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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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Representative flow cytometry and kinetics of CD4+ T cell loss in ND and MD macaques.(A) CD4+ T cell subsets of PBMC, PLN, and spleen of macaques H723 and H718 are shown as representatives of ND and MD macaques, respectively. Naive (CD95lowCD28high) and memory (CD95highCD28high and CD95highCD28low) subsets of CD4+ T cells were analyzed by flow cytometry. (B) CD4+ T cell percentages and their subsets in various tissues from macaques, H723 (upper) and H718 (lower). Naive (blue) and memory (red) CD4+ T cells in total T cells are shown. (C) Kinetics of CD4+ T cell depletion in H723 (upper) and H718 (lower). Naive (blue dotted line), memory (red), and total (green) CD4+ T cell counts in blood are shown.
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ppat-1000372-g002: Representative flow cytometry and kinetics of CD4+ T cell loss in ND and MD macaques.(A) CD4+ T cell subsets of PBMC, PLN, and spleen of macaques H723 and H718 are shown as representatives of ND and MD macaques, respectively. Naive (CD95lowCD28high) and memory (CD95highCD28high and CD95highCD28low) subsets of CD4+ T cells were analyzed by flow cytometry. (B) CD4+ T cell percentages and their subsets in various tissues from macaques, H723 (upper) and H718 (lower). Naive (blue) and memory (red) CD4+ T cells in total T cells are shown. (C) Kinetics of CD4+ T cell depletion in H723 (upper) and H718 (lower). Naive (blue dotted line), memory (red), and total (green) CD4+ T cell counts in blood are shown.

Mentions: To clarify the mechanism of progressive CD4+ T cell decline in the SIV/ rhesus macaque model, we analyzed CD4+ T cell naïve and memory subsets in retrospective samples of blood and various tissues of twenty macaques infected with derivatives of the pathogenic SIVsmE543-3 or SIVmac239 (Table 1). We found that the pattern of depletion of naïve and memory CD4+ T cell subsets in terminal blood samples differed substantially, showing two patterns of depletion, predominantly affecting either naïve or memory CD4+ T cells (Figure 1A and Figure S1). Animals were classified at death as either ND (naïve depleted) or MD (memory depleted) based upon the ratio of naïve to memory CD4+ T cells in the blood (Figure 1B) using a ratio of less than three to identify ND macaques. This classification was confirmed by the naïve to memory ratio in the peripheral lymph nodes (PLN) and spleen of 12 animals (Figure 1B). Twelve macaques showed primarily naïve cell depletion and eight macaques exhibited memory cell depletion (Table 1 and Figure 1A). The naïve to memory ratio of these two groups of animals differed significantly from one another in peripheral blood mononuclear cells (PBMC), PLN and spleen at death (Figure 1B: P = 0.0002, 0.0025 and 0.0006), showing much higher ratios in MD macaques. Comparison of CD4+ T cell subsets at pre-inoculation and at death revealed a significant decline in the memory subset in MD macaques and in both subsets in ND macaques (Figure 1C). Figure 2A shows flow cytometric data for a representative macaque of each group. Animal H723 with naïve cell depletion showed a fairly normal representation of subsets in PBMC but preferential depletion of naïve CD4+ T cells in lymphoid tissues, where naïve cells are normally abundant in healthy macaques (Figure 2A and 2B). Conversely, H718, a macaque with primarily memory CD4+ T cell depletion showed selective depletion of the CD4+ memory subset in all tissues (Figure 2A and 2B). As shown in Figure 2C, both memory and naïve CD4+ T cell populations gradually declined in H723 during the course of infection, but only the memory population declined in H718. Due to the predominance of naïve cells in peripheral blood in H718, a progressive decline of total CD4+ T cells in the chronic phase was only observed in H723. Similar patterns in the kinetics of naïve and memory CD4+ T cell loss were observed in the remaining animals of each group. These data were confirmed by examining the kinetics of CD4+ T cell declines in 12 individual animals (n = 8 ND and n = 4 MD) as shown in Figure 3. A progressive loss of CD4+ T cells, a slow decline of both naïve and memory subsets, was observed in the ND macaques (Figure 3; left panels). Although a precipitous decline in all CD4 subsets (as well as CD8+ T cells and B cells, data not shown) occurred terminally in many of the MD macaques possibly due to acute regenerative failure, MD macaques primarily exhibited selective memory CD4+ T cell depletion (Figure 3; right panels). Both groups contained macaques infected with a variety of inocula with the exception of SIVsmH635FC-infected macaques that were all classified to the ND group (Table 1). Thus, it appears that the inoculum was not a major factor in determining the type of disease course.


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)

Representative flow cytometry and kinetics of CD4+ T cell loss in ND and MD macaques.(A) CD4+ T cell subsets of PBMC, PLN, and spleen of macaques H723 and H718 are shown as representatives of ND and MD macaques, respectively. Naive (CD95lowCD28high) and memory (CD95highCD28high and CD95highCD28low) subsets of CD4+ T cells were analyzed by flow cytometry. (B) CD4+ T cell percentages and their subsets in various tissues from macaques, H723 (upper) and H718 (lower). Naive (blue) and memory (red) CD4+ T cells in total T cells are shown. (C) Kinetics of CD4+ T cell depletion in H723 (upper) and H718 (lower). Naive (blue dotted line), memory (red), and total (green) CD4+ T cell counts in blood are shown.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2662887&req=5

ppat-1000372-g002: Representative flow cytometry and kinetics of CD4+ T cell loss in ND and MD macaques.(A) CD4+ T cell subsets of PBMC, PLN, and spleen of macaques H723 and H718 are shown as representatives of ND and MD macaques, respectively. Naive (CD95lowCD28high) and memory (CD95highCD28high and CD95highCD28low) subsets of CD4+ T cells were analyzed by flow cytometry. (B) CD4+ T cell percentages and their subsets in various tissues from macaques, H723 (upper) and H718 (lower). Naive (blue) and memory (red) CD4+ T cells in total T cells are shown. (C) Kinetics of CD4+ T cell depletion in H723 (upper) and H718 (lower). Naive (blue dotted line), memory (red), and total (green) CD4+ T cell counts in blood are shown.
Mentions: To clarify the mechanism of progressive CD4+ T cell decline in the SIV/ rhesus macaque model, we analyzed CD4+ T cell naïve and memory subsets in retrospective samples of blood and various tissues of twenty macaques infected with derivatives of the pathogenic SIVsmE543-3 or SIVmac239 (Table 1). We found that the pattern of depletion of naïve and memory CD4+ T cell subsets in terminal blood samples differed substantially, showing two patterns of depletion, predominantly affecting either naïve or memory CD4+ T cells (Figure 1A and Figure S1). Animals were classified at death as either ND (naïve depleted) or MD (memory depleted) based upon the ratio of naïve to memory CD4+ T cells in the blood (Figure 1B) using a ratio of less than three to identify ND macaques. This classification was confirmed by the naïve to memory ratio in the peripheral lymph nodes (PLN) and spleen of 12 animals (Figure 1B). Twelve macaques showed primarily naïve cell depletion and eight macaques exhibited memory cell depletion (Table 1 and Figure 1A). The naïve to memory ratio of these two groups of animals differed significantly from one another in peripheral blood mononuclear cells (PBMC), PLN and spleen at death (Figure 1B: P = 0.0002, 0.0025 and 0.0006), showing much higher ratios in MD macaques. Comparison of CD4+ T cell subsets at pre-inoculation and at death revealed a significant decline in the memory subset in MD macaques and in both subsets in ND macaques (Figure 1C). Figure 2A shows flow cytometric data for a representative macaque of each group. Animal H723 with naïve cell depletion showed a fairly normal representation of subsets in PBMC but preferential depletion of naïve CD4+ T cells in lymphoid tissues, where naïve cells are normally abundant in healthy macaques (Figure 2A and 2B). Conversely, H718, a macaque with primarily memory CD4+ T cell depletion showed selective depletion of the CD4+ memory subset in all tissues (Figure 2A and 2B). As shown in Figure 2C, both memory and naïve CD4+ T cell populations gradually declined in H723 during the course of infection, but only the memory population declined in H718. Due to the predominance of naïve cells in peripheral blood in H718, a progressive decline of total CD4+ T cells in the chronic phase was only observed in H723. Similar patterns in the kinetics of naïve and memory CD4+ T cell loss were observed in the remaining animals of each group. These data were confirmed by examining the kinetics of CD4+ T cell declines in 12 individual animals (n = 8 ND and n = 4 MD) as shown in Figure 3. A progressive loss of CD4+ T cells, a slow decline of both naïve and memory subsets, was observed in the ND macaques (Figure 3; left panels). Although a precipitous decline in all CD4 subsets (as well as CD8+ T cells and B cells, data not shown) occurred terminally in many of the MD macaques possibly due to acute regenerative failure, MD macaques primarily exhibited selective memory CD4+ T cell depletion (Figure 3; right panels). Both groups contained macaques infected with a variety of inocula with the exception of SIVsmH635FC-infected macaques that were all classified to the ND group (Table 1). Thus, it appears that the inoculum was not a major factor in determining the type of disease course.

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