Limits...
CD8+ lymphocytes control viral replication in SIVmac239-infected rhesus macaques without decreasing the lifespan of productively infected cells.

Klatt NR, Shudo E, Ortiz AM, Engram JC, Paiardini M, Lawson B, Miller MD, Else J, Pandrea I, Estes JD, Apetrei C, Schmitz JE, Ribeiro RM, Perelson AS, Silvestri G - PLoS Pathog. (2010)

Bottom Line: While CD8+ T cells are clearly important in controlling virus replication during HIV and SIV infections, the mechanisms underlying this antiviral effect remain poorly understood.In this study, we assessed the in vivo effect of CD8+ lymphocyte depletion on the lifespan of productively infected cells during chronic SIVmac239 infection of rhesus macaques.This result indicates that the presence of CD8+ lymphocytes does not result in a noticeably shorter lifespan of productively SIV-infected cells, and thus that direct cell killing is unlikely to be the main mechanism underlying the antiviral effect of CD8+ T cells in SIV-infected macaques with high virus replication.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
While CD8+ T cells are clearly important in controlling virus replication during HIV and SIV infections, the mechanisms underlying this antiviral effect remain poorly understood. In this study, we assessed the in vivo effect of CD8+ lymphocyte depletion on the lifespan of productively infected cells during chronic SIVmac239 infection of rhesus macaques. We treated two groups of animals that were either CD8+ lymphocyte-depleted or controls with antiretroviral therapy, and used mathematical modeling to assess the lifespan of infected cells either in the presence or absence of CD8+ lymphocytes. We found that, in both early (day 57 post-SIV) and late (day 177 post-SIV) chronic SIV infection, depletion of CD8+ lymphocytes did not result in a measurable increase in the lifespan of either short- or long-lived productively infected cells in vivo. This result indicates that the presence of CD8+ lymphocytes does not result in a noticeably shorter lifespan of productively SIV-infected cells, and thus that direct cell killing is unlikely to be the main mechanism underlying the antiviral effect of CD8+ T cells in SIV-infected macaques with high virus replication.

Show MeSH

Related in: MedlinePlus

CD8+ lymphocyte depletion results in a rise in activated CD4+ T cells.(A) Longitudinal assessment (individual animals from CD8-depleted group and mean and s.d. from control group) of the percent of CD4+CCR5+ (top left), CD4+Ki67+ (top right), CD4+HLA-DR+ (bottom left), and CD4+CD69+ (bottom right) T cells during early chronic infection. (B) Longitudinal assessment of the mean (and s.d.) percent of CD4+Ki67+ T cells in rectal biopsies (left) and bronchoalveolar lavage (right).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2813271&req=5

ppat-1000747-g007: CD8+ lymphocyte depletion results in a rise in activated CD4+ T cells.(A) Longitudinal assessment (individual animals from CD8-depleted group and mean and s.d. from control group) of the percent of CD4+CCR5+ (top left), CD4+Ki67+ (top right), CD4+HLA-DR+ (bottom left), and CD4+CD69+ (bottom right) T cells during early chronic infection. (B) Longitudinal assessment of the mean (and s.d.) percent of CD4+Ki67+ T cells in rectal biopsies (left) and bronchoalveolar lavage (right).

Mentions: The finding that CD8+ lymphocyte depletion does not result in a prolonged lifespan of productively infected cells is also consistent with the possibility that the observed increase in virus replication is caused, at least in part, by increased CD4+ T cell activation, which would result in an increased availability of target cells for SIV infection. Several factors may be involved in this CD4+ T cell activation, including homeostatic responses to lymphopenia, increased availability of CD4+ T cell tropic and/or pro-inflammatory cytokines, reactivation of latent virus infections, and other potential changes in the lymphoid microenvironment(s). To address this possibility, we measured the expression of activation and proliferation markers in CD4+ T cells before and after CD8+ lymphocyte depletion. As shown in Figure 7, we found that CD8+ lymphocyte depletion was followed by a marked increase in CD4+ T cell activation that occurred in all examined tissues. In peripheral blood, the peak of CD4+ T cell activation occurred at day 15 post-depletion, and most activation did not increase at all until day 8. On average at peak activation, the fraction of CD4+Ki67+ T cells was 6.7 fold higher than baseline levels, the fraction of CD4+CCR5+ T cells was 6.2 fold higher than baseline, the fraction of CD4+HLA-DR+ T cells was 19.2 fold higher than baseline, and the fraction of CD4+CD69+ T cells was 10.6 fold higher than baseline levels (Figure 7A). The kinetics of CD4+ T cell activation was also delayed in mucosal tissues, although it should be noted that the relative infrequent sampling schedule raises the possibility that we missed the peak of CD4+ T cell activation in these tissues. In rectal biopsies, during early chronic infection, the fraction of CD4+Ki67+ T cells was 1.4 fold higher than baseline levels at day 6 post-depletion and 1.8 fold higher than baseline levels at day 13 post-depletion (Figure 7B, left). Similarly, during late chronic infection, CD4+Ki67+ T cells were 0.9 fold higher than baseline at day 5 post-depletion, and 1.2 fold higher than baseline levels at day 12 post-depletion (data not shown). The same trend was observed in bronchoalveolar lavage, where CD4+Ki67+ T cells were 0.7 fold higher than baseline at day 6 post-depletion, and 1.5 fold higher at day 13 post-depletion (Figure 7B, right). Importantly, the observed changes in CD4+ T cell activation followed, rather than preceded, the increase in plasma viral load, thus suggesting that the activation of CD4+ T cells that occurs after CD8+ lymphocyte depletion is unlikely to be the predominant source of the increased viremia. As such, these data support a model in which CD8+ T cells play a key, direct role in maintaining the steady state of viral load during chronic SIV infection.


CD8+ lymphocytes control viral replication in SIVmac239-infected rhesus macaques without decreasing the lifespan of productively infected cells.

Klatt NR, Shudo E, Ortiz AM, Engram JC, Paiardini M, Lawson B, Miller MD, Else J, Pandrea I, Estes JD, Apetrei C, Schmitz JE, Ribeiro RM, Perelson AS, Silvestri G - PLoS Pathog. (2010)

CD8+ lymphocyte depletion results in a rise in activated CD4+ T cells.(A) Longitudinal assessment (individual animals from CD8-depleted group and mean and s.d. from control group) of the percent of CD4+CCR5+ (top left), CD4+Ki67+ (top right), CD4+HLA-DR+ (bottom left), and CD4+CD69+ (bottom right) T cells during early chronic infection. (B) Longitudinal assessment of the mean (and s.d.) percent of CD4+Ki67+ T cells in rectal biopsies (left) and bronchoalveolar lavage (right).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2813271&req=5

ppat-1000747-g007: CD8+ lymphocyte depletion results in a rise in activated CD4+ T cells.(A) Longitudinal assessment (individual animals from CD8-depleted group and mean and s.d. from control group) of the percent of CD4+CCR5+ (top left), CD4+Ki67+ (top right), CD4+HLA-DR+ (bottom left), and CD4+CD69+ (bottom right) T cells during early chronic infection. (B) Longitudinal assessment of the mean (and s.d.) percent of CD4+Ki67+ T cells in rectal biopsies (left) and bronchoalveolar lavage (right).
Mentions: The finding that CD8+ lymphocyte depletion does not result in a prolonged lifespan of productively infected cells is also consistent with the possibility that the observed increase in virus replication is caused, at least in part, by increased CD4+ T cell activation, which would result in an increased availability of target cells for SIV infection. Several factors may be involved in this CD4+ T cell activation, including homeostatic responses to lymphopenia, increased availability of CD4+ T cell tropic and/or pro-inflammatory cytokines, reactivation of latent virus infections, and other potential changes in the lymphoid microenvironment(s). To address this possibility, we measured the expression of activation and proliferation markers in CD4+ T cells before and after CD8+ lymphocyte depletion. As shown in Figure 7, we found that CD8+ lymphocyte depletion was followed by a marked increase in CD4+ T cell activation that occurred in all examined tissues. In peripheral blood, the peak of CD4+ T cell activation occurred at day 15 post-depletion, and most activation did not increase at all until day 8. On average at peak activation, the fraction of CD4+Ki67+ T cells was 6.7 fold higher than baseline levels, the fraction of CD4+CCR5+ T cells was 6.2 fold higher than baseline, the fraction of CD4+HLA-DR+ T cells was 19.2 fold higher than baseline, and the fraction of CD4+CD69+ T cells was 10.6 fold higher than baseline levels (Figure 7A). The kinetics of CD4+ T cell activation was also delayed in mucosal tissues, although it should be noted that the relative infrequent sampling schedule raises the possibility that we missed the peak of CD4+ T cell activation in these tissues. In rectal biopsies, during early chronic infection, the fraction of CD4+Ki67+ T cells was 1.4 fold higher than baseline levels at day 6 post-depletion and 1.8 fold higher than baseline levels at day 13 post-depletion (Figure 7B, left). Similarly, during late chronic infection, CD4+Ki67+ T cells were 0.9 fold higher than baseline at day 5 post-depletion, and 1.2 fold higher than baseline levels at day 12 post-depletion (data not shown). The same trend was observed in bronchoalveolar lavage, where CD4+Ki67+ T cells were 0.7 fold higher than baseline at day 6 post-depletion, and 1.5 fold higher at day 13 post-depletion (Figure 7B, right). Importantly, the observed changes in CD4+ T cell activation followed, rather than preceded, the increase in plasma viral load, thus suggesting that the activation of CD4+ T cells that occurs after CD8+ lymphocyte depletion is unlikely to be the predominant source of the increased viremia. As such, these data support a model in which CD8+ T cells play a key, direct role in maintaining the steady state of viral load during chronic SIV infection.

Bottom Line: While CD8+ T cells are clearly important in controlling virus replication during HIV and SIV infections, the mechanisms underlying this antiviral effect remain poorly understood.In this study, we assessed the in vivo effect of CD8+ lymphocyte depletion on the lifespan of productively infected cells during chronic SIVmac239 infection of rhesus macaques.This result indicates that the presence of CD8+ lymphocytes does not result in a noticeably shorter lifespan of productively SIV-infected cells, and thus that direct cell killing is unlikely to be the main mechanism underlying the antiviral effect of CD8+ T cells in SIV-infected macaques with high virus replication.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
While CD8+ T cells are clearly important in controlling virus replication during HIV and SIV infections, the mechanisms underlying this antiviral effect remain poorly understood. In this study, we assessed the in vivo effect of CD8+ lymphocyte depletion on the lifespan of productively infected cells during chronic SIVmac239 infection of rhesus macaques. We treated two groups of animals that were either CD8+ lymphocyte-depleted or controls with antiretroviral therapy, and used mathematical modeling to assess the lifespan of infected cells either in the presence or absence of CD8+ lymphocytes. We found that, in both early (day 57 post-SIV) and late (day 177 post-SIV) chronic SIV infection, depletion of CD8+ lymphocytes did not result in a measurable increase in the lifespan of either short- or long-lived productively infected cells in vivo. This result indicates that the presence of CD8+ lymphocytes does not result in a noticeably shorter lifespan of productively SIV-infected cells, and thus that direct cell killing is unlikely to be the main mechanism underlying the antiviral effect of CD8+ T cells in SIV-infected macaques with high virus replication.

Show MeSH
Related in: MedlinePlus