Abstract

The incidence of several types of cancer is higher in HIV-1 infected patients in comparison to the general population. Little is known about the mechanistic basis for these observations. This R21 proposal addresses RFA-CA-15-013 and, specifically, provocative question 2: Other than immune dysfunction (including inflammation), what are the HIV-mediated mechanisms that underlie differential cancer risk in individuals with HIV infection? We will use molecular virology and molecular biology approaches, together with bioinformatics, to investigate a mechanistic link between viral infection of CD4-positive T lymphocytes and a signaling mechanism that causes the trans-upregulation of antiviral APOBEC3 enzymes in bystander cells, leading to increased levels of genomic mutation that in turn result in a higher likelihood of cancer. The demonstration of such a mechanism would be a significant advance because it is novel and suggests multiple points for therapeutic intervention.

Public Health Relevance

The mechanistic basis for higher incidences of cancer in HIV-1 infected individuals is not well understood. This proposal will investigate a mechanistic link between infection and increased somatic mutation, which could help to explain the observed higher cancer incidences and suggest points for therapeutic intervention.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA206309-02
Application #
9271943
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2016-05-10
Project End
2018-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost

  Institution

Name
University of Minnesota Twin Cities
Department
Biochemistry
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455

  Publications

Jarvis, Matthew C; Ebrahimi, Diako; Temiz, Nuri A et al. (2018) Mutation Signatures Including APOBEC in Cancer Cell Lines. JNCI Cancer Spectr 2:
Ebrahimi, Diako; Richards, Christopher M; Carpenter, Michael A et al. (2018) Genetic and mechanistic basis for APOBEC3H alternative splicing, retrovirus restriction, and counteraction by HIV-1 protease. Nat Commun 9:4137
Olson, Margaret E; Harris, Reuben S; Harki, Daniel A (2018) APOBEC Enzymes as Targets for Virus and Cancer Therapy. Cell Chem Biol 25:36-49
Shaban, Nadine M; Shi, Ke; Lauer, Kate V et al. (2018) The Antiviral and Cancer Genomic DNA Deaminase APOBEC3H Is Regulated by an RNA-Mediated Dimerization Mechanism. Mol Cell 69:75-86.e9
Cheng, Adam Z; Yockteng-Melgar, Jaime; Jarvis, Matthew C et al. (2018) Epstein-Barr virus BORF2 inhibits cellular APOBEC3B to preserve viral genome integrity. Nat Microbiol :
Wang, Jiayi; Shaban, Nadine M; Land, Allison M et al. (2018) Simian Immunodeficiency Virus Vif and Human APOBEC3B Interactions Resemble Those between HIV-1 Vif and Human APOBEC3G. J Virol 92:
Venkatesan, S; Rosenthal, R; Kanu, N et al. (2018) Perspective: APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution. Ann Oncol 29:563-572
St Martin, Amber; Salamango, Daniel; Serebrenik, Artur et al. (2018) A fluorescent reporter for quantification and enrichment of DNA editing by APOBEC-Cas9 or cleavage by Cas9 in living cells. Nucleic Acids Res 46:e84
Ikeda, Terumasa; Symeonides, Menelaos; Albin, John S et al. (2018) HIV-1 adaptation studies reveal a novel Env-mediated homeostasis mechanism for evading lethal hypermutation by APOBEC3G. PLoS Pathog 14:e1007010
Shi, Ke; Carpenter, Michael A; Banerjee, Surajit et al. (2017) Structural basis for targeted DNA cytosine deamination and mutagenesis by APOBEC3A and APOBEC3B. Nat Struct Mol Biol 24:131-139

Showing the most recent 10 out of 16 publications