Normal T-Cell Turnover in Sooty Mangabeys Harboring Active Simian Immunodeficiency Virus Infection

Chakrabarti, Lisa A.; Lewin, Sharon R.; Zhang, Linqi; Gettie, Agegnehu; Luckay, Amara; Martin, Louis N.; Skulsky, Eva; Ho, David D.; Cheng‐Mayer, Cecilia; Marx, Preston A.

doi:10.1128/jvi.74.3.1209-1223.2000

Cited by 178 publications

(186 citation statements)

References 86 publications

(113 reference statements)

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“…Although the determinants of the variable SIVsmE660 replication dynamics are not fully understood (19), known animal-toanimal differences in the extent of CD4 T cell activation at the time of virus challenge could potentially influence SIV replication in the newly infected host (20). On the day of SIV challenge, all eight RMs in this vaccine study had levels of circulating proliferating CD4 T cells (1.2-2.4% Ki67 ϩ CD4 T cells) that were lower than those typically observed in RMs at the Yerkes Primate Research Center and elsewhere (21,22). We speculated that this less activated immunophenotype (which resembles that of healthy human subjects in the US; data not shown) related to prolonged housing of the RMs from an early age in the clean biocontainment facility environment, a point discussed later.…”

Section: Siv Replication and Disease Are Significantly Enhanced In Rvmentioning

confidence: 85%

Enhanced SIV replication and accelerated progression to AIDS in macaques primed to mount a CD4 T cell response to the SIV envelope protein

Staprans

Barry

Silvestri

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

130

113

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Given the dual role of CD4 T cells as both immune effectors and targets for HIV infection, the balance of CD4 versus CD8 T cellmediated responses induced by candidate AIDS vaccines may be critical in determining postvaccination infection outcomes. An attenuated recombinant varicella-zoster virus vaccine expressing the simian immunodeficiency virus (SIV) envelope (Env) elicited nonneutralizing Env-binding antibodies and little if any cytotoxic T lymphocyte responses in rhesus macaques (Macaca mulatta). After challenge with SIV, Env vaccinees manifested increased levels of SIV replication, more rapid CD4 depletion, and accelerated progression to AIDS compared with controls. Enhanced SIV replication correlated with increased CD4 T cell proliferation soon after SIV challenge, apparently the result of an anamnestic response to SIV antigens. Thus activation of virusspecific CD4 T cells at the time of exposure to a CD4 T cell-tropic lentivirus, in the absence of an effective CD8 response, may enhance virus replication and disease. These data suggest suggest that candidate AIDS vaccines may not simply be either efficacious or neutral; they may also have the potential to be harmful.

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Section: Siv Replication and Disease Are Significantly Enhanced In Rvmentioning

confidence: 85%

Enhanced SIV replication and accelerated progression to AIDS in macaques primed to mount a CD4 T cell response to the SIV envelope protein

Staprans

Barry

Silvestri

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

130

113

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“…However, whereas SIV-infected macaques-like HIV-infected humans-exhibit high-level immune activation and progressive immunodeficiency, SIV-infected sooty mangabeys exhibit no consistent increase in immune activation and rarely exhibit evidence of progressive immunodeficiency. [41][42][43] Also, constitutive expression of CD70 (which binds the T-cell costimulatory molecule CD27) in transgenic mice results in chronic T-cell activation, progressive loss of memory and naive T cells, and the eventual development of an AIDS-like syndrome (even in the absence of a cytopathic virus). Finally, our group has recently assessed the role of monocyte/macrophage activation in recently infected individuals initiating highly active antiretroviral therapy.…”

Section: Discussionmentioning

confidence: 99%

Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load

Deeks

Kitchen

Liu

et al. 2004

Blood

693

601

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Although generalized T-cell activation is an important factor in chronic HIV disease pathogenesis, its role in primary infection remains poorly defined. To investigate the effect of immune activation on T-cell changes in subjects with early HIV infection, and to test the hypothesis that an immunologic activation "set point" is established early in the natural history of HIV disease, a prospective cohort of acutely infected adults was performed. The median density of CD38 molecules on CD4 ؉ and CD8 ؉ T cells was measured longitudinally in 68 antiretroviral-untreated individuals and 83 antiretroviraltreated individuals. At study entry, T-cell activation was positively associated with viremia, with CD8 ؉ T-cell activation levels increasing exponentially at plasma HIV RNA levels more than 10 000 copies/mL. Among untreated patients, the level of CD8 ؉ T-cell activation varied widely among individuals but often remained stable within a given individual. CD8 ؉ T-cell activation and plasma HIV RNA levels over time were independently associated with the rate of CD4 ؉ T-cell loss in untreated individuals. These data indicate that immunologic activation set point is established early in HIV infection, and that this set point determines the rate at which CD4 ؉ T cells are lost over time. IntroductionUntreated HIV-1 infection is associated with a gradual loss of peripheral CD4 ϩ T cells. Although the direct cytopathic effect of HIV-1 on CD4 ϩ T cells almost certainly contributes to this gradual depletion, 1 most cells destined to die in vivo as a consequence of HIV infection are not productively infected with HIV. 2 This observation has led to the hypothesis that progressive CD4 ϩ T-cell depletion occurs due to indirect effects of viral replication. [3][4][5][6] The mechanism for these indirect effects of HIV replication on CD4 ϩ T-cell depletion is not understood.One widely accepted model postulates that HIV causes accelerated proliferation, expansion, and death of T cells, and that this heightened T-cell turnover eventually results in depletion or exhaustion of the regenerative capacity of the immune system. 4,5 Multiple studies have shown that HIV infection results in a state of high T-cell turnover (ie, the rates of T-cell proliferation and death are increased). For example, in vivo labeling of T cells indicates that HIV infection results in increased numbers of rapidly cycling CD4 ϩ and CD8 ϩ T cells. 7,8 These cells are primarily of memoryeffector phenotype, and are destined to proliferate and die rapidly. 9 The rate at which HIV recruits cells into this rapid turnover state is directly proportional to the level of viremia, 8 which in turn is directly related to the rate at which CD4 ϩ T cells are lost. 10 In the absence of antiretroviral treatment, markers of T-cell activation and T-cell turnover predict the rate of disease progression 11-14 and the rate of CD4 ϩ T-cell loss. 15 When antiretroviral therapy is initiated, the rate of T-cell turnover and the degree of generalized T-cell activation both decrease, suggest...

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“…Reaction was stopped by adding ice-cold paraformaldehyde (PFA) to a final concentration of 1% and incubation on ice. Cells were permeabilized with ice-cold methanol and processed for intracellular staining as described (39), using the anti-phospho Erk-1/2 MAPK mAb, followed by the secondary Ab anti-mouse IgG1 conjugated to Alexa-488 (Molecular Probes). The percentage of phospho-Erk-1/2-positive cells was evaluated by flow cytometry.…”

Section: Evaluation Of Cxcr4 Functionsmentioning

confidence: 99%

CXCR4-Tropic HIV-1 Envelope Glycoprotein Functions as a Viral Chemokine in Unstimulated Primary CD4+ T Lymphocytes

Balabanian

Harriague

Décrion

et al. 2004

The Journal of Immunology

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Interaction of HIV-1 envelope glycoprotein gp120 with the chemokine receptor CXCR4 triggers not only viral entry but also an array of signal transduction cascades. Whether gp120 induces an incomplete or aberrant set of signals, or whether it can function as a full CXCR4 agonist, remains unclear. We report that, in unstimulated human primary CD4+ T cells, the spectrum of signaling responses induced by gp120 through CXCR4 paralleled that induced by the natural ligand stromal cell-derived factor 1/CXCL12. gp120 activated heterotrimeric G proteins and the major G protein-dependent pathways, including calcium mobilization, phosphoinositide-3 kinase, and Erk-1/2 MAPK activation. Interestingly, gp120 caused rapid actin cytoskeleton rearrangements and profuse membrane ruffling, as evidenced by dynamic confocal imaging. This coordinated set of events resulted in a bona fide chemotactic response. Inactivated HIV-1 virions that harbored conformationally intact envelope glycoproteins also caused actin polymerization and chemotaxis, while similar virions devoid of envelope glycoproteins did not. Thus gp120, in monomeric as well as oligomeric, virion-associated form, elicited a complex cellular response that mimicked the effects of a chemokine. HIV-1 has therefore the capacity to dysregulate the vast CD4+ T cell population that expresses CXCR4. In addition, HIV-1 may exploit its chemotactic properties to retain potential target cells and locally perturb their cytoskeleton, thereby facilitating viral transmission.

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Normal T-Cell Turnover in Sooty Mangabeys Harboring Active Simian Immunodeficiency Virus Infection

Cited by 178 publications

References 86 publications

Enhanced SIV replication and accelerated progression to AIDS in macaques primed to mount a CD4 T cell response to the SIV envelope protein

Enhanced SIV replication and accelerated progression to AIDS in macaques primed to mount a CD4 T cell response to the SIV envelope protein

Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load

CXCR4-Tropic HIV-1 Envelope Glycoprotein Functions as a Viral Chemokine in Unstimulated Primary CD4+ T Lymphocytes

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