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Onco-immunologic factors contributing to OPSCC among people living with HIV

Award Number: R01DE033864
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Onco-immunologic factors contributing to OPSCC among people living with HIV - Oropharyngeal cancer (OPC) is a type of head and neck cancer and ~70% cases of OPC are associated with high-risk (hr) human papillomaviruses (HPV) infection. OPC cancers are increasing in prevalence especially in persons living with HIV (PWH) and this group also has higher rates on HPV associated OPC. Reasons for these findings are not well understood. While antiretroviral treatment (ART) does diminish HIV replication and immune activation, in a large majority of PWH it is generally started in chronic infection, when HIV reservoirs have already been established and uncontrolled HIV replication has resulted in significant immune dysfunction. Based on our preliminary data and what is known in the literature, we hypothesize that ongoing HIV replication and the resultant production of its proteins upregulates oncogenic HPV proteins (E6 and E7) thereby enhancing the probability of OPC development. HIV replication also results in exhaustion of CD8 T cells which is further exacerbated by increased HPV replication making HPV-specific CD8 T cells especially prone to overstimulation and exhaustion. These dysfunctional CD8 T cells thus make it even more likely for OPC to occur in PWH. Furthermore, both HIV protein production and immune activation continue after potent ART is started. As such, production of HIV proteins from previously latently infected CD4 T cells continues to drive HPV oncogenic protein production as well as CD8 T cell exhaustion and OPC continues to occur at higher rates in these PWH. Solidifying this overall hypothesis as proposed in our 3 aims would provide comprehensive insights into the mechanisms of OPC in PWH leading to improved prevention and therapies. Our overall study hypothesis is that chronic inflammation despite ART in PWH favors both persistence and proliferation of hrHPV16 infected oropharyngeal epithelial cells and contributes to impaired anti-HPV specific T cell immunity leading to initiation of OPC. We will test this hypothesis in the following three aims: In aim 1, we will determine the HPV types present in OPC from PWH and how T cell mediated anti-tumor immunity is impaired. We will examine whether multiple HPV subtypes persist. In addition, we will determine whether tumor and CD8 are spatially distant and whether the intra-tumoral CD8 are exhausted. Our aim 2 will determine how an HIV infection influences HPV infection, its gene expression and DNA replication to facilitate oncogenic transformation of oropharyngeal epithelial cells. Using 3D based models, we will show that HIV infection via its specific proteins (Tat and/or envelope gp120) modulates HPV pathogenesis by interfering at one or more steps in its life cycle. In aim 3, we will determine the mechanisms of HPV specific CD8 T cell dysfunction in PWH with OPC and whether tumor specific immunity can be restored. Our successfully completed studies will show how chronic, albeit low grade inflammation in PWH on ART is beneficial to the initiation of HPV associated OPC via increased susceptibility of epithelial cells to HPV infection, increased oncogene expression which when coupled with an inability of CD8 T cells to kill HPV infected cells tips the balance of an HPV infected cells towards OPC initiation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $697,916 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	2	5/23/2025	NON-COMPETING CONTINUATION	$697,916
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	001	2	6/26/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $697,916

Issue Date FY: 2024 ( Subtotal = $672,147 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	001	1	9/21/2024	NEW	$1
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	1	9/20/2024	NEW	$672,146
														Subtotal = $672,147

Grand Total All Awards = $1,370,063

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Onco-immunologic factors contributing to OPSCC among people living with HIV

Award Number: R01DE033864

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/20/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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