AEGiS-11IAC: Shortened telomeres in the expanded CD28-CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis.

11th International AIDS Conference

Vancouver, British Columbia — July 7-12, 1996

Shortened telomeres in the expanded CD28-CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis.

Int Conf AIDS 1996 Jul 7-12; 11:23 (abstract no. LB.A.6010)
Chiu CP, Effros RB, Allsopp R, Hausner MA, Hirji K, Wang L, Harley CB, Villeponteau B, West MD, Giorgi JV; Geron Corporation, Menlo Park, CA. Fax: (415) 473-7750. E-mail: cchiu@geron.com.

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. Design: 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 have been identified in aging 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 telomere lengths of sorted CD28-CD8+ cells in HIV-infected subjects ranged between 5-7 Kb and were significantly shorter than telomere lengths of CD28-CD8+ cells in uninfected subjects (p=0.003). The telomere length of CD28-CD8+ cells in 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 5-7 Kb length of 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.

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