AIDS pathogenesis: a tale of two monkeys

Silvestri, Guido

doi:10.1111/j.1600-0684.2008.00328.x

Cited by 33 publications

(31 citation statements)

References 56 publications

(74 reference statements)

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“…[18][19][20][21][22]35 The robust genetic, 36,37 phenotypic, and functional similarities 25,38 between the macaque and human immune systems have made it a preferred model for the study of both transplant immunology [20][21][22]38,39 and of protective immunity and infectious disease. 40,41 Our results with this model document rapid, significant lymphocyte mobilization with AMD3100, which included mobilization of multiple subpopulations, including B cells, NK cells, both CD4 and CD8 T cells, and their Tn, Tcm, and Tem subpopulations. In contrast, G-CSF treatment alone led to no B-, T-, or NK-cell mobilization, despite Figure 5.…”

Section: Discussionmentioning

confidence: 68%

Significant mobilization of both conventional and regulatory T cells with AMD3100

Kean

Sen

Onabajo

et al. 2011

Blood

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In this study, we used the rhesus macaque model to determine the impact that AMD3100 has on lymphocyte mobilization, both alone and in combination with G-CSF. Our results indicate that, unlike G-CSF, AMD3100 substantially mobilizes both B and T lymphocytes into the peripheral blood. This led to significant increases in the peripheral blood content of both effector and regulatory T-cell populations, which translated into greater accumulation of these cells in the resulting leukapheresis products. Notably, CD4 ؉ / CD25 high /CD127 low /FoxP3 ؉ Tregs were efficiently mobilized with AMD3100-containing regimens, with as much as a 4.0-fold enrichment in the leukapheresis product compared with G-CSF alone. CD8 ؉ T cells were mobilized to a greater extent than CD4 ؉ T cells, with accumulation of 3.7 ؎ 0.4-fold more total CD8؉ T cells and 6.2 ؎ 0.4-fold more CD8 ؉ effector memory T cells in the leukapheresis product compared with G-CSF alone.Given that effector memory T-cell subpopulations may mediate less GVHD compared with other effector T-cell populations and that Tregs are protective against GVHD, our results indicate that AMD3100 may mobilize a GVHD-protective T-cell repertoire, which would be of benefit in allogeneic hematopoietic stem cell transplantation. (Blood. 2011;118(25): 6580-6590) IntroductionThe widespread use of cytokine-mediated mobilization has had a major impact on hematopoietic stem cell transplantation (HSCT). For auto-HSCT, peripheral blood-derived stem cell (PBSC) transplantation is associated with more rapid hematopoietic reconstitution and better outcomes compared with bone marrow transplantation. [1][2][3][4][5] For allo-HSCT, the choice is more complex. A metaanalysis showed that PBSC transplants in adults resulted in more rapid hematopoietic reconstitution, decreased relapse, and increased disease-free survival compared with bone marrow transplantation 6 but did not lead to an overall survival advantage compared with bone marrow, except in patients with late-stage disease. 6 This was probably because of the higher T-cell content of PBSC grafts (10-to 50-fold more than bone marrow-derived allografts), [7][8][9] leading to a significantly greater risk of GVHD. 6 In pediatrics, this increased risk of GVHD and transplant-related mortality shifted the risk/benefit balance, favoring bone marrow over PBSCs. 10 These dichotomous results between pediatric and adult patients suggest that a narrow therapeutic window exists for infused lymphocytes.With the FDA approval of AMD3100 (Plerixafor or Mozobil), 11 mobilization can now occur by multiple regimens, including G-CSF alone, AMD3100 alone, or G-CSF plus AMD3100. Therefore, the risks and benefits of each of these mobilization strategies must be understood and compared with those associated with bone marrow transplantation. AMD3100 is US Food and Drug Administration (FDA)-approved for auto-HSCT, and the combination of G-CSF and AMD3100 was shown to be superior to G-CSF for stem cell mobilization. 12-14 Furthermore, there was accelerated lymphocyte recov...

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Section: Discussionmentioning

confidence: 68%

Significant mobilization of both conventional and regulatory T cells with AMD3100

Kean

Sen

Onabajo

et al. 2011

Blood

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“…We first show that naive CD4 T cells are indeed the principal source of lymphotoxin-␤ for maintenance of the FRC network because antibody-mediated depletion of CD4 T cells, but not CD8 T cells, in rhesus macaques reproduced the depletion of the FRC network in SIV-infected rhesus macaques and HIV-1 infection. Furthermore, we found that, in the nonpathogenic model of SIV infection of sooty mangabeys (Cercocebus atys), 53,54 the maintenance of CD4 T cells in sooty mangabeys correlated with maintenance of the FRC network and that CD4 T-cell depletion by antibody in uninfected sooty mangabeys, also significantly depleted the FRC and follicular dendritic cell networks, reproducing the pathogenic effect in SIV-infected rhesus macaques.…”

Section: Introductionmentioning

confidence: 58%

Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution

Zeng

Paiardini

Engram

et al. 2012

Blood

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“…In contrast, the dynamics of SIV infection in rhesus macaques (Macaca mulatta; RM) have been comprehensively studied and described (10,26,27,35,56). Moreover, previous studies have demonstrated that the course of SIV infection in PTM more closely resembles HIV infection in humans than does SIV infection in RM (3).…”

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confidence: 99%

Dynamics of Simian Immunodeficiency Virus SIVmac239 Infection in Pigtail Macaques

Klatt

Canary

Vanderford

et al. 2012

J Virol

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Pigtail macaques (PTM) are an excellent model for HIV research; however, the dynamics of simian immunodeficiency virus (SIV) SIVmac239 infection in PTM have not been fully evaluated. We studied nine PTM prior to infection, during acute and chronic SIVmac239 infections, until progression to AIDS. We found PTM manifest clinical AIDS more rapidly than rhesus macaques (RM), as AIDS-defining events occurred at an average of 42.17 weeks after infection in PTM compared to 69.56 weeks in RM (P ‫؍‬ 0.0018). However, increased SIV progression was not associated with increased viremia, as both peak and set-point plasma viremias were similar between PTM and RM (P ‫؍‬ 0.7953 and P ‫؍‬ 0.1006, respectively). Moreover, this increased disease progression was not associated with rapid CD4 ؉ T cell depletion, as CD4 ؉ T cell decline resembled other SIV/human immunodeficiency virus (HIV) models. Since immune activation is the best predictor of disease progression during HIV infection, we analyzed immune activation by turnover of T cells by BrdU decay and Ki67 expression. We found increased levels of turnover prior to SIV infection of PTM compared to that observed with RM, which may contribute to their increased disease progression rate. These data evaluate the kinetics of SIVmac239-induced disease progression and highlight PTM as a model for HIV infection and the importance of immune activation in SIV disease progression.

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AIDS pathogenesis: a tale of two monkeys

Cited by 33 publications

References 56 publications

Significant mobilization of both conventional and regulatory T cells with AMD3100

Significant mobilization of both conventional and regulatory T cells with AMD3100

Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution

Dynamics of Simian Immunodeficiency Virus SIVmac239 Infection in Pigtail Macaques

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