The role of mutation accumulation in HIV progression

Galvani, Alison P.

doi:10.1098/rspb.2005.3083

Cited by 20 publications

(22 citation statements)

References 71 publications

(134 reference statements)

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“…In this model, increased turnover of T cells results in the accumulation of deleterious mutations and impairs their regenerative or survival capacity [61]. The rate at which these mutations accumulate could then determine the time scale of decline.…”

Section: Discussionmentioning

confidence: 99%

Understanding the Slow Depletion of Memory CD4+ T Cells in HIV Infection

Yates

Stark

Klein³

et al. 2007

PLoS Med

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BackgroundThe asymptomatic phase of HIV infection is characterised by a slow decline of peripheral blood CD4+ T cells. Why this decline is slow is not understood. One potential explanation is that the low average rate of homeostatic proliferation or immune activation dictates the pace of a “runaway” decline of memory CD4+ T cells, in which activation drives infection, higher viral loads, more recruitment of cells into an activated state, and further infection events. We explore this hypothesis using mathematical models.Methods and FindingsUsing simple mathematical models of the dynamics of T cell homeostasis and proliferation, we find that this mechanism fails to explain the time scale of CD4+ memory T cell loss. Instead it predicts the rapid attainment of a stable set point, so other mechanisms must be invoked to explain the slow decline in CD4+ cells.ConclusionsA runaway cycle in which elevated CD4+ T cell activation and proliferation drive HIV production and vice versa cannot explain the pace of depletion during chronic HIV infection. We summarize some alternative mechanisms by which the CD4+ memory T cell homeostatic set point might slowly diminish. While none are mutually exclusive, the phenomenon of viral rebound, in which interruption of antiretroviral therapy causes a rapid return to pretreatment viral load and T cell counts, supports the model of virus adaptation as a major force driving depletion.

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Section: Discussionmentioning

confidence: 99%

Understanding the Slow Depletion of Memory CD4+ T Cells in HIV Infection

Yates

Stark

Klein³

et al. 2007

PLoS Med

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“…An important factor in understanding the unusual incubation period distribution in the development of AIDS is the dynamics of the long-lasting struggle between HIV and our immune system [19]. Until now, several approaches have been proposed to explain the long-term fight in HIV infection [1,10,11,14,15,19,29,47]. For example, in very early models of HIV infection worked by Martin A. Nowak, increasing of HIV variants' diversity, which leads to an explosion in the virus load, explained the collapse of immune system after a long incubation period.…”

Section: Discussionmentioning

confidence: 99%

“…Some HIV infected patients are still asymptomatic after 15 or more years of infection but some patients develop AIDS within 2 years [4,27](the similar disease progression patterns are also observed in SIV/SHIV infected individuals [2,21]). Although the mechanistic basis of the disease progression has remained obscure, several factors such as viral reproductive abilities and immune proliferative abilities are considered as a cause of the diverse disease progression [1,10,11,14,15,19,29,47].…”

Section: Introductionmentioning

confidence: 99%

Immune impairment thresholds in HIV infection

et al. 2009

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Longitudinal studies of patients infected with HIV-1 reveal a long and variable length of asymptomatic phase between infection and development of AIDS. Some HIV infected patients are still asymptomatic after 15 or more years of infection but some patients develop AIDS within 2 years. The mechanistic basis of the disease progression has remained obscure but many researchers have been trying to explain it. For example, the possible importance of viral diversity for the disease progression and the development of AIDS has been very well worked out in the early-1990s, especially by some important works of Martin A. Nowak. These studies can give an elegant explanation for a variability of asymptomatic phase. Here, a simple mathematical model was used to propose a new explanation for a variable length of asymptomatic phase. The main idea is that the immune impairment rate increases over the HIV infection. Our model suggested the existence of so-called "Risky threshold" and "Immunodeficiency threshold" on the impairment rate. The former implies that immune system may collapse when the impairment rate of HIV exceeds the threshold value. The latter implies that immune system always collapses when the impairment rate exceeds the value. We found that the length of asymptomatic phase is determined stochastically between these threshold values depending on the virological and immunological states. Furthermore, we investigated a distribution of the length of asymptomatic phase and a survival rate of the immune responses in one HIV patient.

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“…Mutation accumulation may also play a role in the deterioration of the human immune system during HIV infection. The elevated turnover of lymphocytes stimulated by HIV has been postulated to lead to deleterious mutation accumulation in progenitor cells, essentially causing the immune system to age at a rapid rate [38]. It should be noted, however, that genetic entropy is distinct from (though related to) the concept of genetic load in population genetics.…”

Section: Entropy In the Sign (The Gene Code): Genetic Entropymentioning

confidence: 96%

Biosemiotic Entropy of the Genome: Mutations and Epigenetic Imbalances Resulting in Cancer

Gryder

Nelson

Shepard

2013

Entropy

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Biosemiotic entropy involves the deterioration of biological sign systems. The genome is a coded sign system that is connected to phenotypic outputs through the interpretive functions of the tRNA/ribosome machinery. This symbolic sign system (semiosis) at the core of all biology has been termed "biosemiosis". Layers of biosemiosis and cellular information management are analogous in varying degrees to the semiotics of computer programming, spoken, and written human languages. Biosemiotic entropy-an error or deviation from a healthy state-results from errors in copying functional information (mutations) and errors in the appropriate context or quantity of gene expression (epigenetic imbalance). The concept of biosemiotic entropy is a deeply imbedded assumption in the study of cancer biology. Cells have a homeostatic, preprogrammed, ideal or healthy state that is rooted in genomics, strictly orchestrated by epigenetic regulation, and maintained by DNA repair mechanisms. Cancer is an eminent illustration of biosemiotic entropy, in which the corrosion of genetic information via substitutions, deletions, insertions, fusions, and aberrant regulation results in malignant phenotypes. However, little attention has been given to explicitly outlining the paradigm of biosemiotic entropy in the context of cancer. Herein we distill semiotic theory (from the familiar and well understood spheres of human language and computer code) to draw analogies useful for understanding the operation of biological semiosis at the genetic level. OPEN ACCESSEntropy 2013, 15 235We propose that the myriad checkpoints, error correcting mechanisms, and immunities are all systems whose primary role is to defend against the constant pressure of biosemiotic entropy, which malignancy must shut down in order to achieve advanced stages. In lieu of the narrower tumor suppressor/oncogene model, characterization of oncogenesis into the biosemiotic framework of sign, index, or object entropy may allow for more effective explanatory hypotheses for cancer diagnosis, with consequence in improving profiling and bettering therapeutic outcomes.

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The role of mutation accumulation in HIV progression

Cited by 20 publications

References 71 publications

Understanding the Slow Depletion of Memory CD4+ T Cells in HIV Infection

Understanding the Slow Depletion of Memory CD4+ T Cells in HIV Infection

Immune impairment thresholds in HIV infection

Biosemiotic Entropy of the Genome: Mutations and Epigenetic Imbalances Resulting in Cancer

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