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Review
. 2024 Sep 7;3(6):100200.
doi: 10.1016/j.cellin.2024.100200. eCollection 2024 Dec.

Hypoxic reactivation of Kaposi's sarcoma associated herpesvirus

Rajnish Kumar Singh  1 , Atharva S Torne  1 , Erle S Robertson  1
Affiliations
Review

Hypoxic reactivation of Kaposi's sarcoma associated herpesvirus

Rajnish Kumar Singh et al. Cell Insight. .

Abstract

Hypoxic reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV) refers to the phenomenon under low oxygen where the virus goes from latent to lytic replication. Typically, healthy cells generally cease cell division and DNA replication under hypoxic conditions due to limited resources, and the presence of physiological inhibitors. This restricted replication under hypoxic conditions is considered an employed strategy of the cell to minimize energy consumption. However, cancerous cells continuously replicate and divide in hypoxic conditions by reprogramming several aspects of their cell physiology, including but not limited to metabolism, cell cycle, DNA replication, transcription, translation, and the epigenome. KSHV infection, similar to cancerous cells, is known to bypass hypoxia-induced restrictions and undergo reactivation to produce progeny viruses. In previous studies we have mapped several aspects of cell physiology that are manipulated by KSHV through its latent antigens during hypoxic conditions, which allows for a permissive environment for its replication. We discuss the major strategies utilized by KSHV to bypass hypoxia-induced repression. We also describe the KSHV-encoded antigens responsible for modulating these cellular processes important for successful viral replication and persistence in hypoxia.

Keywords: Epigenetics; Hypoxia; KSHV; LANA; Reactivation; Replication; Transcription.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
An inhibitory role for hypoxia on cell cycle progression and DNA replication. Hypoxic conditions lead to inactivation of PHD activities which allows stabilization of HIF1α. In its stabilized condition, HIF1α interacts with CDC6 to facilitate MCMs loading onto replicating DNA but inhibits their activation. In this stabilized condition, HIF1α up-regulates expression of genes required for metabolic reprogramming leading to enhanced glucose uptake and glycolysis. Low oxygen levels also promote reactive oxygen species production, which in turn can mediate protein carbonylation and interfere with DNMTs activity. Hypoxic conditions can mediate degradation of key components of DNA replication and RNA transcription related proteins by promoting their ubiquitination. The tapering end of the red triangle represents a decrease in O2 concentration.
Fig. 2
Fig. 2
Metabolic reprogramming during KSHV infection and HIF1α-induced expression of vGPCR. In KSHV infected cells, stabilization of HIF1α following the induction of hypoxia enables sustained expression of KSHV-encoded vGPCR. RNA sequencing data revealed diverse metabolic changes as a direct result of KSHV infection through the action of vGPCR. Expression of glycolytic genes and glucose uptake in particular, is substantially up-regulated in KSHV infected cells, while direct complementary down-regulation of glycogen metabolism and TCA cycle genes has also been shown. vGPCR has been shown to negatively affect transketolase (TKT) in the pentose phosphate pathway, and has been shown to be required for efficient blocking of TKT expression during hypoxia. Frame-shift knock-out of vGPCR or its knock-down, does not result in any significant change in the expression of TKT reported, under similar hypoxic conditions. Further, vGPCR has also been shown to induce the generation of reactive oxygen species (ROS), with a potential role in epigenetic reprogramming viral and host genomes, which mediate changes in the expression of metabolic genes.
Fig. 3
Fig. 3
KSHV-encoded antigens and HIF1α interactions in host cell during DNA replication and transcription. The induction of hypoxia and subsequent stabilization of HIF1α can induce the formation of a HIF1α-LANA complex in KSHV infected cell, which interacts with the NEDD4 ubiquitin ligase which prevents ubiquitination of RNA Pol II to prevent its degradation in hypoxic micro-environment. Similarly, hypoxia and HIF1α stimulates expression of KSHV-encoded LANA, vCyclin, and vGPCR. LANA engages in a feedback cycle wherein HIF1α-induced expression of LANA induces the expression of HIF1α itself, which then allows for the arrest of DNA replication by the formation of HIF1α-CDC6 complex that prevent the binding of MCMs to ORCs. Complementarily, HIF1α-induced expression of vCyclin can abrogate HIF1α activity by generation of HIF1α-vCyclin complexes which are targeted for lysosomal degradation. Following this degradation of HIF1α, CDC6 and MCMs are then able to form the MCMs-ORCs-CDC6 complex necessary for DNA replication, thus allowing for sustained DNA replication under conditions of hypoxic stress.
Fig. 4
Fig. 4
KSHV-encoded antigens and the differential enrichment of epigenetic markers on the KSHV genome during hypoxia. During induction of hypoxia, major epigenetic histone markers are enriched at critical sites of the KSHV genome. Most notably, H3 acetylation at two major sites and the increase in H3K4 and H3K27 trimethylation across the KSHV genome. This enrichment is facilitated largely by both the latent as well as lytic antigens of KSHV such as LANA, RTA and vGPCR. Although, studies have also shown that the latent-to-lytic switch mediator RTA can also increase the enrichment of specific markers, such as H3K9Me3, in certain conditions. The broad-spectrum effect of these modifications is the marginal stabilization of certain DNMTs in both naturally infected and artificially transfected KSHV-positive cells. The end result of such modification is the preferential recruitment of host replication machinery to specific sites on the KSHV genome. These changes allow the virus to bypass replication checkpoints and replicate during hypoxic conditions. The non-scaled schematic represents various antigens and their downstream effects.
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