Alan S Perelson

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

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Publications (552)3055.27 Total impact

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    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.
    Antiviral therapy 11/2015; DOI:10.3851/IMP3006 · 3.02 Impact Factor

  • AIDS 11/2015; 29(18):2419-2426. DOI:10.1097/QAD.0000000000000843 · 5.55 Impact Factor
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    Ruian Ke · Sharon R Lewin · Julian H Elliott · Alan S Perelson ·
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    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.
    PLoS Pathogens 10/2015; 11(10):e1005237. DOI:10.1371/journal.ppat.1005237 · 7.56 Impact Factor
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    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.
    Journal of Virology 10/2015; DOI:10.1128/JVI.02156-15 · 4.44 Impact Factor
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    Shishi Luo · Alan S Perelson ·
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    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.
    Philosophical Transactions of The Royal Society B Biological Sciences 09/2015; 370(1676). DOI:10.1098/rstb.2014.0247 · 7.06 Impact Factor
  • Shishi Luo · Alan S Perelson ·
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    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.
    Proceedings of the National Academy of Sciences 08/2015; 112(37). DOI:10.1073/pnas.1505207112 · 9.67 Impact Factor
  • Alan S Perelson · Jeremie Guedj ·
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    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.
    Nature Reviews Gastroenterology &#38 Hepatology 06/2015; 12(8). DOI:10.1038/nrgastro.2015.97 · 12.61 Impact Factor
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    ABSTRACT: Background: Emerging data relating to human immunodeficiency virus type 1 (HIV-1) cure suggest that vaccination to stimulate the host immune response, particularly cytotoxic cells, may be critical to clearing of reactivated HIV-1-infected cells. However, evidence for this approach in humans is lacking, and parameters required for a vaccine are unknown because opportunities to study HIV-1 reactivation are rare. Methods: We present observations from a HIV-1 elite controller, not treated with combination antiretroviral therapy, who experienced viral reactivation following treatment for myeloma with melphalan and autologous stem cell transplantation. Mathematical modeling was performed using a standard viral dynamic model. Enzyme-linked immunospot, intracellular cytokine staining, and tetramer staining were performed on peripheral blood mononuclear cells; in vitro CD8 T-cell-mediated control of virion production by autologous CD4 T cells was quantified; and neutralizing antibody titers were measured. Results: Viral rebound was measured at 28,000 copies/mL on day 13 post-transplant before rapid decay to <50 copies/mL in 2 distinct phases with t1/2 of 0.71 days and 4.1 days. These kinetics were consistent with an expansion of cytotoxic effector cells and killing of productively infected CD4 T cells. Following transplantation, innate immune cells, including natural killer cells, recovered with virus rebound. However, most striking was the expansion of highly functional HIV-1-specific cytotoxic CD8 T cells, at numbers consistent with those applied in modeling, as virus control was regained. Conclusions: These observations provide evidence that the human immune response is capable of controlling coordinated global HIV-1 reactivation, remarkably with potency equivalent to combination antiretroviral therapy. These data will inform design of vaccines for use in HIV-1 curative interventions.
    Clinical Infectious Diseases 06/2015; 61(1). DOI:10.1093/cid/civ219 · 8.89 Impact Factor
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    ABSTRACT: BACKGROUND: HCV kinetic analysis and modeling during antiviral therapy have not been performed in decompensated cirrhotic patients awaiting liver transplantation. Here, viral and host parameters were compared in patients treated with daily intravenous silibinin (SIL) monotherapy for 7 days according to the severity of their liver disease. METHODS: Data were obtained from 25 patients, 12 non-cirrhotic, 8 with compensated cirrhosis and 5 with decompensated cirrhosis. The standard-biphasic model with time-varying SIL effectiveness (from 0 to εmax) was fit to viral kinetic data. RESULTS: Baseline viral load and age were significantly associated with the severity of liver disease (p<0.0001). A biphasic viral decline was observed in most patients with a higher first phase decline patients with less severe liver disease. The maximal effectiveness, εmax, was significantly (p≤0.032) associated with increasing severity of liver disease (εmax[s.e.]=0.86[0.05], εmax=0.69[0.06] and εmax=0.59[0.1]). . The 2(nd) phase decline slope was not significantly different among groups (mean 1.88±0.15 log10IU/ml/wk, p=0.75) as was the rate of change of SIL effectiveness (k=2.12/day[standard error, s.e.=0.18/day]). HCV-infected cell loss rate (δ[s.e.]=0.62/day[0.05/day]) was high and similar among groups. CONCLUSIONS: The high loss rate of HCV-infected cells suggests that sufficient dose and duration of SIL might achieve viral suppression in advanced liver disease.
    Antiviral therapy 05/2015; 20(2):149-155. DOI:10.3851/IMP2806 · 3.02 Impact Factor
  • Jessica M Conway · Alan S Perelson ·
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    ABSTRACT: Antiretroviral therapy (ART) for HIV is not a cure. However, recent studies suggest that ART, initiated early during primary infection, may induce post-treatment control (PTC) of HIV infection with HIV RNA maintained at <50 copies per mL. We investigate the hypothesis that ART initiated early during primary infection permits PTC by limiting the size of the latent reservoir, which, if small enough at treatment termination, may allow the adaptive immune response to prevent viral rebound (VR) and control infection. We use a mathematical model of within host HIV dynamics to capture interactions among target cells, productively infected cells, latently infected cells, virus, and cytotoxic T lymphocytes (CTLs). Analysis of our model reveals a range in CTL response strengths where a patient may show either VR or PTC, depending on the size of the latent reservoir at treatment termination. Below this range, patients will always rebound, whereas above this range, patients are predicted to behave like elite controllers. Using data on latent reservoir sizes in patients treated during primary infection, we also predict population-level VR times for noncontrollers consistent with observations.
    Proceedings of the National Academy of Sciences 04/2015; 112(17). DOI:10.1073/pnas.1419162112 · 9.67 Impact Factor
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    ABSTRACT: It has been proposed that viral cell-to-cell transmission plays a role in establishing and maintaining chronic infections. Thus, understanding the mechanisms and kinetics of cell-to-cell spread are fundamental to elucidating the dynamics of infection and may provide insight into factors that determine chronicity. Because hepatitis C virus (HCV) spreads cell-to-cell and HCV has a chronicity rate of up to 80% in exposed individuals, we examined the dynamics of HCV cell-to-cell spread in vitro and quantified the effect of inhibiting individual host factors. Using a multidisciplinary approach, we performed HCV spread assays and assessed the appropriateness of different stochastic models for describing HCV foci expansion. To evaluate the effect of blocking specific host cell factors on HCV cell-to-cell transmission, assays were performed in the presence of blocking antibodies and/or small molecule inhibitors targeting different cellular HCV entry factors. In all experiments, HCV positive cells were identified by immunohistochemical staining and the number of HCV-positive cells per focus was counted to determine focus size. We found that HCV foci expansion can best be explained by mathematical models assuming foci size-dependent growth. Consistent with previous reports suggesting some factors impact HCV cell-to-cell spread to different extents, modeling results estimate a hierarchy of efficacies for blocking HCV cell-to-cell spread when targeting different host factors (e.g. CLDN1 > NPC1L1 > TfR1). This approach can be adapted to describe foci expansion dynamics under a variety of experimental conditions as a means to quantify cell-to-cell transmission and assess the impact of cellular factors, viral factors and antivirals. The ability of viruses to efficiently spread by direct cell-to-cell transmission is thought to play an important role the establishment and maintenance of viral persistence. As such, elucidating the dynamics of cell-to-cell spread and quantifying the effect of blocking the factors involved has important implications for the design of potent antiviral strategies and controlling viral escape. Mathematical modeling has been widely used to understand HCV infection dynamics and treatment response, however these models typically assume only cell-free virus infection mechanisms. Here, we used stochastic models describing foci expansion as a means to understand and quantify the dynamics of HCV cell-to-cell spread in vitro and determined the degree to which cell-to-cell spread is reduced when individual HCV entry factors are blocked. The results presented demonstrate the ability of this approach to recapitulate and quantify cell-to-cell transmission, as well as the impact of specific factors and potential antivirals. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Journal of Virology 04/2015; 89(13). DOI:10.1128/JVI.00016-15 · 4.44 Impact Factor
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    ABSTRACT: Control of virus replication in HIV-1 infection is critical to delaying disease progression. While cellular immune responses are a key determinant of control, relatively little is known about the contribution of the infecting virus to this process. To gain insight into this interplay between virus and host in viral control, we conducted a detailed analysis of two heterosexual HIV-1 subtype A transmission pairs in which female recipients sharing three HLA class I alleles exhibited contrasting clinical outcomes: R880F controlled virus replication while R463F experienced high viral loads and rapid disease progression. Near full-length single genome amplification defined the infecting transmitted/founder (T/F) virus proteome and subsequent sequence evolution over the first year of infection for both acutely infected recipients. T/F virus replicative capacities were compared in vitro, while the development of the earliest cellular immune response was defined using autologous virus sequence-based peptides. The R880F T/F virus replicated significantly slower in vitro than that transmitted to R463F. While neutralizing antibody responses were similar in both subjects, during acute infection R880F mounted a broad T cell response, the most dominant components of which targeted epitopes from which escape was limited. In contrast, the primary HIV-specific T cell response in R463F was focused on just two epitopes, one of which rapidly escaped. This comprehensive study highlights both the importance of the contribution of the lower replication capacity of the transmitted/founder virus and an associated induction of a broad primary HIV-specific T cell response, which was not undermined by rapid epitope escape, to long-term viral control in HIV-1 infection. It underscores the importance of the earliest CD8 T cell response targeting regions of the virus proteome that cannot mutate without a high fitness cost, further emphasizing the need for vaccines that elicit a breadth of T cell responses to conserved viral epitopes.
    PLoS Pathogens 01/2015; 11(1):e1004565. DOI:10.1371/journal.ppat.1004565 · 7.56 Impact Factor
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    ABSTRACT: Background Fitness costs and slower disease progression are associated with a cytolytic T lymphocyte (CTL) escape mutation T242N in Gag in HIV-1-infected individuals carrying HLA-B*57/5801 alleles. However, the impact of different context in diverse HIV-1 strains on the fitness costs due to the T242N mutation has not been well characterized. To better understand the extent of fitness costs of the T242N mutation and the repair of fitness loss through compensatory amino acids, we investigated its fitness impact in different transmitted/founder (T/F) viruses.ResultsThe T242N mutation resulted in various levels of fitness loss in four different T/F viruses. However, the fitness costs were significantly compromised by preexisting compensatory amino acids in (Isoleucine at position 247) or outside (glutamine at position 219) the CTL epitope. Moreover, the transmitted T242N escape mutant in subject CH131 was as fit as the revertant N242T mutant and the elimination of the compensatory amino acid I247 in the T/F viral genome resulted in significant fitness cost, suggesting the fitness loss caused by the T242N mutation had been fully repaired in the donor at transmission. Analysis of the global circulating HIV-1 sequences in the Los Alamos HIV Sequence Database showed a high prevalence of compensatory amino acids for the T242N mutation and other T cell escape mutations.Conclusions Our results show that the preexisting compensatory amino acids in the majority of circulating HIV-1 strains could significantly compromise the fitness loss due to CTL escape mutations and thus increase challenges for T cell based vaccines.
    Retrovirology 11/2014; 11(1):101. DOI:10.1186/s12977-014-0101-0 · 4.19 Impact Factor
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    ABSTRACT: Chronic liver infection by hepatitis C virus (HCV) is a major public health concern. Despite partly successful treatment options, several aspects of intrahepatic HCV infection dynamics are still poorly understood, including the preferred mode of viral propagation, as well as the proportion of infected hepatocytes. Answers to these questions have important implications for the development of therapeutic interventions. In this study, we present methods to analyze the spatial distribution of infected hepatocytes obtained by single cell laser capture microdissection from liver biopsy samples of patients chronically infected with HCV. By characterizing the internal structure of clusters of infected cells, we are able to evaluate hypotheses about intrahepatic infection dynamics. We found that individual clusters on biopsy samples range in size from [Formula: see text] infected cells. In addition, the HCV RNA content in a cluster declines from the cell that presumably founded the cluster to cells at the maximal cluster extension. These observations support the idea that HCV infection in the liver is seeded randomly (e.g. from the blood) and then spreads locally. Assuming that the amount of intracellular HCV RNA is a proxy for how long a cell has been infected, we estimate based on models of intracellular HCV RNA replication and accumulation that cells in clusters have been infected on average for less than a week. Further, we do not find a relationship between the cluster size and the estimated cluster expansion time. Our method represents a novel approach to make inferences about infection dynamics in solid tissues from static spatial data.
    PLoS Computational Biology 11/2014; 10(11):e1003934. DOI:10.1371/journal.pcbi.1003934 · 4.62 Impact Factor
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    ABSTRACT: Background: Viral kinetic models have proven useful to characterize treatment effectiveness during HCV therapy with interferon (IFN) or with direct-acting antivirals. Methods: We use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with danoprevir, a protease inhibitor. In a Phase I study, danoprevir monotherapy was administered for 14 days in ascending doses ranging from 200 to 600 mg per day to 40 patients of whom 32 were treatment-naive and 8 were non-responders to prior pegylated IFN-α/ribavirin treatment. Results: In all patients, a biphasic decline of HCV RNA during therapy was observed. A two-compartment PK model and a VK model that considered treatment effectiveness to vary with the predicted danoprevir concentration inside the second compartment provided a good fit to the viral load data. A time-varying effectiveness model was also used to fit the viral load data. The antiviral effectiveness increased in a dose-dependent manner, with a 14-day time-averaged effectiveness of 0.95 at the lowest dose (100 mg twice daily) and 0.99 at the highest dose (200 mg three times daily). Prior IFN non-responders exhibited a 14-day time-averaged effectiveness of 0.98 (300 mg twice daily). The second phase decline showed two different behaviours, with 30% of patients exhibiting a rapid decline of HCV RNA, comparable to that seen with other protease inhibitors (>0.3 day(-1)), whereas the viral decline was slower in the other patients. Conclusions: Our results are consistent with the modest SVR rates from the INFORM-SVR study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir.
    Antiviral therapy 10/2014; DOI:10.3851/IMP2879 · 3.02 Impact Factor
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    Christian L Althaus · Beda Joos · Alan S Perelson · Huldrych F Günthard ·
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    ABSTRACT: HIV-1-infected cells in peripheral blood can be grouped into different transcriptional subclasses. Quantifying the turnover of these cellular subclasses can provide important insights into the viral life cycle and the generation and maintenance of latently infected cells. We used previously published data from five patients chronically infected with HIV-1 that initiated combination antiretroviral therapy (cART). Patient-matched PCR for unspliced and multiply spliced viral RNAs combined with limiting dilution analysis provided measurements of transcriptional profiles at the single cell level. Furthermore, measurement of intracellular transcripts and extracellular virion-enclosed HIV-1 RNA allowed us to distinguish productive from non-productive cells. We developed a mathematical model describing the dynamics of plasma virus and the transcriptional subclasses of HIV-1-infected cells. Fitting the model to the data allowed us to better understand the phenotype of different transcriptional subclasses and their contribution to the overall turnover of HIV-1 before and during cART. The average number of virus-producing cells in peripheral blood is small during chronic infection. We find that a substantial fraction of cells can become defectively infected. Assuming that the infection is homogenous throughout the body, we estimate an average in vivo viral burst size on the order of 104 virions per cell. Our study provides novel quantitative insights into the turnover and development of different subclasses of HIV-1-infected cells, and indicates that cells containing solely unspliced viral RNA are a good marker for viral latency. The model illustrates how the pool of latently infected cells becomes rapidly established during the first months of acute infection and continues to increase slowly during the first years of chronic infection. Having a detailed understanding of this process will be useful for the evaluation of viral eradication strategies that aim to deplete the latent reservoir of HIV-1.
    PLoS Computational Biology 10/2014; 10(10):e1003871. DOI:10.1371/journal.pcbi.1003871 · 4.62 Impact Factor
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    ABSTRACT: The B cell response to influenza infection of the respiratory tract contributes to viral clearance and establishes profound resistance to reinfection by related viruses. Numerous studies have measured virus-specific antibody-secreting cell (ASC) frequencies in different anatomical compartments after influenza infection and provided a general picture of the kinetics of ASC formation and dispersion. However, the dynamics of ASC populations are difficult to determine experimentally and have received little attention. Here, we applied mathematical modeling to investigate the dynamics of ASC growth, death, and migration over the 2-week period following primary influenza infection in mice. Experimental data for model fitting came from high frequency measurements of virus-specific IgM, IgG, and IgA ASCs in the mediastinal lymph node (MLN), spleen, and lung. Model construction was based on a set of assumptions about ASC gain and loss from the sampled sites, and also on the directionality of ASC trafficking pathways. Most notably, modeling results suggest that differences in ASC fate and trafficking patterns reflect the site of formation and the expressed antibody class. Essentially all early IgA ASCs in the MLN migrated to spleen or lung, whereas cell death was likely the major reason for IgM and IgG ASC loss from the MLN. In contrast, the spleen contributed most of the IgM and IgG ASCs that migrated to the lung, but essentially none of the IgA ASCs. This finding points to a critical role for regional lymph nodes such as the MLN in the rapid generation of IgA ASCs that seed the lung. Results for the MLN also suggest that ASC death is a significant early feature of the B cell response. Overall, our analysis is consistent with accepted concepts in many regards, but it also indicates novel features of the B cell response to influenza that warrant further investigation.
    PLoS ONE 08/2014; 9(8):e104781. DOI:10.1371/journal.pone.0104781 · 3.23 Impact Factor
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    Jessica M Conway · Alan S Perelson ·
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    ABSTRACT: Simple models of therapy for viral diseases such as hepatitis C virus (HCV) or human immunodeficiency virus assume that, once therapy is started, the drug has a constant effectiveness. More realistic models have assumed either that the drug effectiveness depends on the drug concentration or that the effectiveness varies over time. Here a previously introduced varying-effectiveness (VE) model is studied mathematically in the context of HCV infection. We show that while the model is linear, it has no closed-form solution due to the time-varying nature of the effectiveness. We then show that the model can be transformed into a Bessel equation and derive an analytic solution in terms of modified Bessel functions, which are defined as infinite series, with time-varying arguments. Fitting the solution to data from HCV infected patients under therapy has yielded values for the parameters in the model. We show that for biologically realistic parameters, the predicted viral decay on therapy is generally biphasic and resembles that predicted by constant-effectiveness (CE) models. We introduce a general method for determining the time at which the transition between decay phases occurs based on calculating the point of maximum curvature of the viral decay curve. For the parameter regimes of interest, we also find approximate solutions for the VE model and establish the asymptotic behavior of the system. We show that the rate of second phase decay is determined by the death rate of infected cells multiplied by the maximum effectiveness of therapy, whereas the rate of first phase decline depends on multiple parameters including the rate of increase of drug effectiveness with time.
    PLoS Computational Biology 08/2014; 10(8):e1003769. DOI:10.1371/journal.pcbi.1003769 · 4.62 Impact Factor
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    ABSTRACT: The hepatitis C virus (HCV) is an important contributor to morbidity and mortality in patients co-infected with HIV. Co-infection results in increased HCV replication and more rapid rates of liver disease progression. The effect of HIV combination antiretroviral therapy (cART) on HCV replication has not been studied in depth. To address this issue, we enrolled a small cohort of HCV/HIV co-infected patients into a cART initiation trial and used dynamic modeling combined with evaluation of immune responses and microarray profiles to determine how effective treatment of HIV affects HCV. Treatment with cART resulted in increased HCV replication and increased alanine aminotransferase (ALT) in a subset of patients. Subjects with evidence of hepatic injury (increased ALT) were more likely to have HCV-specific immune responses directed against HCV epitopes. Over time, HCV viral loads declined. Reproducible and biologically important gene expression changes occurred in co-infected patients who underwent successful cART. The effective suppression of HIV by cART initiated a cascade of early and late events in treated patients. Early events involving down-regulation of interferon-stimulated genes may have led to transiently increased viral replication and hepatic injury. At later time points, HCV viral load declined to levels comparable to those seen in the setting of HCV monoinfection. These findings support early antiretroviral therapy in those with HCV/HIV co-infection.
    Science translational medicine 07/2014; 6(246):246ra98. DOI:10.1126/scitranslmed.3008195 · 15.84 Impact Factor
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    ABSTRACT: scitranslmed.3008195 , 246ra98 (2014); 6 Sci Transl Med et al. Kenneth E. Sherman HCV/HIV co-infected patients Modulation of HCV replication after combination antiretroviral therapy in Editor's Summary infection. HIV suppression with antiretroviral medications plays an important role in the management of those with HCV and HIV This process is highly modulated by responses of the interferon-responsive gene family. The findings suggest that viral replication and evidence of liver injury. Over time, however, HIV suppression leads to reduced HCV replication. biological effects. They show that the initial response to effective HIV treatment results in a transient increase in HCV try and unravel some of these et al. virus (HCV). In a new study of patients co-infected with HCV and HIV, Sherman There is a complex interaction of biological effects when patients are infected with both HIV and the hepatitis C
    Science translational medicine 07/2014; 6(246):98. · 15.84 Impact Factor

Publication Stats

38k Citations
3,055.27 Total Impact Points


  • 1982-2015
    • Los Alamos National Laboratory
      • • Theoretical Biology and Biophysics Group
      • • Theoretical Division
      Лос-Аламос, California, United States
    • Universiteit Twente
      Enschede, Overijssel, Netherlands
  • 1989-2013
    • Santa Fe Institute
      Santa Fe, New Mexico, United States
  • 2011
    • University Center Rochester
      • Department of Medicine
      Rochester, Minnesota, United States
  • 2008-2011
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      North Carolina, United States
    • Massachusetts General Hospital
      • Pediatric Infectious Disease Unit
      Boston, Massachusetts, United States
  • 2002-2011
    • University of Rochester
      • Department of Biostatistics and Computational Biology
      Rochester, NY, United States
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      Erlangen, Bavaria, Germany
  • 2010
    • Wisconsin National Primate Research Center
      Madison, Wisconsin, United States
  • 2007
    • Purdue University
      • Department of Mathematics
      ウェストラファイエット, Indiana, United States
  • 1997-2007
    • The Rockefeller University
      • • Laboratory of Virology and Infectious Disease
      • • Aaron Diamond AIDS Research Center (ADARC)
      New York City, New York, United States
  • 2006
    • Weill Cornell Medical College
      • Center for the Study of Hepatitis C
      New York City, New York, United States
    • University Medical Center Utrecht
      • Department of Immunology
      Utrecht, Provincie Utrecht, Netherlands
  • 1997-2005
    • University of Illinois at Chicago
      • • Department of Medicine (Chicago)
      • • Department of Pharmacy Practice
      Chicago, Illinois, United States
  • 2004
    • University of New South Wales
      Kensington, New South Wales, Australia
    • Columbia University
      New York, New York, United States
    • Prince of Wales Hospital and Community Health Services
      Sydney, New South Wales, Australia
  • 1997-2004
    • University of New Mexico
      • Department of Computer Science
      Albuquerque, New Mexico, United States
  • 1989-2004
    • University of Michigan
      • • Department of Mathematics
      • • Division of Computer Science and Engineering
      Ann Arbor, MI, United States
  • 2003
    • University of California, San Diego
      • Division of Infectious Diseases
      San Diego, CA, United States
    • Cornell University
      • Department of Ecology and Evolutionary Biology
      Ithaca, NY, United States
  • 2001
    • Royal Melbourne Hospital
      Melbourne, Victoria, Australia
    • Brigham Young University - Provo Main Campus
      Provo, Utah, United States
  • 1998-1999
    • Northern Arizona University
      • Department of Chemistry and Biochemistry
      Flagstaff, Arizona, United States
    • Harvard University
      • Department of Molecular and Cell Biology
      Cambridge, Massachusetts, United States
    • Bar Ilan University
      • Faculty of Life Sciences
      Ramat Gan, Tel Aviv, Israel
  • 1993-1998
    • Utrecht University
      • Division of Theoretical Biology and Bioinformatics
      Utrecht, Utrecht, Netherlands
  • 1992-1997
    • Princeton University
      • • Department of Molecular Biology
      • • Department of Chemical and Biological Engineering
      Princeton, NJ, United States
  • 1989-1993
    • Stanford University
      • Department of Mathematics
      Stanford, CA, United States
  • 1972-1987
    • University of California, Berkeley
      • Lawrence Berkeley Laboratory
      Berkeley, California, United States
    • University of Berkley
      Berkley, Michigan, United States
  • 1980-1982
    • Brown University
      • • The Lefschetz Center for Dynamical Systems
      • • Division of Biology and Medicine
      Providence, Rhode Island, United States
    • National Institutes of Health
      베서스다, Maryland, United States
  • 1976-1981
    • University of California, Los Angeles
      Los Ángeles, California, United States