title: Impaired base excision repair and accumulation of oxidative base lesions in CD4+ T cells of HIV-infected patients.
abstract: Several studies have reported enhanced oxidative stress in patients with HIV infection. An important pathophysiologic consequence of increased oxidative stress is endogenous DNA damage, and the base excision repair pathway is the most important mechanism to withstand such deleterious effects. To investigate the role of base excision repair in HIV infection, we examined 7,8-dihydro-8-oxoguanine (8-oxoG) levels as a marker of oxidative DNA damage and DNA glycosylase activities in CD4(+) and CD8(+) T cells of HIV-infected patients and controls. These results showed that the HIV-infected patients, particularly those with advanced disease, had increased levels of 8-oxoG in CD4(+) T cells and marked declines in DNA glycosylase activity for the repair of oxidative base lesions in these cells. In contrast, CD8(+) T cells from HIV-infected patients, with 8-oxoG levels similar to those in healthy controls, showed enhanced capacity to repair oxidative DNA damage. Finally, highly active antiretroviral therapy induced increased glycosylase activity in CD4(+) T cells and normalized 8-oxoG levels. This imbalance between the accumulation of oxidative DNA damage and the capacity to repair such lesions in CD4(+) T cells may represent a previously unrecognized mechanism involved in the numerical and functional impairment of CD4(+) T cells in patients with HIV infection.
authors.affiliation: Section of Clinical Immunology and Infectious Diseases, Research Institute for Internal Medicine, Oslo, Norway. pal.aukrust@rikshospitalet.no <pal.aukrust@rikshospitalet.no>
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Luisa
authors.initials: L
authors.lastname: Luna
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
authors.forename: Rune F
authors.initials: RF
authors.lastname: Johansen
authors.forename: Fredrik
authors.initials: F
authors.lastname: Müller
authors.forename: Stig S
authors.initials: SS
authors.lastname: Frøland
authors.forename: Erling C
authors.initials: EC
authors.lastname: Seeberg
authors.forename: Magnar
authors.initials: M
authors.lastname: Bjørås
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000494:pharmacology; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D004260:DNA Repair; D005260:Female; D006151:Guanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D006678:HIV / Q000378:metabolism*; D015658:HIV Infections / Q000378:metabolism / Q000628:therapy; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D044966:Anti-Retroviral Agents; D006151:Guanosine; C046215:8-hydroxyguanosine; C017400:5-hydroxycytosine; D003596:Cytosine; D004247:DNA; D045647:DNA Glycosylases; D010100:Oxygen