Ronit Sarid,Inna Kalt

doi:10.3390/ijms222111994

Chen Gam Ze Letova, Meir Shamay + Show 2 more

Open Access

https://doi.org/10.3390/ijms222111994

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Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) is a cancer-related virus which engages in two forms of infection: latent and lytic. Latent infection allows the virus to establish long-term persistent infection, whereas the lytic cycle is needed for the maintenance of the viral reservoir and for virus spread. By using recombinant KSHV viruses encoding mNeonGreen and mCherry fluorescent proteins, we show that various cell types that are latently-infected with KSHV can be superinfected, and that the new incoming viruses establish latent infection. Moreover, we show that latency establishment is enhanced in superinfected cells compared to primary infected ones. Further analysis revealed that cells that ectopically express the major latency protein of KSHV, LANA-1, prior to and during infection exhibit enhanced establishment of latency, but not cells expressing LANA-1 fragments. This observation supports the notion that the expression level of LANA-1 following infection determines the efficiency of latency establishment and avoids loss of viral genomes. These findings imply that a host can be infected with more than a single viral genome and that superinfection may support the maintenance of long-term latency.

Highlights

Kaposi’s sarcoma-associated herpesvirus (KSHV), referred to as human herpes virus-8 (HHV-8), is a gamma-2 herpesvirus that is implicated in the etiology of Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), plasmablastic variant of multicentricCastleman’s disease and KSHV-inflammatory cytokine syndrome (KICS) [1–7]
Naive uninfected iSLK cells were used as a negative control, while iSLK-BAC16-mCherry and iSLK-BAC16-mNeonGreen served as positive controls
Our results indicate that KSHV-infected cells are permissive for secondary superinfection with KSHV, and that this infection results in establishment of greater latency relative to that of primary infection

Summary

Introduction

Kaposi’s sarcoma-associated herpesvirus (KSHV), referred to as human herpes virus-8 (HHV-8), is a gamma-2 herpesvirus that is implicated in the etiology of Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), plasmablastic variant of multicentricCastleman’s disease and KSHV-inflammatory cytokine syndrome (KICS) [1–7]. Primary infection with KSHV results in life-long infection, which is mostly latent, coupled with sporadic lytic reactivation episodes that produce new virions and enable virus dissemination between hosts and within the host, while increasing the risk for disease development [8,9]. This biphasic infection cycle has been widely explored using various cell models in which a reversible latent infection can be shifted by different physiological and chemical treatments toward the productive/lytic infection phase [9,10]. The epigenetic modifications are predominantly orchestrated by the viral latency-associated nuclear antigen 1

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