Accelerated replicative senescence of the peripheral immune system induced by HIV infection.
OBJECTIVE
HIV induces rapid turnover of T lymphocytes but whether this leads to replicative senescence of CD4+ and CD8+ cells and contributes to AIDS symptoms is unclear. The aim of this study was to address this question by analyzing telomere length in blood cell populations as a measure of replicative history in a significant number of patients infected with HIV.


METHODS
Total peripheral blood mononuclear cells (PBMCs), CD4+ or CD8+ cells were isolated from blood collected from a total of 73 HIV patients and 27 controls. Samples were isolated to measure telomere length, telomerase activity and proliferative ability, and analyses were carried out in a blind experimental protocol.


METHODS
PBMCs isolated on Ficoll-Hypaque gradients were washed and prepared for additional fractionation into CD4+ and CD8+ cells using antibody-bound magnetic beads. Total PBMCs, CD4+ and CD8+ cells were used for cell cycle analysis, for telomerase activity assays and were measured for telomere length using the terminal restriction fragment assay.


RESULTS
Telomere analyses in this study show a clear (P < 0.0001) inverse relationship between telomere length and progression of immunosuppression, with HIV infection resulting in a five-fold or greater acceleration of aging of the circulating PBMC component of the immune system. Patients who are 37 years old showed telomere lengths similar to uninfected 75-year-olds. Telomere loss correlated well with progression of AIDS and with reduced proliferative ability of patient PBMCs but was unrelated to telomerase activity. Mean telomere length was shorter in both CD4+ and CD8+ cells, with three-fold higher rates of telomere loss for CD8+ lymphocytes.


CONCLUSIONS
These data provide strong support for the occurrence of accelerated replicative aging of the peripheral immune system, possibly resulting in a loss of T cells leading to AIDS symptoms.
Bestilny
L J
LJ
Department of Medical Biochemistry and Oncology, The University of Calgary Health Sciences Centre, Alberta, Canada.
Gill
M J
MJ
Mody
C H
CH
Riabowol
K T
KT
D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D007231:Infant, Newborn; D007963:Leukocytes, Mononuclear / Q000473:pathology / Q000502:physiology*; D008213:Lymphocyte Activation / Q000502:physiology*; D008875:Middle Aged; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000502:physiology
D019098:Telomerase