The evolutionary dynamics of rapidly adapting intra-patient pathogens through space and time
Abstract/Contents
- Abstract
- At the beginning of the HIV epidemic, drug resistance to treatment evolved quickly and predictably across all patients. Now we treat HIV with combination therapies of three drugs so any single HIV mutation is insufficient for viral replication. The rate of drug resistance evolution has plummeted in response. Despite these advances, a minority of viral populations become resistant nonetheless. Why and how do certain populations overcome efficacious combination therapy? In answer to the first question, I analyze how the mode of drug resistance evolution changed within patients throughout the epidemic using historical HIV sequences. I find evolution has shifted from multiple origins of drug resistance ("soft sweeps") to single origins ("hard sweeps") as treatments have improved. This observation suggests that while drug resistance was once inevitable, now patients that fail combination therapy are merely unlucky, and not predestined to fail due to factors like poor adherence. However, questions remain about how hard sweeps of drug resistance can occur at all under combination therapy. Theory suggests that spatial structure of the intra-patient population drive multidrug resistance through creating pockets of spatial monotherapy whereby mutations can be acquired sequentially instead of simultaneously (Moreno-Gamez et al., 2015). However within-body population structure remains unknown. To bridge this gap, I analyze Simian-HIV-infected macaques sampled spatially and temporally during drug resistance evolution. I observe that populations from different organs (gut, plasma, lymph node, vagina) within the same macaque can be significantly different although the magnitude of the difference varies through time as drug resistance emerges. From these data, I quantify the population genetic parameters of the intra-patient environment to aid modeling efforts such as the spatial-monotherapy hypothesis. Notably, I develop a new ABC framework for estimation in adapting populations that can estimate migration rates much larger than those possible to estimate from tracking neutral alleles. This represents the first quantitative description (to our knowledge) of the within-patient spatial structure of HIV that accounts for adaptation.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2018; ©2018 |
| Publication date | 2018; 2018 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Feder, Alison |
|---|---|
| Degree supervisor | Petrov, Dmitri Alex, 1969- |
| Thesis advisor | Petrov, Dmitri Alex, 1969- |
| Thesis advisor | Feldman, Marcus W |
| Thesis advisor | Pennings, Pleuni, 1975- |
| Thesis advisor | Pritchard, Jonathan D |
| Thesis advisor | Rosenberg, Noah |
| Degree committee member | Feldman, Marcus W |
| Degree committee member | Pennings, Pleuni, 1975- |
| Degree committee member | Pritchard, Jonathan D |
| Degree committee member | Rosenberg, Noah |
| Associated with | Stanford University, Department of Biology. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Alison Feder. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Thesis Ph.D. Stanford University 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Alison F Feder
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