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Telomere length, telomerase activity, and replicative potential in HIV infection: analysis of CD4+ and CD8+ T cells from HIV-discordant monozygotic twins.

Palmer LD, Weng N, Levine BL, June CH, Lane HC, Hodes RJ - J. Exp. Med. (1997)

Bottom Line: Genetic and age-specific effects on these parameters were controlled by studying HIV-discordant pairs of monozygotic twins.Telomere terminal restriction fragment (TRF) lengths from CD4+ T cells of HIV+ donors were significantly greater than those from HIV- twins.These results suggest that HIV infection is associated with alterations in the population dynamics of both CD4+ and CD8+ T cells, but fail to provide evidence for clonal exhaustion or replicative senescence as a mechanism underlying the decline in CD4+ T cells of HIV-infected donors.

View Article: PubMed Central - PubMed

Affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT
To address the possible role of replicative senescence in human immunodeficiency virus (HIV) infection, telomere length, telomerase activity, and in vitro replicative capacity were assessed in peripheral blood T cells from HIV+ and HIV- donors. Genetic and age-specific effects on these parameters were controlled by studying HIV-discordant pairs of monozygotic twins. Telomere terminal restriction fragment (TRF) lengths from CD4+ T cells of HIV+ donors were significantly greater than those from HIV- twins. In contrast, telomere lengths in CD8+ T cells from HIV+ donors were shorter than in HIV- donors. The in vitro replicative capacity of CD4+ cells from HIV+ donors was equivalent to that of HIV- donors in response to stimulation through T cell receptor CD3 and CD28. Little or no telomerase activity was detected in freshly isolated CD4+ or CD8+ lymphocytes from HIV+ or HIV- donors, but was induced by in vitro stimulation of both HIV+ and HIV- donor cells. These results suggest that HIV infection is associated with alterations in the population dynamics of both CD4+ and CD8+ T cells, but fail to provide evidence for clonal exhaustion or replicative senescence as a mechanism underlying the decline in CD4+ T cells of HIV-infected donors.

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Telomere length in CD4+ and CD8+ T cells from HIV-positive and -negative twins. TRF analysis was carried out as described in  Fig. 1, and mean TRF length calculated. (A) TRF length is shown for  CD4+ T cells from HIV-negative (stippled bars) and HIV-positive (closed  bars) twin donors. (B) TRF length is shown for CD8+ T cells from HIVnegative (stippled bars) and HIV-positive (closed bars) twin donors. (C) The  difference in TRF length for HIV-positive and HIV-negative twin donors is shown for CD4+ (closed bar) and CD8+ (stippled bar) T cells. Positive values indicate TRF length that is greater in the HIV-positive twin, and  negative values indicate TRF length that is greater in the HIV-negative  twin.
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Figure 2: Telomere length in CD4+ and CD8+ T cells from HIV-positive and -negative twins. TRF analysis was carried out as described in Fig. 1, and mean TRF length calculated. (A) TRF length is shown for CD4+ T cells from HIV-negative (stippled bars) and HIV-positive (closed bars) twin donors. (B) TRF length is shown for CD8+ T cells from HIVnegative (stippled bars) and HIV-positive (closed bars) twin donors. (C) The difference in TRF length for HIV-positive and HIV-negative twin donors is shown for CD4+ (closed bar) and CD8+ (stippled bar) T cells. Positive values indicate TRF length that is greater in the HIV-positive twin, and negative values indicate TRF length that is greater in the HIV-negative twin.

Mentions: If, as has been suggested (14, 15), peripheral blood CD4+ cells from HIV-positive donors undergo increased cell division, this difference might be reflected in shortening of telomeres from infected donors when compared with uninfected twins. Representative telomere terminal restriction fragment (TRF) length analysis of CD4+ and CD8+ T cells from HIV-positive and negative monozygotic twins is presented in Fig. 1. When comparisons of mean TRF length were made within each twin pair, it was observed that TRF length in CD4+ cells on average was significantly greater in the infected than in the uninfected twins (mean difference 1.2 ± 0.4 kb) (Fig. 2, A and C). When TRF length was analyzed in CD8+ populations from HIV-discordant twins, the opposite pattern was observed, with TRF length in CD8+ cells shorter in HIV-infected twins than in uninfected twins (mean difference 1.1 ± 0.3 kb) (Fig. 2, B and C). In HIV-uninfected donors, TRF length in CD8+ T cells tended to be longer than in CD4+ cells from the same individual (mean difference 1.2 ± 0.7 kb); whereas in HIV-infected twins, TRF length was greater in CD4+ cells (mean difference 0.9 ± 0.4 kb).


Telomere length, telomerase activity, and replicative potential in HIV infection: analysis of CD4+ and CD8+ T cells from HIV-discordant monozygotic twins.

Palmer LD, Weng N, Levine BL, June CH, Lane HC, Hodes RJ - J. Exp. Med. (1997)

Telomere length in CD4+ and CD8+ T cells from HIV-positive and -negative twins. TRF analysis was carried out as described in  Fig. 1, and mean TRF length calculated. (A) TRF length is shown for  CD4+ T cells from HIV-negative (stippled bars) and HIV-positive (closed  bars) twin donors. (B) TRF length is shown for CD8+ T cells from HIVnegative (stippled bars) and HIV-positive (closed bars) twin donors. (C) The  difference in TRF length for HIV-positive and HIV-negative twin donors is shown for CD4+ (closed bar) and CD8+ (stippled bar) T cells. Positive values indicate TRF length that is greater in the HIV-positive twin, and  negative values indicate TRF length that is greater in the HIV-negative  twin.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196247&req=5

Figure 2: Telomere length in CD4+ and CD8+ T cells from HIV-positive and -negative twins. TRF analysis was carried out as described in Fig. 1, and mean TRF length calculated. (A) TRF length is shown for CD4+ T cells from HIV-negative (stippled bars) and HIV-positive (closed bars) twin donors. (B) TRF length is shown for CD8+ T cells from HIVnegative (stippled bars) and HIV-positive (closed bars) twin donors. (C) The difference in TRF length for HIV-positive and HIV-negative twin donors is shown for CD4+ (closed bar) and CD8+ (stippled bar) T cells. Positive values indicate TRF length that is greater in the HIV-positive twin, and negative values indicate TRF length that is greater in the HIV-negative twin.
Mentions: If, as has been suggested (14, 15), peripheral blood CD4+ cells from HIV-positive donors undergo increased cell division, this difference might be reflected in shortening of telomeres from infected donors when compared with uninfected twins. Representative telomere terminal restriction fragment (TRF) length analysis of CD4+ and CD8+ T cells from HIV-positive and negative monozygotic twins is presented in Fig. 1. When comparisons of mean TRF length were made within each twin pair, it was observed that TRF length in CD4+ cells on average was significantly greater in the infected than in the uninfected twins (mean difference 1.2 ± 0.4 kb) (Fig. 2, A and C). When TRF length was analyzed in CD8+ populations from HIV-discordant twins, the opposite pattern was observed, with TRF length in CD8+ cells shorter in HIV-infected twins than in uninfected twins (mean difference 1.1 ± 0.3 kb) (Fig. 2, B and C). In HIV-uninfected donors, TRF length in CD8+ T cells tended to be longer than in CD4+ cells from the same individual (mean difference 1.2 ± 0.7 kb); whereas in HIV-infected twins, TRF length was greater in CD4+ cells (mean difference 0.9 ± 0.4 kb).

Bottom Line: Genetic and age-specific effects on these parameters were controlled by studying HIV-discordant pairs of monozygotic twins.Telomere terminal restriction fragment (TRF) lengths from CD4+ T cells of HIV+ donors were significantly greater than those from HIV- twins.These results suggest that HIV infection is associated with alterations in the population dynamics of both CD4+ and CD8+ T cells, but fail to provide evidence for clonal exhaustion or replicative senescence as a mechanism underlying the decline in CD4+ T cells of HIV-infected donors.

View Article: PubMed Central - PubMed

Affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT
To address the possible role of replicative senescence in human immunodeficiency virus (HIV) infection, telomere length, telomerase activity, and in vitro replicative capacity were assessed in peripheral blood T cells from HIV+ and HIV- donors. Genetic and age-specific effects on these parameters were controlled by studying HIV-discordant pairs of monozygotic twins. Telomere terminal restriction fragment (TRF) lengths from CD4+ T cells of HIV+ donors were significantly greater than those from HIV- twins. In contrast, telomere lengths in CD8+ T cells from HIV+ donors were shorter than in HIV- donors. The in vitro replicative capacity of CD4+ cells from HIV+ donors was equivalent to that of HIV- donors in response to stimulation through T cell receptor CD3 and CD28. Little or no telomerase activity was detected in freshly isolated CD4+ or CD8+ lymphocytes from HIV+ or HIV- donors, but was induced by in vitro stimulation of both HIV+ and HIV- donor cells. These results suggest that HIV infection is associated with alterations in the population dynamics of both CD4+ and CD8+ T cells, but fail to provide evidence for clonal exhaustion or replicative senescence as a mechanism underlying the decline in CD4+ T cells of HIV-infected donors.

Show MeSH
Related in: MedlinePlus