Hypoxia and hypoxia‐inducible factors in Kaposi sarcoma‐associated herpesvirus infection and disease pathogenesis

Davis, David A.; Shrestha, Prabha; Yarchoan, Robert

doi:10.1002/jmv.29071

Cited by 3 publications

(1 citation statement)

References 95 publications

(236 reference statements)

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“…After infecting cells, the virus mainly exists in a latent state, and only a limited number of viral genes are expressed in order to evade the immune response of host cells and maintain the survival of the virus ( Li et al, 2018 ; Gam Ze Letova et al, 2021 ; Sharma and Zheng, 2021 ). When it is stimulated by hypoxia, phorbol ester induction, and a variety of inflammatory factors, it will quickly enter the lytic state and produce infectious virus particles, thus infecting neighboring cells ( Long et al, 2021 ; Chinna et al, 2023 ; Davis et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Targeted delivery of miR-34a-5p by phenylborate-coupled polyethylenimide nanocarriers for anti-KSHV treatment

Li,

Cao,

Yao

et al. 2024

Front. Bioeng. Biotechnol.

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Kaposi’s sarcoma-associated herpesvirus (KSHV) can infect a variety of cells and cause malignant tumors. At present, the use of microRNA (miRNA) for anti-KSHV is a promising treatment strategy, but the instability and non-specific uptake of miRNA still limit its use in the treatment of KSHV. In the present study, we constructed a nano-drug delivery system employing chemical grafting and electrostatic adsorption to solve the problems of easy degradation and low cell uptake of miRNA during direct administration. This nano-drug delivery system is to graft 4-carboxyphenylboric acid (PBA) and lauric acid (LA) onto polyethylenimine (PEI) through amidation reaction, and then prepare cationic copolymer nanocarriers (LA-PEI-PBA). The drug-carrying nanocomplex LA-PEI-PBA/miR-34a-5p was formed after further electrostatic adsorption of miR-34a-5p on the carrier and could protect miR-34a-5p from nuclease and serum degradation. Modification of the drug-carrying nanocomplex LA-PEI-PBA/miR-34a-5p by targeted molecule PBA showed effective uptake, increase in the level of miR-34a-5p, and inhibition of cell proliferation and migration in KSHV-infected cells. In addition, the drug-carrying nanocomplex could also significantly reduce the expression of KSHV lytic and latent genes, achieving the purpose of anti-KSHV treatment. In conclusion, these cationic copolymer nanocarriers with PBA targeting possess potential applications in nucleic acid delivery and anti-KSHV therapy.

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Section: Introductionmentioning

confidence: 99%

Targeted delivery of miR-34a-5p by phenylborate-coupled polyethylenimide nanocarriers for anti-KSHV treatment

Li,

Cao,

Yao

et al. 2024

Front. Bioeng. Biotechnol.

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Hypoxia and HIF-1α promote lytic de novo KSHV infection

Lee,

Naik,

Tombácz

et al. 2023

J Virol

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The impact of different stress conditions on the oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV) primary infection that can occur in vivo remains largely unknown. We hypothesized that KSHV can establish a latency or lytic cycle following de novo infection, depending on the conditions of the cellular environment. Previous studies showed that hypoxia is a natural stress condition that promotes lytic reactivation and contributes to KSHV pathogenesis, but its effect on de novo KSHV infection is unknown. To test the effect of hypoxia on KSHV infection, we infected cells under normoxia and hypoxia, performed a comparative analysis of viral gene expression and viral replication, and tested chromatinization of the KSHV genome during infection. We found that hypoxia induces viral lytic gene expression and viral replication following de novo infection in several biologically relevant cell types, in which the virus normally establishes latency under normoxia. We also found that hypoxia reduces the level of repressive heterochromatin and promotes the formation of a transcriptionally permissive chromatin on the incoming viral DNA during infection. We demonstrate that silencing hypoxia-inducible factor-1α (HIF-1α) during hypoxia abrogates lytic KSHV infection, while the overexpression of HIF-1α under normoxia is sufficient to drive lytic KSHV infection. Also, we determined that the DNA-binding domain and the N-terminal but not the C-terminal transactivation domain of HIF-1α are required for HIF-1α-induced lytic gene expression. Altogether, our data indicate that HIF-1α accumulation, which can be induced by hypoxia, prevents the establishment of latency and promotes lytic KSHV infection following primary infection. IMPORTANCE The current view is that the default pathway of Kaposi’s sarcoma-associated herpesvirus (KSHV) infection is the establishment of latency, which is a prerequisite for lifelong infection and viral oncogenesis. This view about KSHV infection is supported by the observations that KSHV latently infects most of the cell lines cultured in vitro in the absence of any environmental stresses that may occur in vivo . The goal of this study was to determine the effect of hypoxia, a natural stress stimulus, on primary KSHV infection. Our data indicate that hypoxia promotes euchromatin formation on the KSHV genome following infection and supports lytic de novo KSHV infection. We also discovered that hypoxia-inducible factor-1α is required and sufficient for allowing lytic KSHV infection. Based on our results, we propose that hypoxia promotes lytic de novo infection in cells that otherwise support latent infection under normoxia; that is, the environmental conditions can determine the outcome of KSHV primary infection.

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Targeting hypoxia-inducible factors in malignancies caused by Kaposi’s sarcoma associated herpesvirus

Davis,

Shrestha,

Yarchoan

2024

GHM

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Hypoxia and hypoxia‐inducible factors in Kaposi sarcoma‐associated herpesvirus infection and disease pathogenesis

Cited by 3 publications

References 95 publications

Targeted delivery of miR-34a-5p by phenylborate-coupled polyethylenimide nanocarriers for anti-KSHV treatment

Targeted delivery of miR-34a-5p by phenylborate-coupled polyethylenimide nanocarriers for anti-KSHV treatment

Hypoxia and HIF-1α promote lytic de novo KSHV infection

Targeting hypoxia-inducible factors in malignancies caused by Kaposi’s sarcoma associated herpesvirus

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