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Association of progressive CD4(+) T cell decline in SIV infection with the induction of autoreactive antibodies.

Kuwata T, Nishimura Y, Whitted S, Ourmanov I, Brown CR, Dang Q, Buckler-White A, Iyengar R, Brenchley JM, Hirsch VM - PLoS Pathog. (2009)

Bottom Line: Depletion of naïve CD4(+) T cells was associated with plasma antibodies autoreactive with CD4(+) T cells, increasing numbers of IgG-coated CD4(+) T cells, and increased incidence of autoreactive antibodies to platelets (GPIIIa), dsDNA, and phospholipid (aPL).Consistent with a biological role of these antibodies, these latter antibodies were accompanied by clinical features associated with autoimmune disorders, thrombocytopenia, and catastrophic thrombotic events.These results suggest an important role of autoreactive antibodies in the CD4(+) T cell decline observed during progression to AIDS.

View Article: PubMed Central - PubMed

Affiliation: Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto, Japan.

ABSTRACT
The progressive decline of CD4(+) T cells is a hallmark of disease progression in human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection. Whereas the acute phase of the infection is dominated by virus-mediated depletion of memory CD4(+) T cells, chronic infection is often associated with a progressive decline of total CD4(+) T cells, including the naïve subset. The mechanism of this second phase of CD4(+) T cell loss is unclear and may include immune activation-induced cell death, immune-mediated destruction, and regenerative or homeostatic failure. We studied patterns of CD4(+) T cell subset depletion in blood and tissues in a group of 20 rhesus macaques inoculated with derivatives of the pathogenic SIVsmE543-3 or SIVmac239. Phenotypic analysis of CD4(+) T cells demonstrated two patterns of CD4(+) T cell depletion, primarily affecting either naïve or memory CD4(+) T cells. Progressive decline of total CD4(+) T cells was observed only in macaques with naïve CD4(+) T cell depletion (ND), though the depletion of memory CD4(+) T cells was profound in macaques with memory CD4(+) T cell depletion (MD). ND macaques exhibited lower viral load and higher SIV-specific antibody responses and greater B cell activation than MD macaques. Depletion of naïve CD4(+) T cells was associated with plasma antibodies autoreactive with CD4(+) T cells, increasing numbers of IgG-coated CD4(+) T cells, and increased incidence of autoreactive antibodies to platelets (GPIIIa), dsDNA, and phospholipid (aPL). Consistent with a biological role of these antibodies, these latter antibodies were accompanied by clinical features associated with autoimmune disorders, thrombocytopenia, and catastrophic thrombotic events. More importantly for AIDS pathogenesis, the level of autoreactive antibodies significantly correlated with the extent of naïve CD4(+) T cell depletion. These results suggest an important role of autoreactive antibodies in the CD4(+) T cell decline observed during progression to AIDS.

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Proliferation of CD4+ T cells and microbial translocation in SIV-infected macaques.(A) Proliferation of CD4+ T cells was analyzed by Ki-67 coexpression. Kinetics of percentage of Ki-67+CD4+ T cells in ND (blue) and MD (red) macaques are shown with increasing percentages in ND macaques over the course of infection. (B) Plasma LPS levels were determined in ND (n = 12), MD (n = 8), and SIV-naïve (n = 10) macaques. LPS levels in ND and MD macaques at death were significantly higher than naïve macaques. (C) Plasma levels of sCD14 in ND and MD macaques. LPS and sCD14 levels were compared by nonparametric Mann-Whitney U test.
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ppat-1000372-g006: Proliferation of CD4+ T cells and microbial translocation in SIV-infected macaques.(A) Proliferation of CD4+ T cells was analyzed by Ki-67 coexpression. Kinetics of percentage of Ki-67+CD4+ T cells in ND (blue) and MD (red) macaques are shown with increasing percentages in ND macaques over the course of infection. (B) Plasma LPS levels were determined in ND (n = 12), MD (n = 8), and SIV-naïve (n = 10) macaques. LPS levels in ND and MD macaques at death were significantly higher than naïve macaques. (C) Plasma levels of sCD14 in ND and MD macaques. LPS and sCD14 levels were compared by nonparametric Mann-Whitney U test.

Mentions: Secondary indicators of immune activation such as intestinal amyloidosis (n = 2), generalized lymphadenopathy (n = 12) and lymphoproliferative syndrome (n = 1), were commonly observed in the ND group (Table 1). As a measure of lymphocyte proliferation in lymph nodes, immunohistochemistry for Ki-67 expression was performed on sequential lymph node biopsies. As shown in Figure 5A, this analysis demonstrated increasing proliferation in T cell areas and the germinal centers of ND macaques. The development of follicular hyperplasia was a particularly prominent feature of lymphoid tissue in ND macaques and this was often accompanied by increasing numbers of B cells in the blood (Figure 5B). Although immune activation, as indicated by increased levels of Ki-67+ CD4+ T cells, was observed early in infection in all of the animals, the number of proliferating CD4+ T cells, were higher in ND than MD macaques during the chronic phase of infection (Figure 6A). To examine whether the immune activation in ND macaques was induced by increased microbial translocation across the intestinal lumen [19], we measured lipopolysaccharide (LPS) levels in terminal plasma samples (Figure 6B). Both the ND and MD animals showed elevated levels of LPS (mean; 18.6 and 8.8 pg/ml, respectively) as compared to uninfected rhesus macaque plasma LPS (mean; 1.14 pg/ml). An outlier with extremely elevated LPS resulted from gram-negative bacterial sepsis (H679). While there was no statistical significant difference, LPS levels in ND macaques did trend higher than in MD macaques. The level of soluble CD14, which is secreted from CD14+ monocyte/macrophages in response to chronic LPS stimulation, was also elevated in both groups (Figure 6C), consistent with significant microbial translocation in both groups. The lack of proliferation of CD4+ T cells in MD macaques terminally suggests that these animals have lost the ability to respond to LPS stimulation due to profound immunosuppression.


Association of progressive CD4(+) T cell decline in SIV infection with the induction of autoreactive antibodies.

Kuwata T, Nishimura Y, Whitted S, Ourmanov I, Brown CR, Dang Q, Buckler-White A, Iyengar R, Brenchley JM, Hirsch VM - PLoS Pathog. (2009)

Proliferation of CD4+ T cells and microbial translocation in SIV-infected macaques.(A) Proliferation of CD4+ T cells was analyzed by Ki-67 coexpression. Kinetics of percentage of Ki-67+CD4+ T cells in ND (blue) and MD (red) macaques are shown with increasing percentages in ND macaques over the course of infection. (B) Plasma LPS levels were determined in ND (n = 12), MD (n = 8), and SIV-naïve (n = 10) macaques. LPS levels in ND and MD macaques at death were significantly higher than naïve macaques. (C) Plasma levels of sCD14 in ND and MD macaques. LPS and sCD14 levels were compared by nonparametric Mann-Whitney U test.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2662887&req=5

ppat-1000372-g006: Proliferation of CD4+ T cells and microbial translocation in SIV-infected macaques.(A) Proliferation of CD4+ T cells was analyzed by Ki-67 coexpression. Kinetics of percentage of Ki-67+CD4+ T cells in ND (blue) and MD (red) macaques are shown with increasing percentages in ND macaques over the course of infection. (B) Plasma LPS levels were determined in ND (n = 12), MD (n = 8), and SIV-naïve (n = 10) macaques. LPS levels in ND and MD macaques at death were significantly higher than naïve macaques. (C) Plasma levels of sCD14 in ND and MD macaques. LPS and sCD14 levels were compared by nonparametric Mann-Whitney U test.
Mentions: Secondary indicators of immune activation such as intestinal amyloidosis (n = 2), generalized lymphadenopathy (n = 12) and lymphoproliferative syndrome (n = 1), were commonly observed in the ND group (Table 1). As a measure of lymphocyte proliferation in lymph nodes, immunohistochemistry for Ki-67 expression was performed on sequential lymph node biopsies. As shown in Figure 5A, this analysis demonstrated increasing proliferation in T cell areas and the germinal centers of ND macaques. The development of follicular hyperplasia was a particularly prominent feature of lymphoid tissue in ND macaques and this was often accompanied by increasing numbers of B cells in the blood (Figure 5B). Although immune activation, as indicated by increased levels of Ki-67+ CD4+ T cells, was observed early in infection in all of the animals, the number of proliferating CD4+ T cells, were higher in ND than MD macaques during the chronic phase of infection (Figure 6A). To examine whether the immune activation in ND macaques was induced by increased microbial translocation across the intestinal lumen [19], we measured lipopolysaccharide (LPS) levels in terminal plasma samples (Figure 6B). Both the ND and MD animals showed elevated levels of LPS (mean; 18.6 and 8.8 pg/ml, respectively) as compared to uninfected rhesus macaque plasma LPS (mean; 1.14 pg/ml). An outlier with extremely elevated LPS resulted from gram-negative bacterial sepsis (H679). While there was no statistical significant difference, LPS levels in ND macaques did trend higher than in MD macaques. The level of soluble CD14, which is secreted from CD14+ monocyte/macrophages in response to chronic LPS stimulation, was also elevated in both groups (Figure 6C), consistent with significant microbial translocation in both groups. The lack of proliferation of CD4+ T cells in MD macaques terminally suggests that these animals have lost the ability to respond to LPS stimulation due to profound immunosuppression.

Bottom Line: Depletion of naïve CD4(+) T cells was associated with plasma antibodies autoreactive with CD4(+) T cells, increasing numbers of IgG-coated CD4(+) T cells, and increased incidence of autoreactive antibodies to platelets (GPIIIa), dsDNA, and phospholipid (aPL).Consistent with a biological role of these antibodies, these latter antibodies were accompanied by clinical features associated with autoimmune disorders, thrombocytopenia, and catastrophic thrombotic events.These results suggest an important role of autoreactive antibodies in the CD4(+) T cell decline observed during progression to AIDS.

View Article: PubMed Central - PubMed

Affiliation: Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto, Japan.

ABSTRACT
The progressive decline of CD4(+) T cells is a hallmark of disease progression in human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection. Whereas the acute phase of the infection is dominated by virus-mediated depletion of memory CD4(+) T cells, chronic infection is often associated with a progressive decline of total CD4(+) T cells, including the naïve subset. The mechanism of this second phase of CD4(+) T cell loss is unclear and may include immune activation-induced cell death, immune-mediated destruction, and regenerative or homeostatic failure. We studied patterns of CD4(+) T cell subset depletion in blood and tissues in a group of 20 rhesus macaques inoculated with derivatives of the pathogenic SIVsmE543-3 or SIVmac239. Phenotypic analysis of CD4(+) T cells demonstrated two patterns of CD4(+) T cell depletion, primarily affecting either naïve or memory CD4(+) T cells. Progressive decline of total CD4(+) T cells was observed only in macaques with naïve CD4(+) T cell depletion (ND), though the depletion of memory CD4(+) T cells was profound in macaques with memory CD4(+) T cell depletion (MD). ND macaques exhibited lower viral load and higher SIV-specific antibody responses and greater B cell activation than MD macaques. Depletion of naïve CD4(+) T cells was associated with plasma antibodies autoreactive with CD4(+) T cells, increasing numbers of IgG-coated CD4(+) T cells, and increased incidence of autoreactive antibodies to platelets (GPIIIa), dsDNA, and phospholipid (aPL). Consistent with a biological role of these antibodies, these latter antibodies were accompanied by clinical features associated with autoimmune disorders, thrombocytopenia, and catastrophic thrombotic events. More importantly for AIDS pathogenesis, the level of autoreactive antibodies significantly correlated with the extent of naïve CD4(+) T cell depletion. These results suggest an important role of autoreactive antibodies in the CD4(+) T cell decline observed during progression to AIDS.

Show MeSH
Related in: MedlinePlus