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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.

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Administration of OKT8F results in near complete depletion of CD8+ lymphocytes.(A) Representative flow cytometry plots (x-axis, CD8; y-axis, CD3) demonstrating CD8+ lymphocyte levels in blood (left, 7 days before depletion; right, 6 days after depletion). (B) Longitudinal assessment of the absolute number of CD8+ T cells in peripheral blood for each animal during early chronic phase (left) or late chronic phase (right). Each colored line indicates an individual animal (CD8+ lymphocyte-depleted). Gray lines indicate the average CD8+ T cell number in non-depleted (ART alone) RMs. Dotted vertical line indicates the first day of depleting Ab treatment, solid vertical line indicates the first day of ART. (C) Representative flow cytometry plots (x-axis, CD8; y-axis, CD3) demonstrating CD8+ lymphocyte depletion in rectal biopsies (left, 10 days before depletion; right, 6 days after depletion). (D) Longitudinal assessment of the percent of CD8+ T cells (compared to baseline) in rectal biopsies during early chronic phase (left) or late chronic phase (right). Bars represent average of treated animals. CD8+ T cells previously gated on live lymphocytes.
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ppat-1000747-g002: Administration of OKT8F results in near complete depletion of CD8+ lymphocytes.(A) Representative flow cytometry plots (x-axis, CD8; y-axis, CD3) demonstrating CD8+ lymphocyte levels in blood (left, 7 days before depletion; right, 6 days after depletion). (B) Longitudinal assessment of the absolute number of CD8+ T cells in peripheral blood for each animal during early chronic phase (left) or late chronic phase (right). Each colored line indicates an individual animal (CD8+ lymphocyte-depleted). Gray lines indicate the average CD8+ T cell number in non-depleted (ART alone) RMs. Dotted vertical line indicates the first day of depleting Ab treatment, solid vertical line indicates the first day of ART. (C) Representative flow cytometry plots (x-axis, CD8; y-axis, CD3) demonstrating CD8+ lymphocyte depletion in rectal biopsies (left, 10 days before depletion; right, 6 days after depletion). (D) Longitudinal assessment of the percent of CD8+ T cells (compared to baseline) in rectal biopsies during early chronic phase (left) or late chronic phase (right). Bars represent average of treated animals. CD8+ T cells previously gated on live lymphocytes.

Mentions: As expected based on our previous experience with the use of the OKT8F monoclonal antibody [31] (Engram, J. C. and Silvestri G., unpublished observations), all RMs treated with this antibody showed a very rapid and near complete depletion of CD8+ lymphocytes from both peripheral and mucosal tissues. During the first phase of this experiment (early chronic infection, i.e., day 57 post-inoculation), in group A animals, CD8+ T cells were depleted by an average of 99.97% (±0.01 s.d.) in peripheral blood (Figure 2A, 2B), 99.29% (±0.50 s.d.) in rectal biopsies (Figure 2C, 2D), and 99.23% (±1.07 s.d.) in bronchoalveolar lavage (data not shown) as measured by flow cytometry. During the second phase of this experiment (late chronic infection, i.e., day 177 post inoculation), in group B animals, CD8+ T cells were depleted by an average of 99.95% (±0.03 s.d.) in peripheral blood (Figure 2B) and 98.07% (±1.54 s.d.) in rectal biopsies (Figure 2D) as measured by flow cytometry. Extent of depletion in mucosal tissues was corrected for non-CD8+ T cell fluctuations (as described in [32]). In all cases, and consistent with previous studies [18], CD8+ T cells were depleted very rapidly (>98% depletion after 24 hours) and CD8+ T cell depletion was sustained for 8–13 days with nadir depletion occurring between 5-6 days after the first infusion. Of note, the OKT8F Ab induced a loss of both CD3+CD8+ cells as well as CD3−CD8+ cells, thus indicating that not only CD8+ T cells, but also NK cells, NKT cells, and TCRγδ T cells that express CD8 are also efficiently depleted in this experimental setting. Similar to previous studies in which CD8+ T cells were depleted during pathogenic SIV infection [17],[18],[19],[20], we observed an increase in viremia between 0.7–2.2 logs (Figure 3).


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)

Administration of OKT8F results in near complete depletion of CD8+ lymphocytes.(A) Representative flow cytometry plots (x-axis, CD8; y-axis, CD3) demonstrating CD8+ lymphocyte levels in blood (left, 7 days before depletion; right, 6 days after depletion). (B) Longitudinal assessment of the absolute number of CD8+ T cells in peripheral blood for each animal during early chronic phase (left) or late chronic phase (right). Each colored line indicates an individual animal (CD8+ lymphocyte-depleted). Gray lines indicate the average CD8+ T cell number in non-depleted (ART alone) RMs. Dotted vertical line indicates the first day of depleting Ab treatment, solid vertical line indicates the first day of ART. (C) Representative flow cytometry plots (x-axis, CD8; y-axis, CD3) demonstrating CD8+ lymphocyte depletion in rectal biopsies (left, 10 days before depletion; right, 6 days after depletion). (D) Longitudinal assessment of the percent of CD8+ T cells (compared to baseline) in rectal biopsies during early chronic phase (left) or late chronic phase (right). Bars represent average of treated animals. CD8+ T cells previously gated on live lymphocytes.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2813271&req=5

ppat-1000747-g002: Administration of OKT8F results in near complete depletion of CD8+ lymphocytes.(A) Representative flow cytometry plots (x-axis, CD8; y-axis, CD3) demonstrating CD8+ lymphocyte levels in blood (left, 7 days before depletion; right, 6 days after depletion). (B) Longitudinal assessment of the absolute number of CD8+ T cells in peripheral blood for each animal during early chronic phase (left) or late chronic phase (right). Each colored line indicates an individual animal (CD8+ lymphocyte-depleted). Gray lines indicate the average CD8+ T cell number in non-depleted (ART alone) RMs. Dotted vertical line indicates the first day of depleting Ab treatment, solid vertical line indicates the first day of ART. (C) Representative flow cytometry plots (x-axis, CD8; y-axis, CD3) demonstrating CD8+ lymphocyte depletion in rectal biopsies (left, 10 days before depletion; right, 6 days after depletion). (D) Longitudinal assessment of the percent of CD8+ T cells (compared to baseline) in rectal biopsies during early chronic phase (left) or late chronic phase (right). Bars represent average of treated animals. CD8+ T cells previously gated on live lymphocytes.
Mentions: As expected based on our previous experience with the use of the OKT8F monoclonal antibody [31] (Engram, J. C. and Silvestri G., unpublished observations), all RMs treated with this antibody showed a very rapid and near complete depletion of CD8+ lymphocytes from both peripheral and mucosal tissues. During the first phase of this experiment (early chronic infection, i.e., day 57 post-inoculation), in group A animals, CD8+ T cells were depleted by an average of 99.97% (±0.01 s.d.) in peripheral blood (Figure 2A, 2B), 99.29% (±0.50 s.d.) in rectal biopsies (Figure 2C, 2D), and 99.23% (±1.07 s.d.) in bronchoalveolar lavage (data not shown) as measured by flow cytometry. During the second phase of this experiment (late chronic infection, i.e., day 177 post inoculation), in group B animals, CD8+ T cells were depleted by an average of 99.95% (±0.03 s.d.) in peripheral blood (Figure 2B) and 98.07% (±1.54 s.d.) in rectal biopsies (Figure 2D) as measured by flow cytometry. Extent of depletion in mucosal tissues was corrected for non-CD8+ T cell fluctuations (as described in [32]). In all cases, and consistent with previous studies [18], CD8+ T cells were depleted very rapidly (>98% depletion after 24 hours) and CD8+ T cell depletion was sustained for 8–13 days with nadir depletion occurring between 5-6 days after the first infusion. Of note, the OKT8F Ab induced a loss of both CD3+CD8+ cells as well as CD3−CD8+ cells, thus indicating that not only CD8+ T cells, but also NK cells, NKT cells, and TCRγδ T cells that express CD8 are also efficiently depleted in this experimental setting. Similar to previous studies in which CD8+ T cells were depleted during pathogenic SIV infection [17],[18],[19],[20], we observed an increase in viremia between 0.7–2.2 logs (Figure 3).

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