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Noncytolytic CD8+ Cell Mediated Antiviral Response Represents a Strong Element in the Immune Response of Simian Immunodeficiency Virus-Infected Long-Term Non-Progressing Rhesus Macaques.

Javed A, Leuchte N, Neumann B, Sopper S, Sauermann U - PLoS ONE (2015)

Bottom Line: Loss of this activity appeared to be due to a loss of CNAR-expressing CD8+ cells as well as a reduction of CNAR-responsive CD4+ cells.In contrast, in vitro viral replication did not differ in CD4+ cells from un-infected macaques, CNAR(+) and CNAR(-) LTNPs.CNAR appears to represent an important part of the immune response displayed by CD8+ T cells which might be underestimated up to now.

View Article: PubMed Central - PubMed

Affiliation: Atta-ur-Rahman school of Applied Biosciences(ASAB), National University of Science and Technology (NUST), Islamabad, Pakistan.

ABSTRACT
The ability of long term non progressors to maintain very low levels of HIV/SIV and a healthy state, involves various host genetic and immunological factors. CD8+ non-cytolytic antiviral response (CNAR) most likely plays an important role in this regard. In order to gain a deeper insight into this unique phenomenon, the ability of CD8+ T cells to suppress viral replication in vitro was investigated in 16 uninfected, longitudinally in 23 SIV-infected long-term non-progressing (LTNPs), and 10 SIV-infected rhesus macaques with progressing disease. An acute infection assay utilizing CD4+ cells from MHC-mismatched monkeys to avoid cytolytic responses was employed. The study has identified CNAR as a long-term stable activity that inversely correlated with plasma viral load. The activity was also detected in CD8+ cells of uninfected macaques, which indicates that CNAR is not necessarily a virus specific response but increases after SIV-infection. Physical contact between CD4+ and CD8+ cells was mainly involved in mediating viral inhibition. Loss of this activity appeared to be due to a loss of CNAR-expressing CD8+ cells as well as a reduction of CNAR-responsive CD4+ cells. In contrast, in vitro viral replication did not differ in CD4+ cells from un-infected macaques, CNAR(+) and CNAR(-) LTNPs. A role for transitional memory cells in supporting CNAR in the macaque model of AIDS was questionable. CNAR appears to represent an important part of the immune response displayed by CD8+ T cells which might be underestimated up to now.

No MeSH data available.


Related in: MedlinePlus

CNAR is strongest in LTNPs and correlates inversely with viral load.(A) CNAR was significantly stronger in SIV-infected LTNPs compared to uninfected macaques and progressors. Viral inhibition was tested with CD8+ cells from 15 aviremic and 11 viremic (geometric mean: 1780 viral RNA copies/ml plasma) long-term non-progressing macaques (LTNPs), 16 uninfected macaques and 10 SIV-infected macaques with progressing disease (geometric mean: 2.41E+04 viral RNA copies/ml plasma). Each dot represents the median of up to 10 viral inhibition tests performed with CD8+ cells from one macaque (mean number of tests per animal: 3.3, STABW = 2.4). Significance (nonparametric Kruskal Wallis test followed by Dunn's test for multiple comparison) is indicated by asterisks (*: p<0.05, **: p<0.01, ***: p<0.001). Median is indicated. (B) CNAR correlated inversely with plasma viral load. Fold viral inhibition (log) was assessed in 70 assays, each performed in triplicate, with CD8+ cells from in total 11 viremic LTNPs and 10 progressors (mean number of assays per animal = 3.3, STABW = 2.8) and correlated significantly with plasma viral load (spearman rank order correlation, p<0.0001, rs = -0.51). Data were taken from S2 and S3 Tables.
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pone.0142086.g001: CNAR is strongest in LTNPs and correlates inversely with viral load.(A) CNAR was significantly stronger in SIV-infected LTNPs compared to uninfected macaques and progressors. Viral inhibition was tested with CD8+ cells from 15 aviremic and 11 viremic (geometric mean: 1780 viral RNA copies/ml plasma) long-term non-progressing macaques (LTNPs), 16 uninfected macaques and 10 SIV-infected macaques with progressing disease (geometric mean: 2.41E+04 viral RNA copies/ml plasma). Each dot represents the median of up to 10 viral inhibition tests performed with CD8+ cells from one macaque (mean number of tests per animal: 3.3, STABW = 2.4). Significance (nonparametric Kruskal Wallis test followed by Dunn's test for multiple comparison) is indicated by asterisks (*: p<0.05, **: p<0.01, ***: p<0.001). Median is indicated. (B) CNAR correlated inversely with plasma viral load. Fold viral inhibition (log) was assessed in 70 assays, each performed in triplicate, with CD8+ cells from in total 11 viremic LTNPs and 10 progressors (mean number of assays per animal = 3.3, STABW = 2.8) and correlated significantly with plasma viral load (spearman rank order correlation, p<0.0001, rs = -0.51). Data were taken from S2 and S3 Tables.

Mentions: CD8+ cells from 19 of 23 LTNPs displayed CNAR and inhibited in vitro viral replication 50 to 60.000fold at seventh day post in vitro infection (S2 Table). Aviremic LTNPs (elite controller) displayed higher CNAR than viremic LTNPs (median: 324 vs. 150fold inhibition, p = 0.05, Mann Whitney U test, Fig 1A). Note, that one viremic LTNP displaying high CNAR showed only sporadic low level of virus replication (M2153, Fig 2D). Both viremic as well as aviremic LTNPs displayed significant CNAR as compared to uninfected macaques and progressors (p<0.002; significant for multiple testing, Kruskal Wallis and Dunn's multiple comparison test, Fig 1A). Moreover, CNAR correlated inversely with plasma viral load (spearman rank correlation: p<0.0001, r = -0.51, Fig 1B). Long-term measurements were performed in 11 macaques that had plasma viral RNA copy numbers around the detection limit at the start of study (Figs 2A–2F and 3A–3E). In most aviremic animals CNAR was a stable characteristic of CD8+ cells over years albeit the extent of the activity could vary by 2 to 3 logs (Fig 2A–2F). Only one macaque suppressed viral replication below the detection limit for seven years, but displayed CNAR (fold inhibition ≥50) only in two out of five assays performed at three different time points (M2284).


Noncytolytic CD8+ Cell Mediated Antiviral Response Represents a Strong Element in the Immune Response of Simian Immunodeficiency Virus-Infected Long-Term Non-Progressing Rhesus Macaques.

Javed A, Leuchte N, Neumann B, Sopper S, Sauermann U - PLoS ONE (2015)

CNAR is strongest in LTNPs and correlates inversely with viral load.(A) CNAR was significantly stronger in SIV-infected LTNPs compared to uninfected macaques and progressors. Viral inhibition was tested with CD8+ cells from 15 aviremic and 11 viremic (geometric mean: 1780 viral RNA copies/ml plasma) long-term non-progressing macaques (LTNPs), 16 uninfected macaques and 10 SIV-infected macaques with progressing disease (geometric mean: 2.41E+04 viral RNA copies/ml plasma). Each dot represents the median of up to 10 viral inhibition tests performed with CD8+ cells from one macaque (mean number of tests per animal: 3.3, STABW = 2.4). Significance (nonparametric Kruskal Wallis test followed by Dunn's test for multiple comparison) is indicated by asterisks (*: p<0.05, **: p<0.01, ***: p<0.001). Median is indicated. (B) CNAR correlated inversely with plasma viral load. Fold viral inhibition (log) was assessed in 70 assays, each performed in triplicate, with CD8+ cells from in total 11 viremic LTNPs and 10 progressors (mean number of assays per animal = 3.3, STABW = 2.8) and correlated significantly with plasma viral load (spearman rank order correlation, p<0.0001, rs = -0.51). Data were taken from S2 and S3 Tables.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4638345&req=5

pone.0142086.g001: CNAR is strongest in LTNPs and correlates inversely with viral load.(A) CNAR was significantly stronger in SIV-infected LTNPs compared to uninfected macaques and progressors. Viral inhibition was tested with CD8+ cells from 15 aviremic and 11 viremic (geometric mean: 1780 viral RNA copies/ml plasma) long-term non-progressing macaques (LTNPs), 16 uninfected macaques and 10 SIV-infected macaques with progressing disease (geometric mean: 2.41E+04 viral RNA copies/ml plasma). Each dot represents the median of up to 10 viral inhibition tests performed with CD8+ cells from one macaque (mean number of tests per animal: 3.3, STABW = 2.4). Significance (nonparametric Kruskal Wallis test followed by Dunn's test for multiple comparison) is indicated by asterisks (*: p<0.05, **: p<0.01, ***: p<0.001). Median is indicated. (B) CNAR correlated inversely with plasma viral load. Fold viral inhibition (log) was assessed in 70 assays, each performed in triplicate, with CD8+ cells from in total 11 viremic LTNPs and 10 progressors (mean number of assays per animal = 3.3, STABW = 2.8) and correlated significantly with plasma viral load (spearman rank order correlation, p<0.0001, rs = -0.51). Data were taken from S2 and S3 Tables.
Mentions: CD8+ cells from 19 of 23 LTNPs displayed CNAR and inhibited in vitro viral replication 50 to 60.000fold at seventh day post in vitro infection (S2 Table). Aviremic LTNPs (elite controller) displayed higher CNAR than viremic LTNPs (median: 324 vs. 150fold inhibition, p = 0.05, Mann Whitney U test, Fig 1A). Note, that one viremic LTNP displaying high CNAR showed only sporadic low level of virus replication (M2153, Fig 2D). Both viremic as well as aviremic LTNPs displayed significant CNAR as compared to uninfected macaques and progressors (p<0.002; significant for multiple testing, Kruskal Wallis and Dunn's multiple comparison test, Fig 1A). Moreover, CNAR correlated inversely with plasma viral load (spearman rank correlation: p<0.0001, r = -0.51, Fig 1B). Long-term measurements were performed in 11 macaques that had plasma viral RNA copy numbers around the detection limit at the start of study (Figs 2A–2F and 3A–3E). In most aviremic animals CNAR was a stable characteristic of CD8+ cells over years albeit the extent of the activity could vary by 2 to 3 logs (Fig 2A–2F). Only one macaque suppressed viral replication below the detection limit for seven years, but displayed CNAR (fold inhibition ≥50) only in two out of five assays performed at three different time points (M2284).

Bottom Line: Loss of this activity appeared to be due to a loss of CNAR-expressing CD8+ cells as well as a reduction of CNAR-responsive CD4+ cells.In contrast, in vitro viral replication did not differ in CD4+ cells from un-infected macaques, CNAR(+) and CNAR(-) LTNPs.CNAR appears to represent an important part of the immune response displayed by CD8+ T cells which might be underestimated up to now.

View Article: PubMed Central - PubMed

Affiliation: Atta-ur-Rahman school of Applied Biosciences(ASAB), National University of Science and Technology (NUST), Islamabad, Pakistan.

ABSTRACT
The ability of long term non progressors to maintain very low levels of HIV/SIV and a healthy state, involves various host genetic and immunological factors. CD8+ non-cytolytic antiviral response (CNAR) most likely plays an important role in this regard. In order to gain a deeper insight into this unique phenomenon, the ability of CD8+ T cells to suppress viral replication in vitro was investigated in 16 uninfected, longitudinally in 23 SIV-infected long-term non-progressing (LTNPs), and 10 SIV-infected rhesus macaques with progressing disease. An acute infection assay utilizing CD4+ cells from MHC-mismatched monkeys to avoid cytolytic responses was employed. The study has identified CNAR as a long-term stable activity that inversely correlated with plasma viral load. The activity was also detected in CD8+ cells of uninfected macaques, which indicates that CNAR is not necessarily a virus specific response but increases after SIV-infection. Physical contact between CD4+ and CD8+ cells was mainly involved in mediating viral inhibition. Loss of this activity appeared to be due to a loss of CNAR-expressing CD8+ cells as well as a reduction of CNAR-responsive CD4+ cells. In contrast, in vitro viral replication did not differ in CD4+ cells from un-infected macaques, CNAR(+) and CNAR(-) LTNPs. A role for transitional memory cells in supporting CNAR in the macaque model of AIDS was questionable. CNAR appears to represent an important part of the immune response displayed by CD8+ T cells which might be underestimated up to now.

No MeSH data available.


Related in: MedlinePlus