Shortened telomeres in the expanded CD28-CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis.
OBJECTIVE
To test the hypothesis that the expanded population of non-proliferative CD28-CD8+ T cells in HIV disease have shortened telomeres, thereby providing evidence that increased rounds of CD8+ cell division occur during HIV disease, possibly leading to replicative senescence and exhaustion of CD8+ T-cell responses.


METHODS
CD8+ cells play a central role in control of HIV infection. In late HIV disease, an expanded population of CD28-CD8+ cells with reduced proliferative potential has been documented. A similar population of CD28-CD8+ cells has been identified in ageing humans, where telomere length measurements have suggested that these cells have reached the irreversible state of replicative senescence.


METHODS
CD8+ cells from HIV-infected and control subjects were sorted by flow cytometry into CD28+ and CD28- fractions. Telomere lengths were determined as mean terminal restriction fragment (TRF) lengths by Southern hybridization.


RESULTS
The TRF lengths of sorted CD28-CD8+ cells in HIV-infected subjects ranged between 5 and 7 kilobases (kb) and were significantly shorter than TRF lengths of CD28-CD8+ cells in uninfected subjects (P = 0.003). The TRF length in CD28-CD8+ cells from HIV-infected subjects was the same as that observed for centenarian peripheral blood mononuclear cells and is compatible with a state of replicative senescence.


CONCLUSIONS
The shortened telomeres in the CD28-CD8+ cells in HIV-infected subjects and the poor proliferative potential of these cells identifies CD8+ cell replicative senescence as a newly described feature of HIV disease. Our results provide a mechanism for the loss of CD8+ cell control of viral replication that accompanies advanced HIV disease. Replicative senescence may contribute to exhaustion of the T-cell response as a result of chronic HIV disease. Whether this phenomenon occurs in other chronic viral infections is unknown.
Effros
R B
RB
Department of Pathology and Laboratory Medicine, University of California Los Angeles (UCLA) School of Medicine 90095-1745, USA.
Allsopp
R
R
Chiu
C P
CP
Hausner
M A
MA
Hirji
K
K
Wang
L
L
Harley
C B
CB
Villeponteau
B
B
West
M D
MD
Giorgi
J V
JV
D018106:CD28 Antigens / Q000032:analysis*; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000166:cytology / Q000276:immunology*; D002455:Cell Division; D016922:Cellular Senescence; D004247:DNA / Q000032:analysis; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D008970:Molecular Weight; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D016615:Telomere / Q000737:chemistry / Q000235:genetics*
D018106:CD28 Antigens; D004247:DNA