The findings offer potential new targets for novel anti-HIV drugs that may not lead as quickly to viral resistance as current drugs, the researchers say.
“HIV continues to develop resistance to current therapies,” says first author Kristine Yoder, assistant professor of molecular virology, immunology and medical genetics at Ohio State. “But the proteins we talk about in this paper are made by the cell, so drugs that target them might not lead to resistance as quickly as drugs that target viral proteins. And while targeting host proteins does have the potential for side effects, studies of mice suggest that targeting some of these genes may not lead to significant side effects.”
The paper was published online March 23 in the journal
Cells normally use base excision repair to fix oxidative damage to DNA caused by reactive molecules such as hydrogen peroxide and oxygen radicals, which form during energy production and other metabolic processes.
For this study, Yoder and her colleagues investigated the role of the repair pathway in the virus insertion process by engineering four strains of mouse fibroblast cells that each lacked a component of the pathway. Specifically, they deleted genes for three glycosylase enzymes – Ogg1, Myh, and Neil1 – and one polymerase gene, Pol-beta.
They found that the loss of any of these elements reduced the ability of HIV DNA to integrate with host-cell DNA by about 60 to 70 percent. In an additional experiment, the researchers restored the polymerase in cells that lacked it, which this enabled the HIV DNA to again integrate at its normal level.
“Overall, our findings indicate that HIV infection and integration efficiency depends on the presence of base excision repair proteins, and that these proteins might make novel new targets for the treatment of HIV infection,” Yoder says.
An American Recovery and Reinvestment Act grant from the National Institute of Allergy and Infectious Diseases supported this research.
Other researchers involved in this study were Richard Fishel, Ohio State University; Amy Espeseth and Daria Hazuda, Merck Research Laboratories; Maria Teresa Russo, Istituto Superiore di Sanità, Rome, Italy; R. Stephen Lloyd, Oregon Health and Science University; and Xiao-hong Wang, Qingming Fang and Robert W. Sobol, University of Pittsburgh.
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (http://cancer.osu.edu) is one of only 40 Comprehensive Cancer Centers in the United States designated by the National Cancer Institute. Ranked by U.S. News & World Report among the top cancer hospitals in the nation, The James is the 205-bed adult patient-care component of the cancer program at The Ohio State University. The OSUCCC-James is one of only seven funded programs in the country approved by the NCI to conduct both Phase I and Phase II clinical trials.