Simian Immunodeficiency Virus Replicates to High Levels in Naturally Infected African Green Monkeys without Inducing Immunologic or Neurologic Disease

Broussard, Suzanne R.; Staprans, Silvija I.; White, Robert G.; Whitehead, Evelyn M.; Feinberg, Mark B.; Allan, Jonathan S.

doi:10.1128/jvi.75.5.2262-2275.2001

Cited by 226 publications

(205 citation statements)

References 98 publications

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“…For instance, it has now become more appreciated that although the level of virus replication predicts the rate of progression to AIDS in HIV-infected patients (43), this correlation is actually rather weak, given that virus replication is only a relatively ineffective predictor of the progression of immunodeficiency (44). Lack of relationship between SIV replication and disease progression is also a typical feature of natural SIV infection of sooty mangabeys and African green monkeys, in which the animals remain asymptomatic despite high levels of viremia (25,45,46).…”

Section: Discussionmentioning

confidence: 99%

Vaccine-Induced, Simian Immunodeficiency Virus-Specific CD8+ T Cells Reduce Virus Replication but Do Not Protect from Simian Immunodeficiency Virus Disease Progression

Engram

Dunham

Makedonas

et al. 2009

The Journal of Immunology

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Our limited understanding of the interaction between primate lentiviruses and the host immune system complicates the design of an effective HIV/AIDS vaccine. To identify immunological correlates of protection from SIV disease progression, we immunized two groups of five rhesus macaques (RMs) with either modified vaccinia Ankara (MVA) or MVAΔudg vectors that expressed SIVmac239 Gag and Tat. Both vectors raised a SIV-specific CD8+ T cell response, with a magnitude that was greater in mucosal tissues than in peripheral blood. After challenge with SIVmac239, all vaccinated RMs showed mucosal and systemic CD8+ T cell recall responses that appeared faster and were of greater magnitude than those in five unvaccinated control animals. All vaccinated RMs showed a ∼1-log lower peak and early set-point SIV viral load than the unvaccinated animals, and then, by 8 wk postchallenge, exhibited levels of viremia similar to the controls. We observed a significant direct correlation between the magnitude of postchallenge SIV-specific CD8+ T cell responses and SIV viral load. However, vaccinated RMs showed no protection from either systemic or mucosal CD4+ T cell depletion and no improved survival. The observation that vaccine-induced, SIV-specific CD8+ T cells that partially control SIVmac239 virus replication fail to protect from immunological or clinical progression of SIV infection underscores both the complexity of AIDS pathogenesis and the challenges of properly assessing the efficacy of candidate AIDS vaccines.

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Section: Discussionmentioning

confidence: 99%

Vaccine-Induced, Simian Immunodeficiency Virus-Specific CD8+ T Cells Reduce Virus Replication but Do Not Protect from Simian Immunodeficiency Virus Disease Progression

Engram

Dunham

Makedonas

et al. 2009

The Journal of Immunology

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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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“…In this case, the group-specific responses alone can control the virus.This parameter region applies to non-pathogenic SIV infection. (18)(19)(20)(21) The third, and most interesting, situation arises when the combined effects of group-specific and strain-specific immune responses are able to control the virus replication (of the individual strains), but the group-specific responses alone are unable to do so. Mathematically this means that sk 0 þpk >ru >sk 0 .…”

Section: Virus Evolution and Disease Progression In Individual Patientsmentioning

confidence: 99%

Mathematical models of HIV pathogenesis and treatment

2002

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SummaryWe review mathematical models of HIV dynamics, disease progression, and therapy. We start by introducing a basic model of virus infection and demonstrate how it was used to study HIV dynamics and to measure crucial parameters that lead to a new understanding of the disease process. We discuss the diversity threshold model as an example of the general principle that virus evolution can drive disease progression and the destruction of the immune system. Finally, we show how mathematical models can be used to understand correlates of long-term immunological control of HIV, and to design therapy regimes that convert a progressing patient into a state of long-term non-progression.

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Simian Immunodeficiency Virus Replicates to High Levels in Naturally Infected African Green Monkeys without Inducing Immunologic or Neurologic Disease

Cited by 226 publications

References 98 publications

Vaccine-Induced, Simian Immunodeficiency Virus-Specific CD8+ T Cells Reduce Virus Replication but Do Not Protect from Simian Immunodeficiency Virus Disease Progression

Vaccine-Induced, Simian Immunodeficiency Virus-Specific CD8+ T Cells Reduce Virus Replication but Do Not Protect from Simian Immunodeficiency Virus Disease Progression

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

Mathematical models of HIV pathogenesis and treatment

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