Opportunistic infection as a cause of transient viremia in chronically infected HIV patients under treatment with HAART

When highly active antiretroviral therapy is administered for long periods of time to HIV-1 infected patients, most patients achieve viral loads that are ``undetectable'' by standard assay (i.e., HIV-1 RNA $< 50$ copies/ml). Yet despite exhibiting sustained viral loads below the level of detection, a number of these patients experience unexplained episodes of transient viremia or viral "blips". We propose here that transient activation of the immune system by opportunistic infection may explain these episodes of viremia. Indeed, immune activation by opportunistic infection may spur HIV replication, replenish viral reservoirs and contribute to accelerated disease progression. In order to investigate the effects of concurrent infection on chronically infected HIV patients under treatment with highly active antiretroviral therapy (HAART), we extend a simple dynamic model of the effects of vaccination on HIV infection [Jones and Perelson, JAIDS 31:369-377, 2002] to include growing pathogens. We then propose a more realistic model for immune cell expansion in the presence of pathogen, and include this in a set of competing models that allow low baseline viral loads in the presence of drug treatment. Programmed expansion of immune cells upon exposure to antigen is a feature not previously included in HIV models, and one that is especially important to consider when simulating an immune response to opportunistic infection. Using these models we show that viral blips with realistic duration and amplitude can be generated by concurrent infections in HAART treated patients.Comment: 30 pages, 9 figures, 1 table. Submitted to Bulletin of Mathematical Biolog

Inferring HIV escape rates from multi-locus genotype data

Cytotoxic T-lymphocytes (CTLs) recognize viral protein fragments displayed by major histocompatibility complex (MHC) molecules on the surface of virally infected cells and generate an anti-viral response that can kill the infected cells. Virus variants whose protein fragments are not efficiently presented on infected cells or whose fragments are presented but not recognized by CTLs therefore have a competitive advantage and spread rapidly through the population. We present a method that allows a more robust estimation of these escape rates from serially sampled sequence data. The proposed method accounts for competition between multiple escapes by explicitly modeling the accumulation of escape mutations and the stochastic effects of rare multiple mutants. Applying our method to serially sampled HIV sequence data, we estimate rates of HIV escape that are substantially larger than those previously reported. The method can be extended to complex escapes that require compensatory mutations. We expect our method to be applicable in other contexts such as cancer evolution where time series data is also available

Regulation of T cell expansion by antigen presentation dynamics

An essential feature of the adaptive immune system is the proliferation of antigen-specific lymphocytes during an immune reaction to form a large pool of effector cells. This proliferation must be regulated to ensure an effective response to infection while avoiding immunopathology. Recent experiments in mice have demonstrated that the expansion of a specific clone of T cells in response to cognate antigen obeys a striking inverse power law with respect to the initial number of T cells. Here, we show that such a relationship arises naturally from a model in which T cell expansion is limited by decaying levels of presented antigen. The same model also accounts for the observed dependence of T cell expansion on affinity for antigen and on the kinetics of antigen administration. Extending the model to address expansion of multiple T cell clones competing for antigen, we find that higher affinity clones can suppress the proliferation of lower affinity clones, thereby promoting the specificity of the response. Employing the model to derive optimal vaccination protocols, we find that exponentially increasing antigen doses can achieve a nearly optimized response. We thus conclude that the dynamics of presented antigen is a key regulator of both the size and specificity of the adaptive immune response

Statistical mechanics of red blood cell aggregation: The distribution of rouleaux in thermal equilibrium

When placed in suspension red blood cells adhere face-to-face and form long, cylindrical, and sometimes branched structures called rouleaux. We use methods developed in statistical mechanics to compute various statistical properties describing the size and shape of rouleaux in thermodynamic equilibrium. This leads to analytical expressions for (1) the average number of rouleaux consisting ofn cells and havingm branch points; (2) the average number of cells per rouleau; (3) the average number of branch points per rouleau; and (4) the number of rouleaux withn cells in a system containing a total ofN cells. We also derive asymptotic formulas that simplify these analytic expressions, and present numerical comparisons of the exact and asymptotic results

Introduction to modeling viral infections and immunity

Copyright © 2018 John Wiley & Sons, Inc. All rights reserved.Infectious agents, such as HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), malaria, and influenza remain significant public health threats, with ~41 million people chronically infected by HIV, ~331 million infected by HBV, ~148 million infected by HCV, and ~351 million cases of malaria, according to the Global Burden of Disease 2013 study. In addition, threats of new influenza pandemics or emerging viruses, such as Ebola and Zika, have created alarm in the United States and in many parts of the world. Despite intensive research efforts by public and private institutions, there are still no vaccines for HIV, HCV, malaria, Ebola, Zika, and many other pathogens. Even though there has been enormous progress with antiviral therapies for chronic infections, we are still unable to cure HIV and HBV, and life‐long treatment is needed.info:eu-repo/semantics/publishedVersio

The role of infected cell proliferation in the clearance of acute HBV Infection in humans

© 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Around 90–95% of hepatitis B virus (HBV) infected adults do not progress to the chronic phase and, instead, recover naturally. The strengths of the cytolytic and non-cytolytic immune responses are key players that decide the fate of acute HBV infection. In addition, it has been hypothesized that proliferation of infected cells resulting in uninfected progeny and/or cytokine-mediated degradation of covalently closed circular DNA (cccDNA) leading to the cure of infected cells are two major mechanisms assisting the adaptive immune response in the clearance of acute HBV infection in humans. We employed fitting of mathematical models to human acute infection data together with physiological constraints to investigate the role of these hypothesized mechanisms in the clearance of infection. Results suggest that cellular proliferation of infected cells resulting in two uninfected cells is required to minimize the destruction of the liver during the clearance of acute HBV infection. In contrast, we find that a cytokine-mediated cure of infected cells alone is insufficient to clear acute HBV infection. In conclusion, our modeling indicates that HBV clearance without lethal loss of liver mass is associated with the production of two uninfected cells upon proliferation of an infected cell.This work was funded by National Institutes of Health grants R01-AI116868 (RMR), R01-AI028433 (ASP) and R01-OD011095 (ASP). Portions of this work were performed under the auspices of the U.S. Department of Energy under contract DE-AC52-06NA25396.info:eu-repo/semantics/publishedVersio

Viral and Latent Reservoir Persistence in HIV-1–Infected Patients on Therapy

Despite many years of potent antiretroviral therapy, latently infected cells and low levels of plasma virus have been found to persist in HIV-infected patients. The factors influencing this persistence and their relative contributions have not been fully elucidated and remain controversial. Here, we address these issues by developing and employing a simple, but mechanistic viral dynamics model. The model has two novel features. First, it assumes that latently infected T cells can undergo bystander proliferation without transitioning into active viral production. Second, it assumes that the rate of latent cell activation decreases with time on antiretroviral therapy due to the activation and subsequent loss of latently infected cells specific for common antigens, leaving behind cells that are successively less frequently activated. Using the model, we examined the quantitative contributions of T cell bystander proliferation, latent cell activation, and ongoing viral replication to the stability of the latent reservoir and persisting low-level viremia. Not surprisingly, proliferation of latently infected cells helped maintain the latent reservoir in spite of loss of latent infected cells through activation and death, and affected viral dynamics to an extent that depended on the magnitude of latent cell activation. In the limit of zero latent cell activation, the latent cell pool and viral load became uncoupled. However, as the activation rate increased, the plasma viral load could be maintained without depleting the latent reservoir, even in the absence of viral replication. The influence of ongoing viral replication on the latent reservoir remained insignificant for drug efficacies above the “critical efficacy” irrespective of the activation rate. However, for lower drug efficacies viral replication enabled the stable maintenance of both the latent reservoir and the virus. Our model and analysis methods provide a quantitative and qualitative framework for probing how different viral and host factors contribute to the dynamics of the latent reservoir and the virus, offering new insights into the principal determinants of their persistence