(cache)oncotarget-v0i0-28823 HPV COVID published.pdf

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www.oncotarget.com Oncotarget, 2026, Vol. 17, pp: 30-33

Hypothesis

Hypothesis: HPV E6 and COVID spike proteins cooperate in

targeting tumor suppression by p53

Wafik S. El-Deiry1,2,3,4,5

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University,

Providence, RI 02912, USA

Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912,

USA

Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI 02912, USA

Legorreta Cancer Center at Brown University, Providence, RI 02912, USA

Hematology/Oncology Division, Department of Medicine, Lifespan Health System and Brown University, Providence, RI 02912,

USA

Correspondence to: Wafik S. El-Deiry, email: wafik@brown.edu

Keywords: HPV; COVID; p53; spike; cancer

Received: December 01, 2025 Accepted: December 26, 2025 Published: January 03, 2026

(CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are

credited.

ABSTRACT

Human Papilloma Virus (HPV) is a causative agent in several cancers including

cervical cancer, head and neck cancer, anal cancer, penile, vulvar and vaginal cancers.

HPV through its virus-encoded protein E6 and the cellular E6-Associated Protein (E6-

AP) target the tumor suppressor p53 protein for degradation thereby contributing

to cancer development after HPV infection. As viruses cause cancer, the author

previously hypothesized that SARS-COV-2 virus may be associated with cancer.

More recent insights on the present hypothesis have come from studies suggesting

(1) Spike protein of SARS-COV-2 may suppress p53 function, (2) cancer has been

associated with mRNA vaccines that produce Spike, and (3) a case mentioned by

Dr. Patrick Soon Shiong of a patient who survived HPV-associated head and neck

cancer, but the tumor recurred after COVID mRNA vaccination including with liver

metastases. Thus, the present hypothesis is that virally encoded proteins such as

HPV-E6 or SARS-COV-2 Spike may cooperate in suppressing host defenses including

tumor suppressor mechanisms involving p53. The hypothesis can be further explored

through epidemiologic and laboratory studies.

It is known that HPV E6 targets the tumor

suppressor protein p53 for degradation through the

E6-AP thereby contributing to the development of

cervical cancer, head and neck cancer, anal cancer and

others [1–17].

When the COVID-19 pandemic started, I pursued

studies “to better understand and modulate the host

immune response to SARSCoV-2 to prevent or reduce

disease severity in the current COVID-19 pandemic.

Some effort (was) directed at blocking ACE2, the receptor

SARS-CoV-2 uses to enter cells.” I further explained by

March 24, 2020 (Figure 1) “while the host inflammatory

response makes patients critically ill, the host innate

immune system including natural killer (NK) cells is

involved in fighting and eliminating virally infected

cells. Over the last 25 years we have studied this innate

immune system pathway that the immune system uses to

eliminate transformed and cancer cells as well as virally

infected cells. Natural killer cells secrete TRAIL which is

involved in killing virally infected as well as transformed

cells. This system can be triggered by p53 to suppress

viral infection as well as cancer. Thus, our goal is to better

understand and modulate the host immune response to

increase the innate immune system early in SARS-CoV-2

infection while reducing the severe inflammation that

occurs late. We further want to understand the impact of

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current therapeutics used to treat COVID-19 on both the

innate immune system as well as the cellular inflammatory

response.”

The proposal received a Brown University

COVID-19 Research Seed Award in the amount of $40,000

for “Reducing the lethality of SARS-CoV-2 infection

through immune modulation and drug discovery” in the

Spring of 2020. Four publications emerged subsequently

from these efforts [18–21]:

2020: MEK inhibitors reduce cellular expression of ACE2,

pERK, pRb while stimulating NK-mediated cytotoxicity

and attenuating inflammatory cytokines relevant to SARS- CoV-2 infection.

Figure 1: Original seed grant proposal dated 3-24-2020.

Figure 2: Schematic depicting hypothesized cooperation between HPV and COVID in suppressing p53 and contributing

to cancer.

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2021: Cytokine ranking via mutual information algorithm

correlates cytokine profiles with presenting disease

severity in patients infected with SARS-CoV-2.

2022: Integrin/TGF-β1 Inhibitor GLPG-0187 Blocks

SARS-CoV-2 Delta and Omicron Pseudovirus Infection of

Airway Epithelial Cells In Vitro, Which Could Attenuate

Disease Severity.

2024: Transfected SARS-CoV-2 spike DNA for

mammalian cell expression inhibits p53 activation of

p21(WAF1), TRAIL Death Receptor DR5 and MDM2

proteins in cancer cells and increases cancer cell viability

after chemotherapy exposure.

I listened to an interview (https://www.youtube.

com/watch?v=tnVMjp9mCA0&t=2s) of Dr. Patrick

Soon-Shiong by Chris Cuomo where I learned about

a patient named Jim Johnson with a history of HPV- related head and neck cancer who by 2022 had survived

his HPV-related cancer for 7 years and then he took

the COVID vaccine. The “cancer was back with a

vengeance,” and the tumor had metastasized to his liver.

After I listened to what happened in this case, it occurred

to me that there may be cooperation between HPV and

COVID infection or COVID vaccination and suppression

of p53.

A search of the literature for “cooperation between

HPV and COVID in suppressing p53” found per an

AI overview that there is “no evidence of a direct

molecular “cooperation” between HPV and COVID-19

in suppressing p53, research indicates they both target the

p53 pathway independently, and a COVID-19 infection

may indirectly accelerate HPV-related cancer progression

by impacting the host immune system.” I found a

publication about “SARS-CoV-2 infection heighten[ing]

the risk of developing HPV-related carcinoma in situ and

cancer [22],” and a hypothesis that “COVID-19 can lead

to rapid progression of cervical intraepithelial neoplasia

by dysregulating the immune system [23].”

HYPOTHESIS

Based on existing literature discussed above, here

is a schematic of the hypothesis that HPV E6 and COVID

spike proteins may potentially cooperate in targeting

tumor suppression by p53 (Figure 2). As depicted in

Figure 2, the hypothesis put forth is that virally encoded

proteins such as HPV-E6 or SARS-COV-2 Spike may

cooperate in suppressing host defenses including tumor

suppressor mechanisms involving p53. This hypothesis

can be tested through epidemiologic studies looking at

cancer incidence and recurrence among HPV-positive

individuals who have either been infected by SARS- COV-2 or have been given COVID mRNA vaccines.

Laboratory studies can test the impact of HPV-E6

combined with Spike protein on p53 expression and

function.

ACKNOWLEDGMENTS

W.S.E-D. is an American Cancer Society Research

Professor and is supported by the Mencoff Family

University Professorship at Brown University.

CONFLICTS OF INTEREST

W.S.E-D. is a co-founder of Oncoceutics, Inc.,

a subsidiary of Chimerix (Chimerix was acquired by

Jazz Pharmaceuticals), p53-Therapeutics, Inc. and

SMURF-Therapeutics, Inc. Dr. El-Deiry has disclosed

his relationships and potential conflicts of interest to his

academic institution/employer and is fully compliant with

NIH and institutional policy that manage these potential

conflicts of interest.

FUNDING

This work began early during the COVID pandemic

when it was supported by a Brown University pilot grant.

EDITORIAL NOTE

The Editor-in-Chief, Dr. Wafik S. El-Deiry, was

not involved in the peer-review process or the decision- making for this paper. Dr. El-Deiry shared the submitted

manuscript with National Cancer Institute (NCI) Director

Anthony Letai and NCI Deputy Director Doug Lowy in

separate emails electronically on December 12, 2025.

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