Alan S. Perelson

Los Alamos National Laboratory, Лос-Аламос, California, United States

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Publications (680)

  • Sung Yong Park · Tanzy M. T. Love · Alan S. Perelson · [...] · Ha Youn Lee
    [Show abstract] [Hide abstract] ABSTRACT: Background: The molecular clock hypothesis that genes or proteins evolve at a constant rate is a key tool to reveal phylogenetic relationships among species. Using the molecular clock, we can trace an infection back to transmission using HIV-1 sequences from a single time point. Whether or not a strict molecular clock applies to HIV-1's early evolution in the presence of immune selection has not yet been fully examined. Results: We identified molecular clock signatures from 1587 previously published HIV-1 full envelope gene sequences obtained since acute infection in 15 subjects. Each subject's sequence diversity linearly increased during the first 150 days post infection, with rates ranging from 1.54 × 10-5 to 3.91 × 10-5 with a mean of 2.69 × 10-5 per base per day. The rate of diversification for 12 out of the 15 subjects was comparable to the neutral evolution rate. While temporal diversification was consistent with evolution patterns in the absence of selection, mutations from the founder virus were highly clustered on statistically identified selection sites, which diversified more than 65 times faster than non-selection sites. By mathematically quantifying deviations from the molecular clock under various selection scenarios, we demonstrate that the deviation from a constant clock becomes negligible as multiple escape lineages emerge. The most recent common ancestor of a virus pair from distinct escape lineages is most likely the transmitted founder virus, indicating that HIV-1 molecular dating is feasible even after the founder viruses are no longer detectable. Conclusions: The ability of HIV-1 to escape from immune surveillance in many different directions is the driving force of molecular clock persistence. This finding advances our understanding of the robustness of HIV-1's molecular clock under immune selection, implying the potential for molecular dating.
    Article · Dec 2016 · Retrovirology
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    Article · Sep 2016 · Journal of Viral Hepatitis
  • Article · Jul 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Legalon SIL (SIL) is a chemically hydrophilized version of silibinin, an extract of milk thistle (Silybum marianum) seeds that has exhibited hepatoprotective and antiviral effectiveness against hepatitis C virus (HCV) in patients leading to viral clearance in combination with ribavirin. To elucidate the incompletely understood mode of action of SIL against HCV, mathematical modelling of HCV kinetics and human hepatocyte gene expression studies were performed in uPA-SCID-chimeric mice with humanized livers. Chronically HCV-infected mice (n = 15) were treated for 14 days with daily intravenous SIL at 469, 265 or 61.5 mg/kg. Serum HCV and human albumin (hAlb) were measured frequently, and liver HCV RNA was analysed at days 3 and 14. Microarray analysis of human hepatocyte gene expression was performed at days 0, 3 and 14 of treatment. While hAlb remained constant, a biphasic viral decline in serum was observed consisting of a rapid 1st phase followed by a second slower phase (or plateau with the two lower SIL dosings). SIL effectiveness in blocking viral production was similar among dosing groups (median ε = 77%). However, the rate of HCV-infected hepatocyte decline, δ, was dose-dependent. Intracellular HCV RNA levels correlated (r = 0.66, P = 0.01) with serum HCV RNA. Pathway analysis revealed increased anti-inflammatory and antiproliferative gene expression in human hepatocytes in SIL-treated mice. The results suggest that SIL could lead to a continuous second-phase viral decline, that is potentially viral clearance, in the absence of adaptive immune response along with increased anti-inflammatory and antiproliferative gene expression in human hepatocytes.
    Article · Jun 2016 · Journal of Viral Hepatitis
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    Soumya Banerjee · Jeremie Guedj · Ruy M. Ribeiro · [...] · Alan S. Perelson
    Full-text Dataset · Apr 2016
  • Soumya Banerjee · Jeremie Guedj · Ruy M. Ribeiro · [...] · Alan S. Perelson
    [Show abstract] [Hide abstract] ABSTRACT: West Nile virus (WNV) is an emerging pathogen that has decimated bird populations and caused severe outbreaks of viral encephalitis in humans. Currently, little is known about the within-host viral kinetics of WNV during infection. We developed mathematical models to describe viral replication, spread and host immune response in wild-type and immunocompromised mice. Our approach fits a target cell-limited model to viremia data from immunocompromised knockout mice and an adaptive immune response model to data from wild-type mice. Using this approach, we first estimate parameters governing viral production and viral spread in the host using simple models without immune responses. We then use these parameters in a more complex immune response model to characterize the dynamics of the humoral immune response. Despite substantial uncertainty in input parameters, our analysis generates relatively precise estimates of important viral characteristics that are composed of nonlinear combinations of model parameters: we estimate the mean within-host basic reproductive number, R0, to be 2.3 (95% of values in the range 1.7-2.9); the mean infectious virion burst size to be 2.9 plaqueforming units (95% of values in the range 1.7-4.7); and the average number of cells infected per infectious virion to be between 0.3 and 0.99. Our analysis gives mechanistic insights into the dynamics of WNV infection and produces estimates of viral characteristics that are difficult to measure experimentally. These models are a first step towards a quantitative understanding of the timing and effectiveness of the humoral immune response in reducing host viremia and consequently the epidemic spread of WNV. © 2016 The Author(s) Published by the Royal Society. All rights reserved.
    Article · Apr 2016 · Journal of The Royal Society Interface
  • Laetitia Canini · Jeremie Guedj · Alan S Perelson
    Article · Apr 2016 · Antiviral therapy
  • K E Sherman · R Ke · S D Rouster · [...] · A S Perelson
    [Show abstract] [Hide abstract] ABSTRACT: Aim: Chronic hepatitis C virus (HCV) infection is an important source of morbidity and mortality among haemophiliacs. Limited data are available regarding treatment intervention using direct-acting antivirals (DAAs) and theoretical concerns regarding accumulation of drug-associated resistance variants (RAVs) remain. We conducted a pilot study of treatment with telaprevir/pegylated interferon-alfa/ribavirin to evaluate treatment response and the role of lead-in DAA therapy on mutational selection of resistance variants. Methods: Ultra-deep sequence analysis was performed at baseline, 48 hours and 168 hours after treatment initiation. Results: No dominant RAVs were identified at baseline, but low-level RAVs were noted at baseline in all subjects. Viral dynamic models were used to assess treatment responses. The efficacy parameter (Ɛ) for lead-in ranged from 0 to 0.9745 (mean = 0.514). Subsequent addition of telaprevir resulted in a mean efficacy of more than 0.999. This was comparable to subjects who started all three medications simultaneously. A total of 80% achieved SVR. While rapid shifts in the RAV population following DAA initiation were observed, treatment failure associated with A156V was observed in only one patient. Adverse event profiles were similar to that observed in non-haemophilia cohorts. There was no evidence of factor inhibitor formation. There was no evidence that lead-in provided benefit in terms of response efficacy. Conclusion: These data support DAA-based therapy in those with inherited bleeding disorders.
    Article · Mar 2016 · Haemophilia
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    Jessica M Conway · Alan S Perelson
    [Show abstract] [Hide abstract] ABSTRACT: Antiretroviral therapy (ART) effectively controls HIV infection, suppressing HIV viral loads. However, some residual virus remains, below the level of detection, in HIV-infected patients on ART. The source of this viremia is an area of debate: does it derive primarily from activation of infected cells in the latent reservoir, or from ongoing viral replication? Observations seem to be contradictory: there is evidence of short term evolution, implying that there must be ongoing viral replication, and viral strains should thus evolve. However, phylogenetic analyses, and rare emergent drug resistance, suggest no long-term viral evolution, implying that virus derived from activated latent cells must dominate. We use simple deterministic and stochastic models to gain insight into residual viremia dynamics in HIV-infected patients. Our modeling relies on two underlying assumptions for patients on suppressive ART: that latent cell activation drives viral dynamics and that the reproductive ratio of treated infection is less than 1. Nonetheless, the contribution of viral replication to residual viremia in patients on ART may be non-negligible. However, even if the portion of viremia attributable to viral replication is significant, our model predicts (1) that latent reservoir re-seeding remains negligible, and (2) some short-term viral evolution is permitted, but long-term evolution can still be limited: stochastic analysis of our model shows that de novo emergence of drug resistance is rare. Thus, our simple models reconcile the seemingly contradictory observations on residual viremia and, with relatively few parameters, recapitulates HIV viral dynamics observed in patients on suppressive therapy.
    Full-text Article · Jan 2016 · PLoS Computational Biology
  • [Show abstract] [Hide abstract] ABSTRACT: Motivation: Illustrating how HIV-1 is transmitted and how it evolves in the following weeks is an important step for developing effective vaccination and prevention strategies. It is currently possible through DNA sequencing to account for the diverse array of viral strains within an infected individual. This provides an unprecedented opportunity to pinpoint when each patient was infected and which viruses were transmitted. Results: Here we develop a mathematical tool for early HIV-1 evolution within a subject whose infection originates either from a single or multiple viral variants. The shifted Poisson mixture model (SPMM) provides a quantitative guideline for segregating viral lineages, which in turn enables us to assess when a subject was infected. The infection duration estimated by SPMM showed a statistically significant linear relationship with that by Fiebig laboratory staging (p=0.00059) among 37 acutely infected subjects. Our tool provides a functional approach to understanding early genetic diversity, one of the most important parameters for deciphering HIV-1 transmission and predicting the rate of disease progression. Availability: SPMM, webserver, is available at http://www.hayounlee.org/web-tools.html CONTACT: hayoun@usc.edu.
    Article · Dec 2015 · Bioinformatics
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    [Show abstract] [Hide abstract] ABSTRACT: HIV-1 is subject to immune pressure exerted by the host, giving variants that escape the immune response an advantage. Virus released from activated latent cells competes against variants that have continually evolved and adapted to host immune pressure. Nevertheless, there is increasing evidence that virus displaying a signal of latency survives in patient plasma despite having reduced fitness due to long-term immune memory. We investigated the survival of virus with latent envelope genomic fragments by simulating within-host HIV-1 sequence evolution and the cycling of viral lineages in and out of the latent reservoir. Our model incorporates a detailed mutation process including nucleotide substitution, recombination, latent reservoir dynamics, diversifying selection pressure driven by the immune response, and purifying selection pressure asserted by deleterious mutations. We evaluated the ability of our model to capture sequence evolution in vivo by comparing our simulated sequences to HIV-1 envelope sequence data from 16 HIV-infected untreated patients. Empirical sequence divergence and diversity measures were qualitatively and quantitatively similar to those of our simulated HIV-1 populations, suggesting that our model invokes realistic trends of HIV-1 genetic evolution. Moreover, reconstructed phylogenies of simulated and patient HIV-1 populations showed similar topological structures. Our simulation results suggest that recombination is a key mechanism facilitating the persistence of virus with latent envelope genomic fragments in the productively infected cell population. Recombination increased the survival probability of latent virus forms approximately 13-fold. Prevalence of virus with latent fragments in productively infected cells was observed in only 2% of simulations when we ignored recombination, while the proportion increased to 27% of simulations when we allowed recombination. We also found that the selection pressures exerted by different fitness landscapes influenced the shape of phylogenies, diversity trends, and survival of virus with latent genomic fragments. Our model predicts that the persistence of latent genomic fragments from multiple different ancestral origins increases sequence diversity in plasma for reasonable fitness landscapes.
    Full-text Article · Dec 2015 · PLoS Computational Biology
  • Article · Dec 2015 · Hepatology
  • Laetitia Canini · Jeremie Guedj · Anushree Chatterjee · [...] · Alan S Perelson
    [Show abstract] [Hide abstract] ABSTRACT: Background: Modeling HCV RNA decline kinetics under therapy has proven useful for characterizing treatment effectiveness. Methods: Here we model HCV viral kinetics (VK) in 72 patients given a combination of danoprevir, a protease inhibitor and mericitabine, a nucleoside polymerase inhibitor for 14 days in the INFORM-1 trial. A biphasic VK model with time-varying danoprevir and mericitabine effectiveness and Bliss independence for characterizing the interaction between both drugs provided the best fit to the VK data. Results: The average final antiviral effectiveness of the drug combination varied between 0.998 for 100 mg tid of danoprevir and 500 mg bid of mericitabine and 0.9998 for 600 mg bid of danoprevir and 1000 mg bid of mericitabine. Using the individual parameters estimated from the VK data collected over 2 weeks, we were not able to reproduce the low SVR rates obtained in more recent study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir for 24 weeks. Conclusions: This suggests that drug-resistant viruses emerge after 2 weeks of treatment and that longer studies are necessary to provide accurate predictions of longer treatment outcomes.
    Article · Nov 2015 · Antiviral therapy
  • [Show abstract] [Hide abstract] ABSTRACT: Background: We analyzed the early kinetics with integrase inhibitor treatment to gain new insights into viral dynamics. Methodology: We analyzed data from 39 HIV-1 infected, treatment-naive, participants: 28 treated with raltegravir (RAL; multiple doses) monotherapy for 9 days, and 11 with RAL 400 mg twice daily and emtricitabine (200 mg daily)/tenofovir disoproxil fumarate (300 mg daily). Plasma HIV-1 RNA was measured frequently; the data was fitted using a mathematical model of viral dynamics distinguishing between infected cells with unintegrated HIV DNA and productively infected cells. Parameters were estimated using mixed-effect models. Results: RAL treatment led to a biphasic viral decline with a rapid first phase (1a) lasting approximately 5 days followed by a slower phase (1b). Phase 1a is attributed to the rapid elimination of productively infected cells. Phase 1b reflects the loss of infected cells with nonintegrated provirus due to cell loss and integration of HIV DNA. The half-lives of productively infected cells and of infected cells that had completed reverse transcription but had not yet integrated HIV DNA were approximately 19 h and between 3.6 and 5.8 days, respectively. The effectiveness of RAL in preventing proviral integration was 94% and 99.7%, for the combination therapy and monotherapy groups, respectively. Conclusion: We found that the first phase of viral decay with RAL therapy was composed of two subphases corresponding to the half-lives of infected cells with integrated proviruses and with unintegrated HIV-DNA.
    Article · Nov 2015 · AIDS
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    Ruian Ke · Sharon R Lewin · Julian H Elliott · Alan S Perelson
    [Show abstract] [Hide abstract] ABSTRACT: Recent efforts to cure human immunodeficiency virus type-1 (HIV-1) infection have focused on developing latency reversing agents as a first step to eradicate the latent reservoir. The histone deacetylase inhibitor, vorinostat, has been shown to activate HIV RNA transcription in CD4+ T-cells and alter host cell gene transcription in HIV-infected individuals on antiretroviral therapy. In order to understand how latently infected cells respond dynamically to vorinostat treatment and determine the impact of vorinostat on reservoir size in vivo, we have constructed viral dynamic models of latency that incorporate vorinostat treatment. We fitted these models to data collected from a recent clinical trial in which vorinostat was administered daily for 14 days to HIV-infected individuals on suppressive ART. The results show that HIV transcription is increased transiently during the first few hours or days of treatment and that there is a delay before a sustained increase of HIV transcription, whose duration varies among study participants and may depend on the long term impact of vorinostat on host gene expression. Parameter estimation suggests that in latently infected cells, HIV transcription induced by vorinostat occurs at lower levels than in productively infected cells. Furthermore, the estimated loss rate of transcriptionally induced cells remains close to baseline in most study participants, suggesting vorinostat treatment does not induce latently infected cell killing and thus reduce the latent reservoir in vivo.
    Full-text Article · Oct 2015 · PLoS Pathogens
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    [Show abstract] [Hide abstract] ABSTRACT: Importance: Despite the recent development of highly effective, interferon-sparing anti-hepatitis C virus (HCV) drugs, the global burden of this pathogen remains immense. Control or eradication of HCV will likely require the broad application of antiviral drugs and the development of an effective vaccine, which could be facilitated by a precise molecular identification of transmitted/founder (T/F) viral genomes and their progeny. We used single genome sequencing to show that inferred HCV T/F sequences in recipients were identical to viral sequences in their respective donors and that viral genomes generally evolved early in infection according to a simple model of random sequence evolution. Altogether, the findings validate T/F genome inferences and illustrate how T/F sequence identification can illuminate studies of HCV transmission, immunopathogenesis, drug resistance development and vaccine protection, including sieving effects on breakthrough virus strains.
    Full-text Article · Oct 2015 · Journal of Virology
  • Shishi Luo · Alan S Perelson
    [Show abstract] [Hide abstract] ABSTRACT: Antibody affinity maturation by somatic hypermutation of B-cell immunoglobulin variable region genes has been studied for decades in various model systems using well-defined antigens. While much is known about the molecular details of the process, our understanding of the selective forces that generate affinity maturation are less well developed, particularly in the case of a co-evolving pathogen such as HIV. Despite this gap in understanding, high-throughput antibody sequence data are increasingly being collected to investigate the evolutionary trajectories of antibody lineages in HIV-infected individuals. Here, we review what is known in controlled experimental systems about the mechanisms underlying antibody selection and compare this to the observed temporal patterns of antibody evolution in HIV infection. We describe how our current understanding of antibody selection mechanisms leaves questions about antibody dynamics in HIV infection unanswered. Without a mechanistic understanding of antibody selection in the context of a co-evolving viral population, modelling and analysis of antibody sequences in HIV-infected individuals will be limited in their interpretation and predictive ability. © 2015 The Author(s) Published by the Royal Society. All rights reserved.
    Article · Sep 2015 · Philosophical Transactions of The Royal Society B Biological Sciences
  • Shishi Luo · Alan S Perelson
    [Show abstract] [Hide abstract] ABSTRACT: The past decade has seen the discovery of numerous broad and potent monoclonal antibodies against HIV type 1 (HIV-1). Eliciting these antibodies via vaccination appears to be remarkably difficult, not least because they arise late in infection and are highly mutated relative to germline antibody sequences. Here, using a computational model, we show that broad antibodies could in fact emerge earlier and be less mutated, but that they may be prevented from doing so as a result of competitive exclusion by the autologous antibody response. We further find that this competitive exclusion is weaker in infections founded by multiple distinct strains, with broadly neutralizing antibodies emerging earlier than in infections founded by a single strain. Our computational model simulates coevolving multitype virus and antibody populations. Broadly neutralizing antibodies may therefore be easier for the adaptive immune system to generate than previously thought. If less mutated broad antibodies exist, it may be possible to elicit them with a vaccine containing a mixture of diverse virus strains.
    Article · Aug 2015 · Proceedings of the National Academy of Sciences
  • Article · Jul 2015 · Journal of the International AIDS Society
  • Alan S Perelson · Jeremie Guedj
    [Show abstract] [Hide abstract] ABSTRACT: Mathematically modelling changes in HCV RNA levels measured in patients who receive antiviral therapy has yielded many insights into the pathogenesis and effects of treatment on the virus. By determining how rapidly HCV is cleared when viral replication is interrupted by a therapy, one can deduce how rapidly the virus is produced in patients before treatment. This knowledge, coupled with estimates of the HCV mutation rate, enables one to estimate the frequency with which drug resistant variants arise. Modelling HCV also permits the deduction of the effectiveness of an antiviral agent at blocking HCV replication from the magnitude of the initial viral decline. One can also estimate the lifespan of an HCV-infected cell from the slope of the subsequent viral decline and determine the duration of therapy needed to cure infection. The original understanding of HCV RNA decline under interferon-based therapies obtained by modelling needed to be revised in order to interpret the HCV RNA decline kinetics seen when using direct-acting antiviral agents (DAAs). There also exist unresolved issues involving understanding therapies with combinations of DAAs, such as the presence of detectable HCV RNA at the end of therapy in patients who nonetheless have a sustained virologic response.
    Article · Jun 2015 · Nature Reviews Gastroenterology &#38 Hepatology

Publication Stats

45k Citations

Institutions

  • 1987-2015
    • Los Alamos National Laboratory
      • Theoretical Biology and Biophysics Group
      Лос-Аламос, California, United States
  • 2007
    • Purdue University
      • Department of Mathematics
      ウェストラファイエット, Indiana, United States
  • 2006
    • Weill Cornell Medical College
      • Center for the Study of Hepatitis C
      New York City, New York, United States
    • University of Virginia
      Charlottesville, Virginia, United States
  • 1999-2006
    • The Rockefeller University
      • • Laboratory of Virology and Infectious Disease
      • • Aaron Diamond AIDS Research Center (ADARC)
      New York, New York, United States
    • University of Illinois at Chicago
      Chicago, Illinois, United States
  • 2005
    • Georgia Institute of Technology
      Atlanta, Georgia, United States
  • 2004
    • Columbia University
      New York, New York, United States
    • University of New South Wales
      Kensington, New South Wales, Australia
    • University of Oxford
      Oxford, England, United Kingdom
  • 2001-2004
    • University of Michigan
      • Department of Mathematics
      Ann Arbor, MI, United States
    • Royal Melbourne Hospital
      Melbourne, Victoria, Australia
  • 2002-2003
    • Cornell University
      • Department of Ecology and Evolutionary Biology
      Ithaca, NY, United States
  • 1997-2003
    • University of New Mexico
      • Department of Computer Science
      Albuquerque, NM, United States
  • 1993-2001
    • Santa Fe Institute
      Santa Fe, New Mexico, United States
    • Stanford University
      • Department of Mathematics
      Stanford, CA, United States
  • 1998
    • Northern Arizona University
      • Department of Chemistry and Biochemistry
      Flagstaff, Arizona, United States
    • Bar Ilan University
      • Faculty of Life Sciences
      Ramat Gan, Tel Aviv, Israel
    • Harvard University
      • Department of Molecular and Cell Biology
      Cambridge, Massachusetts, United States
    • University of Washington Seattle
      Seattle, Washington, United States
  • 1992-1997
    • Princeton University
      • • Department of Molecular Biology
      • • Department of Chemical and Biological Engineering
      Princeton, NJ, United States
  • 1994
    • Universiteit Utrecht
      • Division of Theoretical Biology and Bioinformatics
      Utrecht, Provincie Utrecht, Netherlands
  • 1981
    • Brown University
      • The Lefschetz Center for Dynamical Systems
      Providence, RI, United States
  • 1980
    • National Institutes of Health
      베서스다, Maryland, United States
    • University of California
      Oakland, California, United States
  • 1976-1979
    • University of California, Los Angeles
      Los Ángeles, California, United States
  • 1972-1974
    • University of California, Berkeley
      Berkeley, California, United States
    • University of Berkley
      Berkley, Michigan, United States