Dynamics Of HIV Infection Research Articles

Raltegravir blocks the infectivity of red-fluorescent-protein (mCherry)-labeled HIV-1JR-FL in the setting of post-exposure prophylaxis in NOD/SCID/Jak3−/− mice transplanted with human PBMCs

Employing NOD/SCID/Jak3−/− mice transplanted with human PBMCs (hNOJ mice) and replication-competent, red-fluorescent-protein (mCherry; mC)-labeled HIV-1JR-FL (HIVmC), we examined whether early antiretroviral treatment blocked the establishment of HIV-1 infection. The use of hNOJ mice and HIVmC enabled us to visually locate infection foci and to examine the early dynamics of HIVmC infection without using a large amount of antiretroviral unlike in non-human primate models. Although when raltegravir (RAL) administration was begun 1 day after intraperitoneal (ip) inoculation of HIVmC, no plasma p24 or plasma HIV-1-RNA (pRNA) were detected in 10 of 12 hNOJ (hNOJmCRAL+) mice as assessed on the last day of the 14-day continuous twice-daily RAL administration, all 10 untreated hNOJmC (hNOJmCRAL−) mice became positive for p24 and pRNA and had significantly swollen lymph nodes in peritoneal cavity and abundant p24+/mC+/CD3+/CD4+ T cells and p24+/mC+/CD68+ monocytes/macrophages were identified in their omenta and mesenteric lymphoid tissues/lymph nodes upon necropsy of the mice on day 14. In 12 hNOJmCRAL+ mice, no significantly swollen lymph nodes were seen compared to hNOJmCRAL− mice; however, in the omentum of the 2 hNOJmCRAL+ mice that were positive for pRNA and in site RNA, mC+/p24+/CD3+/CD83+ cells were identified, suggesting that viral breakthrough occurred later in the observation period. The present data suggest that the use of hNOJ mouse model and HIVmC may shed light on the study of early-phase dynamics of HIV-1 infection and cellular events in post-exposure/pre-exposure prophylaxis.

Modeling the role of acquired immune response and antiretroviral therapy in the dynamics of HIV infection

This paper deals with the study of a virus dynamics model in order to get better insights into HIV infection within the body. The model incorporates therapeutic modalities such as reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs). RTIs prevent viral replication/entry within the infected CD4+ T cells while PIs block the virus assembly and thus further propagation and production of new virions. The proliferation of uninfected CD4+ T cells has been assumed to be as full logistic growth term to capture the dynamics of HIV virus. The model also considers two important components of the acquired immune response, namely the cytotoxic T lymphocyte (CTL) immune response (self stimulation due to infection and stimulation due to infected cells have been considered) and antibody immune response. Critical threshold conditions for the existence of equilibrium points have been determined. We studied the analytical behavior of these equilibrium points locally as well as globally using Lasalle’s invariance principle and Lyapunov’s direct method. We explored the sensitivity of the therapeutic drugs on the model system. Further, the behavior of the proposed model system has been studied numerically through simulation tools.

Modelo estocástico para la infección con VIH de las células T CD4+ del sistema inmune

En este trabajo se estudia la dinámica de infección por VIH, a través de los procesos estocásticos de nacimiento y muerte y los sistemas de ecuaciones diferenciales que representan un sistema real. Para éste caso en específico, se describe un proceso estocástico que interpreta la dinámica de infección del VIH al interior del organismo de una persona en sus etapas iniciales de infección (post exposición o periodo de ventana); es decir, se considera que el momento mismo en que el virus ingresa en el organismo corresponde al tiempo inicial para el modelo, y a partir de entonces se tiene en cuenta el proceso de replicación y las incidencias que el virus genera cuando ataca las células T CD4+, las cuales, son pieza fundamental en el sistema inmunológico del paciente. El proceso estocástico permite deducir a partir de primeros principios, un modelo básico para la infección por VIH, similar a los estudiados en la literatura; es decir, un sistema basado en ecuaciones diferenciales ordinarias de variable estocástica, donde las variables de estado corresponden a valores esperados (promedios) y en ese sentido se encuentran también ecuaciones diferenciales para la varianza de esas variables de estado, lo que proporcionará información adicional sobre el sistema. Finalmente se presenta el estudio analítico local del modelo completo y un estudio numérico de las soluciones del sistema usando valores de los parámetros obtenidos de fuentes secundarias, con el fin de ilustrar los resultados analíticos.

Genetically-barcoded SIV facilitates enumeration of rebound variants and estimation of reactivation rates in nonhuman primates following interruption of suppressive antiretroviral therapy.

HIV and SIV infection dynamics are commonly investigated by measuring plasma viral loads. However, this total viral load value represents the sum of many individual infection events, which are difficult to independently track using conventional sequencing approaches. To overcome this challenge, we generated a genetically tagged virus stock (SIVmac239M) with a 34-base genetic barcode inserted between the vpx and vpr accessory genes of the infectious molecular clone SIVmac239. Next-generation sequencing of the virus stock identified at least 9,336 individual barcodes, or clonotypes, with an average genetic distance of 7 bases between any two barcodes. In vitro infection of rhesus CD4+ T cells and in vivo infection of rhesus macaques revealed levels of viral replication of SIVmac239M comparable to parental SIVmac239. After intravenous inoculation of 2.2x105 infectious units of SIVmac239M, an average of 1,247 barcodes were identified during acute infection in 26 infected rhesus macaques. Of the barcodes identified in the stock, at least 85.6% actively replicated in at least one animal, and on average each barcode was found in 5 monkeys. Four infected animals were treated with combination antiretroviral therapy (cART) for 82 days starting on day 6 post-infection (study 1). Plasma viremia was reduced from >106 to <15 vRNA copies/mL by the time treatment was interrupted. Virus rapidly rebounded following treatment interruption and between 87 and 136 distinct clonotypes were detected in plasma at peak rebound viremia. This study confirmed that SIVmac239M viremia could be successfully curtailed with cART, and that upon cART discontinuation, rebounding viral variants could be identified and quantified. An additional 6 animals infected with SIVmac239M were treated with cART beginning on day 4 post-infection for 305, 374, or 482 days (study 2). Upon treatment interruption, between 4 and 8 distinct viral clonotypes were detected in each animal at peak rebound viremia. The relative proportions of the rebounding viral clonotypes, spanning a range of 5 logs, were largely preserved over time for each animal. The viral growth rate during recrudescence and the relative abundance of each rebounding clonotype were used to estimate the average frequency of reactivation per animal. Using these parameters, reactivation frequencies were calculated and ranged from 0.33–0.70 events per day, likely representing reactivation from long-lived latently infected cells. The use of SIVmac239M therefore provides a powerful tool to investigate SIV latency and the frequency of viral reactivation after treatment interruption.

Early phase dynamics of traceable mCherry fluorescent protein-carrying HIV-1 infection in human peripheral blood mononuclear cells-transplanted NOD/SCID/Jak3-/- mice

We attempted to elucidate early-phase dynamics of HIV-1 infection using replication-competent, red-fluorescent-protein (mCherry)-labeled HIV-1JR-FL (HIVJR-FLmC) and NOD/SCID/Jak3-/- mice transplanted with Individual-A's human peripheral blood mononuclear cells (hPBMC)(hNOJ mice). On day 7 following HIVJR-FLmC inoculation, mCherry-signal-emitting infection foci were readily identified in the subserosa of 10 of 10 HIVJR-FLmC-inoculated hNOJ mice, although infection foci were not located without the mCherry signal in unlabeled HIV-1JR-FL-inoculated mice (n = 6). Even on day 14, infection foci were hardly located in the unlabeled HIV-1JR-FL-inoculated mice, while in all of 7 HIVJR-FLmC-inoculated hNOJ mice examined, mCherry-signal-emitting lymph nodes were easily identified, in which active viral replication was present. On day 14, a significantly larger number of mesenteric lymph nodes were seen in HIVJR-FLmC-exposed hNOJ mice than in HIVJR-FLmC-unexposed mice (P = 0.0025). The weights of mesenteric lymph nodes of those HIVJR-FLmC-exposed hNOJ mice were also greater than those of HIVJR-FLmC-unexposed mice (P = 0.0005). When hNOJ mice were inoculated with HIVJR-FLmC-exposed hPBMC from Individual-B, significantly greater viremia was seen than in cell-free HIVJR-FLmC-inoculated hNOJ mice as examined on day 7. In the lymph nodes of those mice inoculated with HIVJR-FLmC-exposed hPBMC from Individual-B, a substantial number of Individual-B's HIVJR-FLmC-infected cells were identified together with Individual-A's cells as examined on day 14. The present HIVJR-FLmC-infected mouse model represents the first system reported using traceable HIVJR-FLmC and human target cells, not using SIV or simian cells, which should be of utility in studies of early-phases of HIV-1 transmission and in evaluating the effects of potential agents for post-exposure and pre-exposure prophylaxis.

The dynamics of HIV transmission in out of school young heterosexual men in South Africa: a systematic scoping review protocol

BackgroundIn South Africa, gender inequality dominated by males and heterosexual HIV epidemic are associated with high HIV infection. Underlying epidemiological and social determinants driving HIV acquisition and transmission are critical to understand the extent and complexity of sexual networks as primary mechanisms through which HIV is likely to spread. The aim of the study is to provide an overview of empiric evidence that links the complex interaction of risk of HIV infection in men.Methods and analysisWe will conduct a systematic scoping review to identify, describe, and map literature on the dynamics of HIV infection in men, and we will determine the quality of the studies reporting on the dynamics of HIV infections in men. Primary research articles, published in peer-reviewed journals, review articles, and gray literature that address the research question, will be included. We will search PubMed, Web of Knowledge, Science Direct, EBSCOhost, Google Scholar, World Health Organization library, and UNAIDS database. Reference lists and existing networks such as government organizations and conferences will also be included to source relevant literature. Two independent reviewers will extract data in parallel from all relevant search engines, using specific inclusion and exclusion criteria. A thematic content analysis will be used to present the narrative account of the reviews, using NVivo version 10.DiscussionWe anticipate finding relevant literature on the dynamics of HIV transmission in South African men. Once summarized, data will be useful to guide future research.Systematic review registrationPROSPERO CRD42016039489

Impact of Delay in Immune Response Activation on HIV Infection Dynamics

Impact of Delay in Immune Response Activation on HIV Infection Dynamics

LATENT DEPRESSION IN HIV AFFECTED WOMEN

Depressions negatively affects the patients emotional state and it can determine the development of complications of somatic pathology. Using the «Scale for the Express Psychological Diagnosis of Low-Structured Depressive Disorders» [Bespal’ko I.G., 2004], We have identified masked depressions and apparent depressions accompanying somatic pathology in women in the dynamics of HIV infection, depending on their receipt of antiretroviral therapy. 84 women participated in the experimental psychological study (mean age 32,02±4,36) at different stages and for different duration of the disease. 62 patients received antiretroviral therapy in accordance with domestic and international recommendations, and 22 patients had a natural course of the disease. It was shown that 58% of women in the control group fell into the area of diagnostic uncertainty (the author of this technique consider that the normative group of healthy people occupies an intermediate zone of an indeterminate diagnosis, that is, the area between diseased neuroses and manic-depressive psychosis; that’s, the characterological signs of the scale in the healthy are moderately expressed, and in patients with a clear diagnosis of depression with neuroses or manic-depressive psychosis — to the extreme degree), and 20% in the neurotic spectrum of depression. In the groups of patients with HIV infection, regardless of their receive of antiretroviral therapy, similar results were obtained (to the field of diagnostic uncertainty, depending on the duration of the disease in its natural course, there were 63,64% of patients, against antiretroviral therapy — 58,10%, the neurotic spectrum of depression included 18,2% and 19,35% of patients, respectively). Single cases of depression on the scale I (D-N scale) are probably due to the premorbid properties of the personality of the respondents, both in the study group and in the control group. It is interesting to note the fact that in women with HIV infection both in the absence and in the presence of antiretroviral therapy, the level of endogenous (scale I) in the dynamics of the disease practically does not increase, remaining at the same time significantly higher (p 0,05). Since the question of the possibility of predicting the likelihood of developing HIV-associated psycho-neurological disorders remains open, this requires careful medical and psychological support of such patients.

Mathematical analysis and dynamic active subspaces for a long term model of HIV.

a long-term model of HIV infection dynamics [8] was developed to describe the entire time course of the disease. It consists of a large system of ODEs with many parameters, and is expensive to simulate. In the current paper, this model is analyzed by determining all infection-free steady states and studying the local stability properties of the unique biologically-relevant equilibrium. Active subspace methods are then used to perform a global sensitivity analysis and study the dependence of an infected individual's T-cell count on the parameter space. Building on these results, a global-in-time approximation of the T-cell count is created by constructing dynamic active subspaces and reduced order models are generated, thereby allowing for inexpensive computation.

Modeling the Effects of Morphine on Simian Immunodeficiency Virus Dynamics.

Complications of HIV-1 infection in individuals who utilize drugs of abuse is a significant problem, because these drugs have been associated with higher virus replication and accelerated disease progression as well as severe neuropathogenesis. To gain further insight it is important to quantify the effects of drugs of abuse on HIV-1 infection dynamics. Here, we develop a mathematical model that incorporates experimentally observed effects of morphine on inducing HIV-1 co-receptor expression. For comparison we also considered viral dynamic models with cytolytic or noncytolytic effector cell responses. Based on the small sample size Akaike information criterion, these models were inferior to the new model based on changes in co-receptor expression. The model with morphine affecting co-receptor expression agrees well with the experimental data from simian immunodeficiency virus infections in morphine-addicted macaques. Our results show that morphine promotes a target cell subpopulation switch from a lower level of susceptibility to a state that is about 2-orders of magnitude higher in susceptibility to SIV infection. As a result, the proportion of target cells with higher susceptibility remains extremely high in morphine conditioning. Such a morphine-induced population switch not only has adverse effects on the replication rate, but also results in a higher steady state viral load and larger CD4 count drops. Moreover, morphine conditioning may pose extra obstacles to controlling viral load during antiretroviral therapy, such as pre-exposure prophylaxis and post infection treatments. This study provides, for the first time, a viral dynamics model, viral dynamics parameters, and related analytical and simulation results for SIV dynamics under drugs of abuse.

A reaction diffusion system modeling virus dynamics and CTLs response with chemotaxis

In this paper, we study the effect of chemotactic movement of CTLs on HIV-1 infection dynamics by a reaction diffusion system with chemotaxis. Choosing a typical chemosensitive function, we find that chemoattractive movement of CTLs due to HIV infection does not change stability of a positive steady state of the model, meaning that the stability/instability of the model remains the same as in the model without spatial effect. However, chemorepulsion movement of CTLs can destabilize the positive steady state as the strength of the chemotactic sensitivity increases. In this case, Turing instability occurs, which may result in Hopf bifurcation or steady state bifurcation, and spatial inhomogeneous pattern forms.

Effects of combined drug therapy on HIV-1 infection dynamics

Infection of human immunodeficiency virus (HIV) is determined through the decay of healthy CD4+ T-cells in a well-mixed compartment, such as a bloodstream. A mathematical model is considered to illustrate the effects of combined drug therapy, i.e. reverse transcription plus protease inhibitor, on viral growth and T-cell population dynamics. This model is used to explain the existence and stability of infected and uninfected steady states in HIV growth. An analytical technique, called variational iteration method (VIM), is used to solve the mathematical model. This method is modified to obtain the rapidly convergent successive approximations of the exact solution. These approximations are obtained without any restrictions or the transformations that may change the physical behavior of the problem. Numerical simulations are computed and exhibited to illustrate the effects of proposed drug therapy on the growth or decay of infection.

Analysis of HIV models with two time delays

ABSTRACTTime delays can affect the dynamics of HIV infection predicted by mathematical models. In this paper, we studied two mathematical models each with two time delays. In the first model with HIV latency, one delay is the time between viral entry into a cell and the establishment of HIV latency, and the other delay is the time between cell infection and viral production. We defined the basic reproductive number and showed the local and global stability of the steady states. Numerical simulations were performed to evaluate the influence of time delays on the dynamics. In the second model with HIV immune response, one delay is the time between cell infection and viral production, and the other delay is the time needed for the adaptive immune response to emerge to control viral replication. With two positive delays, we obtained the stability crossing curves for the model, which were shown to be a series of open-ended curves.

Stability and multi-parametric Hopf bifurcation analyses of viral infection model with time delay

Ever since HIV was first diagnosed in human, a great number of scientific works have been undertaken to explore the biological mechanisms involved in the infection and progression of the disease. This paper deals with stability and bifurcation analyses of mathematical model that represents the dynamics of HIV infection of thymus. The existence and stability of the equilibria are investigated. The model is described by a system of delay differential equations with logistic growth term, cure rate and discrete type of time delay. Choosing the time delay as a bifurcation parameter, the analysis is mainly focused on the Hopf bifurcation problem to predict the existence of a limit cycle bifurcating from the infected steady state. Further, using center manifold theory and normal form method we derive explicit formulae to determine the stability and direction of the limit cycles. Moreover the mitosis rate r also plays a vital role in the model, so we fix it as second bifurcation parameter in the incidence of viral infection. Our analysis shows that, while both the bifurcation parameters can destabilize the equilibrium E* and cause limit cycles. Numerical simulations are performed to investigate the qualitative behaviors of the inherent model.

Uncertainty quantification in modeling HIV viral mechanics.

We consider an in-host model for HIV-1 infection dynamics developed and validated with patient data in earlier work [7]. We revisit the earlier model in light of progress over the last several years in understanding HIV-1 progression in humans. We then consider statistical models to describe the data and use these with residual plots in generalized least squares problems to develop accurate descriptions of the proper weights for the data. We use recent parameter subset selection techniques [5,6] to investigate the impact of estimated parameters on the corresponding selection scores. Bootstrapping and asymptotic theory are compared in the context of confidence intervals for the resulting parameter estimates.

Global dynamics of a delayed within-host viral infection model with both virus-to-cell and cell-to-cell transmissions

A within-host viral infection model with both virus-to-cell and cell-to-cell transmissions and three distributed delays is investigated, in which the first distributed delay describes the intracellular latency for the virus-to-cell infection, the second delay represents the intracellular latency for the cell-to-cell infection, and the third delay describes the time period that viruses penetrated into cells and infected cells release new virions. The global stability analysis of the model is carried out in terms of the basic reproduction number R0. If R0≤1, the infection-free (semi-trivial) equilibrium is the unique equilibrium and is globally stable; if R0>1, the chronic infection (positive) equilibrium exists and is globally stable under certain assumptions. Examples and numerical simulations for several special cases are presented, including various within-host dynamics models with discrete or distributed delays that have been well-studied in the literature. It is found that the global stability of the chronic infection equilibrium might change in some special cases when the assumptions do not hold. The results show that the model can be applied to describe the within-host dynamics of HBV, HIV, or HTLV-1 infection.

Hybrid spreading mechanisms and T cell activation shape the dynamics of HIV-1 infection.

HIV-1 can disseminate between susceptible cells by two mechanisms: cell-free infection following fluid-phase diffusion of virions and by highly-efficient direct cell-to-cell transmission at immune cell contacts. The contribution of this hybrid spreading mechanism, which is also a characteristic of some important computer worm outbreaks, to HIV-1 progression in vivo remains unknown. Here we present a new mathematical model that explicitly incorporates the ability of HIV-1 to use hybrid spreading mechanisms and evaluate the consequences for HIV-1 pathogenenesis. The model captures the major phases of the HIV-1 infection course of a cohort of treatment naive patients and also accurately predicts the results of the Short Pulse Anti-Retroviral Therapy at Seroconversion (SPARTAC) trial. Using this model we find that hybrid spreading is critical to seed and establish infection, and that cell-to-cell spread and increased CD4+ T cell activation are important for HIV-1 progression. Notably, the model predicts that cell-to-cell spread becomes increasingly effective as infection progresses and thus may present a considerable treatment barrier. Deriving predictions of various treatments’ influence on HIV-1 progression highlights the importance of earlier intervention and suggests that treatments effectively targeting cell-to-cell HIV-1 spread can delay progression to AIDS. This study suggests that hybrid spreading is a fundamental feature of HIV infection, and provides the mathematical framework incorporating this feature with which to evaluate future therapeutic strategies.

Stochastic modelling of viral blips in HIV-1-infected patients: effects of inhomogeneous density fluctuations.

We propose a stochastic model of HIV-1 infection dynamics under HAART in order to analyse the origin and dynamics of the so-called viral blips, i.e. episodes of transient viremia that occur in the phase of where the disease remains in a latent state during which the viral load raises above the detection limit of standard clinical assays. Based on prior work in the subject, we consider an infection model in which latently infected cell compartment sustains a residual (latent) infection over long periods of time. Unlike previous models, we include the effects of inhomogeneities in cell and virus concentration in the blood stream. We further consider the effect of burst virion production. By comparing with the experimental results obtained during a study in which intensive sampling was carried out on HIV-1-infected patients undergoing HAART over a long period of time, we conclude that our model supports the hypothesis that viral blips are consistent with random fluctuations around the average viral load. We further observe that agreement between our simulation results and the blip statistics obtained in the aforementioned study improves when burst virion production is considered. We also study the effect of sample manipulation artifacts on the results produced by our model, in particular, that of the post-extraction handling time, i.e. the time elapsed between sample extraction and actual test. Our results support the notion that the statistics of viral blips can be critically affected by such artifacts.

Designing Stem-Cell Based Anti-HIV Therapies using Molecular-Detailed Multiscale Models

Although HAART ensures normal lives for HIV-infected individuals, it does not lead to a functional cure. In 2008, the “Berlin patient”, a HIV-infected cancer patient, underwent a bone marrow transplant from a CCR5-/- donor. Since then, he has shown no signs of active HIV-1 replication in the absence of HAART. However, finding such a matched donor for each HIV patient is challenging; instead, inserting anti-HIV genes into patients’ or matched donors’ stem cells before transplantation could provide HIV-resistance to the progeny target cells and lead to a functional cure. We developed a molecular-detailed, mechanistic model of HIV infection to design stem-cell therapies using endogenous anti-HIV genes and to identify logistics of successful treatment. The model simulates the dynamics of HIV infection to track key restriction factors and their interactions with HIV-encoded proteins, the virus, and multiple immune cell types: CD4+ T-cells, macrophages, latently-infected T-cells, and CTLs. Using viral load and T-cell count data from HIV-infected individuals, we explored interpatient variability of stem-cell therapies by creating a virtual population of HIV patients. Our model predicted that APOBEC3G overexpression at medium or high transduction efficiency could effectively stop HIV replication and increase the T-cell count to normal levels. SAMHD1 overexpression in macrophages even at high transduction efficiency is not by itself a potent inhibitor of HIV replication; it stabilizes the viral load and slightly improves the T-cell count. However, the model predicted APOBEC3G-SAMHD1 synergy: faster viral decay and return to normal T-cell counts at lower overexpression levels. Surprisingly, HIV-triggered pro-apoptosis gene circuits combined with APOBEC3G overexpression were predicted to negatively impact HIV replication blockade if expressed at low transduction efficiency. This is because some infected T-cells die at a faster rate, weakening the effect of immune response in killing the remaining infected cells.

An extremal shift method for control of HIV infection dynamics

AbstractOptimal control problems for mathematical models describing HIV infection dynamics in a human body are considered in the paper. An overview of current approaches to solution of control problems for models of HIV dynamics is presented for techniques related to construction of optimal programme (open loop) or positional (feedback) controls for various criteria of control process quality and is based on the Pontryagin’s maximum principle and the Bellman’s theory of dynamic programming, respectively. In the framework of the theory of positional differential games of Krasovskii, there are constructive and efficient methods of synthesis of controls for different classes of dynamical systems. In this paper we present a formalization of a control problem for HIV infection considered as a corresponding positional differential game. The control algorithm based on the method of extremal shift is applied to the ODEs model of HIV infection. The numerical implementation of the extremal shift method is developed to construct the control taking the system to a neighbourhood of a given trajectory using the information on the dynamics of the guides or leaders.