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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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Viruses from ND macaques use CCR5 as co-receptor.Co-receptor usage of viruses in ND macaques and parental SIV strains was analyzed using CCR5 and CXCR4 antagonists, TAK779 and AMD3100, respectively. TZM-bl cells were incubated with pseudotyped viruses in the absence or presence of the designated concentration of antagonist. The mean percentage of the control luciferase activity is shown with standard errors. Pseudotyped viruses were prepared using Env of SIVsmH635FC and SIVsmE543-2, and two Env clones each from H704 and H709. The infection with pseudotyped viruses with Env from H704 and H709 were inhibited by TAK779, but not AMD3100, similar to parental SIVsmH635FC and SIVsmE543-3. In contrast, the X4-tropic HIV-1NL43-3 was inhibited by AMD3100, but not TAK779.
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ppat-1000372-g008: Viruses from ND macaques use CCR5 as co-receptor.Co-receptor usage of viruses in ND macaques and parental SIV strains was analyzed using CCR5 and CXCR4 antagonists, TAK779 and AMD3100, respectively. TZM-bl cells were incubated with pseudotyped viruses in the absence or presence of the designated concentration of antagonist. The mean percentage of the control luciferase activity is shown with standard errors. Pseudotyped viruses were prepared using Env of SIVsmH635FC and SIVsmE543-2, and two Env clones each from H704 and H709. The infection with pseudotyped viruses with Env from H704 and H709 were inhibited by TAK779, but not AMD3100, similar to parental SIVsmH635FC and SIVsmE543-3. In contrast, the X4-tropic HIV-1NL43-3 was inhibited by AMD3100, but not TAK779.

Mentions: The memory CD4+ T cell loss in MD macaques would appear to be mainly explained by direct cell killing of CCR5+CD4+ target cells that is compounded by insufficient production [7],[8],[29]. In contrast, the loss of naïve CD4+ T cells in ND macaques was not readily explained by virus killing since these cells primarily express CXCR4, not CCR5 [11] and SIV strains generally use CCR5 as their major co-receptor. The emergence of a CXCR4-tropic SIV has only been observed once in macaques and was associated with extensive substitutions in the V3 region of Env [29],[36]. Similarly, emergence of X4-tropic SIVs in sooty mangabeys was associated with changes within the V3 loop [37]. Our prior sequence analysis of sequential plasma virus from a number of these animals did not show evolution of this region of Env to X4 tropism [27] (Figure S2). Therefore we used envelope clones from 20 wpi plasma of two of these animals (H704 and H709) to evaluate whether emergence of a X4 variant explained the naïve CD4+ T cell depletion observed in these animals by this time point. Virus pseudotypes produced by cotransfection of appropriate envelope clones with pSG3ΔEnv, a Rev expression plasmid, were assayed for sensitivity to the CCR5 and CXCR4 antagonists, TAK779 and AMD3100 in TZM-bl cells. As observed in Figure 8, the parental viruses SIVsmH635 and SIVsmE543-3 and clones derived from two ND macaques were inhibited only by the CCR5 antagonist, consistent with maintenance of CCR5 as their major co-receptor. This contrasted with the expected inhibition of the CXCR4-tropic HIV-NL4-3 by AMD3100. To validate this finding, we also evaluated the infection frequency by quantitative real time PCR for SIV DNA within sorted populations of naïve and memory CD4+ T cells from samples of spleen collected at necropsy of five of the ND macaques. By this time point, only one sample (H709) had sufficient naïve cells (8.8%) for accurate cell sorting and qPCR. For this sample, the ratio of SIV gag copies per cell number was 29% of memory CD4+ T cells versus 5% of naïve CD4+ T cells, consistent with preferential infection of memory CD4+ T cells. Hence the emergence of CXCR4-tropic SIV within ND macaques did not appear to explain the depletion of naïve CD4+ T cells in at least two of these animals. Further more detailed analysis would be necessary to totally eliminate a role for X4 viruses.


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)

Viruses from ND macaques use CCR5 as co-receptor.Co-receptor usage of viruses in ND macaques and parental SIV strains was analyzed using CCR5 and CXCR4 antagonists, TAK779 and AMD3100, respectively. TZM-bl cells were incubated with pseudotyped viruses in the absence or presence of the designated concentration of antagonist. The mean percentage of the control luciferase activity is shown with standard errors. Pseudotyped viruses were prepared using Env of SIVsmH635FC and SIVsmE543-2, and two Env clones each from H704 and H709. The infection with pseudotyped viruses with Env from H704 and H709 were inhibited by TAK779, but not AMD3100, similar to parental SIVsmH635FC and SIVsmE543-3. In contrast, the X4-tropic HIV-1NL43-3 was inhibited by AMD3100, but not TAK779.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2662887&req=5

ppat-1000372-g008: Viruses from ND macaques use CCR5 as co-receptor.Co-receptor usage of viruses in ND macaques and parental SIV strains was analyzed using CCR5 and CXCR4 antagonists, TAK779 and AMD3100, respectively. TZM-bl cells were incubated with pseudotyped viruses in the absence or presence of the designated concentration of antagonist. The mean percentage of the control luciferase activity is shown with standard errors. Pseudotyped viruses were prepared using Env of SIVsmH635FC and SIVsmE543-2, and two Env clones each from H704 and H709. The infection with pseudotyped viruses with Env from H704 and H709 were inhibited by TAK779, but not AMD3100, similar to parental SIVsmH635FC and SIVsmE543-3. In contrast, the X4-tropic HIV-1NL43-3 was inhibited by AMD3100, but not TAK779.
Mentions: The memory CD4+ T cell loss in MD macaques would appear to be mainly explained by direct cell killing of CCR5+CD4+ target cells that is compounded by insufficient production [7],[8],[29]. In contrast, the loss of naïve CD4+ T cells in ND macaques was not readily explained by virus killing since these cells primarily express CXCR4, not CCR5 [11] and SIV strains generally use CCR5 as their major co-receptor. The emergence of a CXCR4-tropic SIV has only been observed once in macaques and was associated with extensive substitutions in the V3 region of Env [29],[36]. Similarly, emergence of X4-tropic SIVs in sooty mangabeys was associated with changes within the V3 loop [37]. Our prior sequence analysis of sequential plasma virus from a number of these animals did not show evolution of this region of Env to X4 tropism [27] (Figure S2). Therefore we used envelope clones from 20 wpi plasma of two of these animals (H704 and H709) to evaluate whether emergence of a X4 variant explained the naïve CD4+ T cell depletion observed in these animals by this time point. Virus pseudotypes produced by cotransfection of appropriate envelope clones with pSG3ΔEnv, a Rev expression plasmid, were assayed for sensitivity to the CCR5 and CXCR4 antagonists, TAK779 and AMD3100 in TZM-bl cells. As observed in Figure 8, the parental viruses SIVsmH635 and SIVsmE543-3 and clones derived from two ND macaques were inhibited only by the CCR5 antagonist, consistent with maintenance of CCR5 as their major co-receptor. This contrasted with the expected inhibition of the CXCR4-tropic HIV-NL4-3 by AMD3100. To validate this finding, we also evaluated the infection frequency by quantitative real time PCR for SIV DNA within sorted populations of naïve and memory CD4+ T cells from samples of spleen collected at necropsy of five of the ND macaques. By this time point, only one sample (H709) had sufficient naïve cells (8.8%) for accurate cell sorting and qPCR. For this sample, the ratio of SIV gag copies per cell number was 29% of memory CD4+ T cells versus 5% of naïve CD4+ T cells, consistent with preferential infection of memory CD4+ T cells. Hence the emergence of CXCR4-tropic SIV within ND macaques did not appear to explain the depletion of naïve CD4+ T cells in at least two of these animals. Further more detailed analysis would be necessary to totally eliminate a role for X4 viruses.

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