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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

Frequencies of T cell populations in SIV-infected CNAR(+), CNAR(-) and uninfected macaques.(A) Frequency of CD8+PD-1+ cells (percentage of CD3+CD8+) are significantly higher in CNAR(-) LTNPs compared to CNAR(+) LTNPs and uninfected monkeys. P values (Mann Whitney U test) are shown. (B) Frequency of CD8+PD-1+ cells (percentage of CD3+CD8+) correlate with plasma SIV RNA copies in LTNPs (n = 21). Data represent the mean from three independent measurements. P value and spearman r are indicated. (C) Frequency of transitional memory cells (CD3+CD8+CD4−CD45RA−CCR7−CD27+CD28−; percentage of CD3+CD8+) are significantly higher in CNAR(-) LTNPs compared to CNAR(+) or uninfected macaques. (D) Frequencies of CD4+CD8+PD-1+ cells (percentage of CD3+CD4+CD8+) are significantly higher in SIV-infected LTNPs [CNAR(+) or CNAR(-)] compared to uninfected macaques. Results from uninfected macaques represent the mean from two independent measurements of each animal (n = 12). Data in Fig 5A, 5C and 5D from CNAR(+) (n = 11) and CNAR(-) (n = 8) macaques represent the mean of up to 3 time points, each two months apart. P values (Mann Whitney U test) are shown. Horizontal lines depict the median.
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pone.0142086.g005: Frequencies of T cell populations in SIV-infected CNAR(+), CNAR(-) and uninfected macaques.(A) Frequency of CD8+PD-1+ cells (percentage of CD3+CD8+) are significantly higher in CNAR(-) LTNPs compared to CNAR(+) LTNPs and uninfected monkeys. P values (Mann Whitney U test) are shown. (B) Frequency of CD8+PD-1+ cells (percentage of CD3+CD8+) correlate with plasma SIV RNA copies in LTNPs (n = 21). Data represent the mean from three independent measurements. P value and spearman r are indicated. (C) Frequency of transitional memory cells (CD3+CD8+CD4−CD45RA−CCR7−CD27+CD28−; percentage of CD3+CD8+) are significantly higher in CNAR(-) LTNPs compared to CNAR(+) or uninfected macaques. (D) Frequencies of CD4+CD8+PD-1+ cells (percentage of CD3+CD4+CD8+) are significantly higher in SIV-infected LTNPs [CNAR(+) or CNAR(-)] compared to uninfected macaques. Results from uninfected macaques represent the mean from two independent measurements of each animal (n = 12). Data in Fig 5A, 5C and 5D from CNAR(+) (n = 11) and CNAR(-) (n = 8) macaques represent the mean of up to 3 time points, each two months apart. P values (Mann Whitney U test) are shown. Horizontal lines depict the median.

Mentions: Since it has been reported that CNAR may be mediated by transitional memory cells and to some extent by PD-1 expressing CD8+ T cells [20], we investigated the relative frequencies of different T cell subsets in SIV-infected CNAR positive and negative as well as in uninfected macaques by flow cytometry. Data from three time points each two months apart was analyzed. CNAR was tested at least once within this time period in animals with stable plasma viral load. In animals with increasing viral load CNAR was assessed again or FACS data were excluded for analysis. Mean frequencies of naïve (CD28+ CD95−), CD4+ or CD8+ central memory (TCM, CD28high CD95+) and effector memory (TEM, CD28low/- CD95+) cells did not differ between CNAR positive or negative monkeys. However the frequency of PD-1+ CD8+ cells differed significantly between the groups (Fig 5A; S3 Fig). Similar to humans, PD-1+CD8+ cells were lowest in uninfected individuals (Fig 5A)[20]. Furthermore, PD-1+CD8+ (given as frequency of PD-1+ of CD8+) correlated with plasma viral load (rs = 0.59, p = 0.0048, Fig 5B). Since in SIV-infected macaques CNAR was strongest in aviremic LTNPs, we found no evidence that PD-1 expressing CD8+ cells contribute to viral inhibition (Fig 5B).


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)

Frequencies of T cell populations in SIV-infected CNAR(+), CNAR(-) and uninfected macaques.(A) Frequency of CD8+PD-1+ cells (percentage of CD3+CD8+) are significantly higher in CNAR(-) LTNPs compared to CNAR(+) LTNPs and uninfected monkeys. P values (Mann Whitney U test) are shown. (B) Frequency of CD8+PD-1+ cells (percentage of CD3+CD8+) correlate with plasma SIV RNA copies in LTNPs (n = 21). Data represent the mean from three independent measurements. P value and spearman r are indicated. (C) Frequency of transitional memory cells (CD3+CD8+CD4−CD45RA−CCR7−CD27+CD28−; percentage of CD3+CD8+) are significantly higher in CNAR(-) LTNPs compared to CNAR(+) or uninfected macaques. (D) Frequencies of CD4+CD8+PD-1+ cells (percentage of CD3+CD4+CD8+) are significantly higher in SIV-infected LTNPs [CNAR(+) or CNAR(-)] compared to uninfected macaques. Results from uninfected macaques represent the mean from two independent measurements of each animal (n = 12). Data in Fig 5A, 5C and 5D from CNAR(+) (n = 11) and CNAR(-) (n = 8) macaques represent the mean of up to 3 time points, each two months apart. P values (Mann Whitney U test) are shown. Horizontal lines depict the median.
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Related In: Results  -  Collection

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pone.0142086.g005: Frequencies of T cell populations in SIV-infected CNAR(+), CNAR(-) and uninfected macaques.(A) Frequency of CD8+PD-1+ cells (percentage of CD3+CD8+) are significantly higher in CNAR(-) LTNPs compared to CNAR(+) LTNPs and uninfected monkeys. P values (Mann Whitney U test) are shown. (B) Frequency of CD8+PD-1+ cells (percentage of CD3+CD8+) correlate with plasma SIV RNA copies in LTNPs (n = 21). Data represent the mean from three independent measurements. P value and spearman r are indicated. (C) Frequency of transitional memory cells (CD3+CD8+CD4−CD45RA−CCR7−CD27+CD28−; percentage of CD3+CD8+) are significantly higher in CNAR(-) LTNPs compared to CNAR(+) or uninfected macaques. (D) Frequencies of CD4+CD8+PD-1+ cells (percentage of CD3+CD4+CD8+) are significantly higher in SIV-infected LTNPs [CNAR(+) or CNAR(-)] compared to uninfected macaques. Results from uninfected macaques represent the mean from two independent measurements of each animal (n = 12). Data in Fig 5A, 5C and 5D from CNAR(+) (n = 11) and CNAR(-) (n = 8) macaques represent the mean of up to 3 time points, each two months apart. P values (Mann Whitney U test) are shown. Horizontal lines depict the median.
Mentions: Since it has been reported that CNAR may be mediated by transitional memory cells and to some extent by PD-1 expressing CD8+ T cells [20], we investigated the relative frequencies of different T cell subsets in SIV-infected CNAR positive and negative as well as in uninfected macaques by flow cytometry. Data from three time points each two months apart was analyzed. CNAR was tested at least once within this time period in animals with stable plasma viral load. In animals with increasing viral load CNAR was assessed again or FACS data were excluded for analysis. Mean frequencies of naïve (CD28+ CD95−), CD4+ or CD8+ central memory (TCM, CD28high CD95+) and effector memory (TEM, CD28low/- CD95+) cells did not differ between CNAR positive or negative monkeys. However the frequency of PD-1+ CD8+ cells differed significantly between the groups (Fig 5A; S3 Fig). Similar to humans, PD-1+CD8+ cells were lowest in uninfected individuals (Fig 5A)[20]. Furthermore, PD-1+CD8+ (given as frequency of PD-1+ of CD8+) correlated with plasma viral load (rs = 0.59, p = 0.0048, Fig 5B). Since in SIV-infected macaques CNAR was strongest in aviremic LTNPs, we found no evidence that PD-1 expressing CD8+ cells contribute to viral inhibition (Fig 5B).

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