SARS-CoV-2 and anti-COVID-19 drugs activate Kaposi sarcoma-associated herpesvirus

The coronavirus disease (COVID-19) pandemic has devastated many countries, leaving more than a million people dead. Now ten months into the pandemic, more than 35.48 million people have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with the United States reporting the highest number of cases.

COVID-19 may lead to severe disease in high-risk populations, including older adults and those with underlying medical conditions, such as hypertension, diabetes, and heart disease, among others. Septic shock and multiple organ failure represent the most common immediate causes of death in patients with severe COVID-19. These deaths are mostly due to suppurative pulmonary infection, a direct attack on many organs, and the onset of cytokine storms.

A new study published on the preprint server bioRxiv* aimed to investigate the impacts of COVID-19 on people with various illnesses. Specifically, the researchers at the Rockefeller Cancer Institute, and the University of Arkansas for Medical Sciences wanted to see the effects of COVID-19 on patients with cancer and other infectious diseases.

The study, which is not yet peer-reviewed, revealed that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, encoded proteins and some drugs used against the infection can induce lytic reactivation of Kaposi sarcoma-associated herpesvirus (KSHV).

Patients with KSHV in areas where COVID-19 is actively spreading or undergoing treatment against the coronavirus have an increased risk of developing virus-associated cancers, even if they have already recovered from COVID-19.

Transmission electron micrograph of SARS-CoV-2 virus particles, isolated from a patient. Image captured and color-enhanced at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID
Transmission electron micrograph of SARS-CoV-2 virus particles, isolated from a patient. Image captured and color-enhanced at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID

What is Kaposi sarcoma-associated herpesvirus (KSHV)?

Kaposi sarcoma-associated herpesvirus (KSHV), with taxonomical name human gammaherpesvirus 8, is a phylogenetically old human virus that co-evolved with human populations. However, it became common in some parts of South America, around the Mediterranean Sea, sub-Saharan Africa, and some ethnic communities.

The infection can cause three human malignancies or cancers, including primary effusion lymphoma, Kaposi’s sarcoma, and some cases of the plasmablastic form of multicentric Castleman’s disease (MCD). It has also been tied to other diseases such as bone marrow failure and hepatitis.

Kaposi’s sarcoma (KS), cancer caused by the KSHV, is the most common cancer in HIV-infected people. Mostly, KSHV is seen in people who are immunocompromised or those with weak immune systems.

Further, the oncogenic virus belongs to the human herpesvirus subfamily, with two alternating life cycle programs after the primary infection – the latent and lytic phases. During the latent stage, viral genomes thrive as circular episomes with no progeny virion produced, and only a few latency-associated genes are expressed.

Meanwhile, as the infection enters the lytic stage or phase, almost all viral genes are already expressed, then replication and release of mature virions occur. Many previous studies have revealed that both viral latent and lytic proteins play important roles in the initiation and progression of virus-associated cancers.

The study

The new study aimed to provide a better understanding of the current COVID-19 infection, and the related treatments may affect the replication of the KSHV, which may increase the risk of developing virus-associated cancers.

To arrive at the study findings, the research team transfected the iSLK.219 cell lines, which carry a recombinant rKHSV.219 virus encoding a fundamental GFP reported and an RTA-inducible RFP reporter in the viral genome, aiding the monitoring of viral maintenance and lytic reactivation. To do this, the team used a vector control encoding two of SARS-CoV-2 major proteins, the spike protein, and the nucleocapsid protein, and KSHV-RTA, which is the key viral protein controlling the latency to lytic switch.

The team found that SARS-CoV-2 may induce the lytic reactivation of KSHV, and from there, they examined whether drugs used in the fight against COVID-19 patients may affect it. The team tested six drugs, including Chloroquine diphosphate, Azithromycin, Hydroxychloroquine sulfate, Remdesivir, Nafamostat mesylate, and Tocilizumab.

They revealed that two of the drugs, namely Nafamostat and Azithromycin, promoted the production of mature virions, potentially inducing KSHV lytic reactivation.

Further, the team tested the drugs on the KSHV+ PEL cell line and found that all of the drugs except Tocilizumab showed inhibitory effects on the BCP-1 cell growth at high concentrations. When the team used non-toxic concentrations of Azithromycin and Nafamostat mesylate, they found that these drugs increased viral lytic gene expression from BCP-1 cells.

Interestingly, one drug, Remdesivir, manifested induced effects on the BCP-12 cells, which were not seen on iSLK.219 cells.

“These events may facilitate KSHV dissemination as well as initiate viral oncogenesis in those KSHV+ patients exposed to COVID-19 and the related treatments, especially in the case of immunosuppressed patients,” the team concluded.

“Therefore, these patients need follow-ups to monitor KSHV viral loads and virus-associated malignancies development risks, even after they have fully recovered from COVID-19,” they added.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Angela Betsaida B. Laguipo

Written by

Angela Betsaida B. Laguipo

Angela is a nurse by profession and a writer by heart. She graduated with honors (Cum Laude) for her Bachelor of Nursing degree at the University of Baguio, Philippines. She is currently completing her Master's Degree where she specialized in Maternal and Child Nursing and worked as a clinical instructor and educator in the School of Nursing at the University of Baguio.

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