title: Regeneration and tolerance factor prevents bystander T-cell death associated with human immunodeficiency virus infection.
abstract: Human immunodeficiency virus (HIV) infection is characterized by a depletion of T cells. This depletion is caused both by the virus-induced death of infected T cells and by the death of uninfected cells (bystander depletion) by a mechanism which is largely uncharacterized. Regeneration and tolerance factor (RTF) is a subunit of the vacuolar ATPase and a protein that is involved with activation and apoptosis. Anti-RTF antibodies mediate apoptosis in T lymphocytes. When anti-RTF was added to lymphocytes from an HIV-positive individual, they underwent larger amounts of apoptosis than cells taken from healthy controls. When lymphocytes were examined by Western blotting, those from HIV-positive individuals exhibited increased levels of expression of the 50-kDa protein (P < 0.001). A 70-kDa protein was the predominant form of RTF in uninfected control lymphocytes, being expressed in 100% of individuals studied. The expression of the 50-kDa protein in HIV-positive individuals correlated with decreased absolute CD4 counts with a sensitivity of 92% and a positive predictive value of 86%. When uninfected lymphocytes were stimulated with anti-CD3 and anti-CD28, no RTF was detected during early stimulation but a 50-kDa protein was expressed during late stimulation. When the susceptibilities of the lymphocytes to anti-RTF-induced apoptosis were measured, they correlated with the size of the RTF protein expressed. The cells were not susceptible to apoptosis when the 70-kDa RTF was present but were susceptible when the 50-kDa RTF was present. We propose that the increase in the levels of the 50-kDa RTF on cells from HIV-positive individuals is important in preventing the cell from undergoing apoptosis.
authors.affiliation: Department of Microbiology and Immunology, Finch University of Health Sciences/The Chicago Medical School, North Chicago, IL 60064, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Derks
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Beaman
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D017209:Apoptosis; D024201:Bystander Effect; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000473:pathology / Q000821:virology; D016022:Case-Control Studies; D015658:HIV Infections / Q000276:immunology / Q000473:pathology*; D006801:Humans; D008970:Molecular Weight; D013491:Suppressor Factors, Immunologic / Q000032:analysis / Q000502:physiology*; D013601:T-Lymphocytes / Q000737:chemistry / Q000473:pathology* / Q000821:virology; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
chemical_list: D013491:Suppressor Factors, Immunologic; C475700:regeneration and tolerance factor; D000255:Adenosine Triphosphate; D025262:Vacuolar Proton-Translocating ATPases