HIV low viral load persistence under treatment: Insights from a model of cell-to-cell viral transmission

HIV infection persists despite long-term administration of antiretroviral therapy. The mechanisms underlying HIV persistence are not fully understood. Direct viral transmission from infected to uninfected cells (cell-to-cell transmission) may be one of them. During cell-to-cell transmission, multiple virions are delivered to an uninfected cell, making it possible that at least one virion can escape HIV drugs and establish infection. In this paper, we develop a mathematical model that includes cell-to-cell viral transmission to study HIV persistence. During cell-to-cell transmission, it is assumed that various number of virus particles are transmitted with different probabilities and antiretroviral therapy has different effectiveness in blocking their infection. We analyze the model by deriving the basic reproduction number and investigating the stability of equilibria. Sensitivity analysis and numerical simulation show that the viral load is still sensitive to the change of the treatment effectiveness in blocking cell-free virus infection. To reduce this sensitivity, we modify the model by including density-dependent infected cell death or HIV latent infection. The model results suggest that although cell-to-cell transmission may have reduced susceptibility to HIV drugs, HIV latency represents a major reason for HIV persistence in patients on suppressive treatment.     

A delay-dependent model with HIV drug resistance during therapy

The use of combination antiretroviral therapy has proven remarkably effective in controlling HIV disease progression and prolonging survival. However, the emergence of drug resistance can occur. It is necessary that we gain a greater understanding of the evolution of drug resistance. Here, we consider an HIV viral dynamical model with general form of target cell density, drug resistance and intracellular delay incorporating antiretroviral therapy. The model includes two strains: wild-type and drug-resistant. The basic reproductive ratio for each strain is obtained for the existence of steady states. Qualitative analysis of the model such as the well-posedness of the solutions and the equilibrium stability is provided. Global asymptotic stability of the disease-free and drug-resistant steady states is shown by constructing Lyapunov functions. Furthermore, sufficient conditions related to the properties of the target cell density are obtained for the local asymptotic stability of the positive steady state. Numerical simulations are conducted to study the impact of target cell density and intracellular delay focusing on the stability of the positive steady state. The occurrence of Hopf bifurcation of periodic solutions is shown to depend on the target cell density.     

A nested model on HIV/AIDs, antiretroviral therapy and drug resistance

A coupled within- (immunological) and between-host (epidemiological) dynamic model was developed which is about the spreading of drug-sensitive HIV strain and drug-resistant HIV strain in men who have sex with men (MSM) population. The within-host model was nested within the between-host model by linking the dynamics of the within-host model to the additional host mortality and transmission rate of the infection. The existences of equilibria and their stabilities were found, as well as the thresholds $\mathcal {R}_S$ and $\mathcal {R}_R$ for the two different strains of the nested model. Some simulations about the spreading of the two HIV strains in Beijing MSM population were given. Our results show that the drug-resistant strain will increase quite fast in this population and both strains can coexist, which will make a big pressure for China''s ``Four-Free-One-Care Policy''.     

The global dynamics of a model about HIV-1 infection in vivo

A four dimension ODE model is built to study the infection of human immunodeficiency virus (HIV) in vivo. We include in this model four components: the healthy T cells, the latent-infected T cells, the active-infected T cells and the HIV virus. Two types of HIV transmissions in vivo are also included in the model: the virus-to-cell transmission, and the cell-to-cell HIV transmission. There are two possible equilibriums: the healthy equilibrium, and the infected steady state. The basic reproduction number R ₀ is introduced. When R ₀ < 1, the healthy equilibrium is globally stable and when R ₀ > 1, the infected equilibrium exists and is globally stable. Through simulations, we find that, the cell-to-cell HIV transmission is very important for the final outcome of the HIV attacking. Some important clinical observations about the HIV infection situation in lymph node are also verified.      

The population‐level impact of HBV and its vaccination on HIV transmission dynamics

Hepatitis B virus (HBV) and its vaccination strategy may affect human immunodeficiency virus (HIV) transmission dynamics because both viruses have synergistic effects. To quantitatively assess the potential impact of HBV and its vaccination strategy on HIV transmission dynamics at the population level, in this paper, we formulate a deterministic compartmental model that describes the joint dynamics of HBV and HIV. We first derive the explicit expressions for the basic reproduction numbers of HIV and HBV and analyze the dynamics of HIV and HBV subsystems, respectively. Then a systematic qualitative analysis of the full system is also provided, which includes the local and global behavior. By using a set of reasonable parameter values, the full system is numerically investigated to assess the potential impact of HBV and its vaccination strategy on HIV transmission. The direct and indirect population level impact of HBV on HIV is demonstrated by calculating the fraction of HIV infections attributable to HBV and the difference between HIV prevalence in the presence and absence of HBV, respectively. The findings imply that the increase of HBV vaccination rate may unusually accelerate HIV epidemics indirectly, although the direct effect of HBV on HIV transmission decreases as HBV vaccination rate increases. Finally, the potential impact of HIV on HBV transmission dynamics is investigated by way of parenthesis. Copyright © 2016 John Wiley & Sons, Ltd.     

Analysis of an age structured HIV infection model with virus-to-cell infection and cell-to-cell transmission

Recent studies reveal that cell-to-cell transmission via formation of virological synapses can contribute significantly to virus spread, and hence, may play a more important role than virus-to-cell infection in some situations. Age-structured models can be employed to study the variations w.r.t. infection age in modeling the death rate and virus production rate of infected cells. Considering the above characteristics for within-host dynamics of HIV, in this paper, we formulate an age-structured hybrid model to explore the effects of the two infection modes in viral production and spread. We offer a rigorous analysis for the model, including addressing the relative compactness and persistence of the solution semiflow, and existence of a global attractor. By subtle construction and estimates of Lyapunov functions, we show that the global attractor actually consists of an singleton, being either the infection free steady state if the basic reproduction number is less than one, or the infection steady state if the basic reproduction number is larger than one.     

一类SIQA模型解的全局稳定性

讨论用脉冲隔离的方案控制HIV的传播.假定艾滋病感染者发展成艾滋病人和感染年龄有关,我们建立了带脉冲隔离类和感染年龄的HIV模型.在一定条件下证明该模型的无病平衡态是全局稳定的.     

Dynamics of an HIV infection model with virus diffusion and latently infected cell activation

Effective combination therapy usually reduces the plasma viral load of HIV to below the detection limit, but it cannot eradicate the virus. The latently infected cell activation is considered to be the main obstacle to completely eradicating HIV infection. In this paper, we consider an HIV infection model with latently infected cell activation, virus diffusion and spatial heterogeneity under Neumann boundary condition. The basic reproduction ratio is characterized by the principal eigenvalue of the related elliptic eigenvalue problem. Besides, by constructing Lyapunov functionals and using Green’s first identity, the global threshold dynamics of the system are completely established. Numerical simulations are carried out to illustrate the theoretical results, in particular, the influence of virus diffusion rate on the basic reproduction ratio is addressed.     

SWEIA艾滋病毒传染模型及应用

人类免疫缺陷病毒(HIV)是一种严重威胁生命的病毒,感染艾滋病毒患者一般经历四个阶段:i)艾滋病毒阴性的窗口期(W);ii)阳性的无症状潜伏期(E);iii)有症状期(Ⅰ);以及iv)移除阶段(A).为深入研究艾滋病传播过程,建立SWEIA艾滋病毒传染模型,定义基本再生数,分析无病与地方病平衡点的存在性和局部稳定性,根据2004至2015年中国艾滋病患者数据,采用遗传算法对SWEIA模型中参数进行估计.通过对基本再生数敏感性分析以及模型数值随参数不同而产生的变化,揭示艾滋病窗口期的接触率是影响艾滋病流行的主要原因之一.     

一类具有双线性传染率的HIV/AIDS病毒动力学改进模型

针对HIV/AIDS传播的具有常数移民和指数出生的SI型模型,为了更加符合实际意义,对具有双线性传染率的模型进行局部改进,并对改进后的动力学模型进行了简化.对于改进后的模型,证明了平衡点的存在与局部稳定性,并证明了传染病毒的灭绝与持续性,得到了传染病毒的基本再生数.结果表明:当单位时间内从外界迁入人口中染病者的比例系数c近似等于零时,基本再生数小于1时,传染病毒最终灭绝;当基本再生数大于1时,模型存在唯一的正平衡点,且是局部渐近稳定的,说明传染病毒一致持续存在.     

具有垂直传染和接触传染的传染病模型的稳定性研究

本文研究了一类具有垂直传染和接触传染的传染病模型.利用常微分方程定性与稳定性方法,分析了该模型非负平衡点的存在性及其局部稳定性.同时,利用LaSalle不变性原理和通过构造适当的Lyapunov函数,获得了平凡平衡点、无病平衡点和地方病平衡点全局渐近稳定的充分条件.结果表明当基本再生数小于等于1时,所有种群趋于灭绝;当基本再生数大于1和病毒主导再生数小于1时,病毒很快被清除;当基本再生数大于1和病毒主导再生数大于1以及满足一定条件时,病毒持续流行并将成为一种地方病.     

Global stability of delay-distributed viral infection model with two modes of viral transmission and B-cell impairment

This paper formulates a virus dynamics model with impairment of B-cell functions. The model incorporates two modes of viral transmission: cell-free and cell-to-cell. The cell-free and cell-cell incidence rates are modeled by general functions. The model incorporates both, latently and actively, infected cells as well as three distributed time delays. Nonnegativity and boundedness properties of the solutions are proven to show the well-posedness of the model. The model admits two equilibria that are determined by the basic reproduction number R₀. The global stability of each equilibrium is proven by utilizing Lyapunov function and LaSalle's invariance principle. The theoretical results are illustrated by numerical simulations. The effect of impairment of B-cell functions and time delays on the virus dynamics are studied. We have shown that if the functions of B-cell is impaired, then the concentration of viruses is increased in the plasma. Moreover, we have observed that increasing the time delay will suppress the viral replication.     

Dynamics of virus infection models with density‐dependent diffusion and Beddington–DeAngelis functional response

In this work, we integrate both density‐dependent diffusion process and Beddington–DeAngelis functional response into virus infection models to consider their combined effects on viral infection and its control. We perform global analysis by constructing Lyapunov functions and prove that the system is well posed. We investigated the viral dynamics for scenarios of single‐strain and multi‐strain viruses and find that, for the multi‐strain model, if the basic reproduction number for all viral strains is greater than 1, then each strain persists in the host. Our investigation indicates that treating a patient using only a single type of therapy may cause competitive exclusion, which is disadvantageous to the patient's health. For patients infected with several viral strains, the combination of several therapies is a better choice. Copyright © 2017 John Wiley & Sons, Ltd.     

Stability analysis of delay differential equation models of HIV-1 therapy for fighting a virus with another virus

Considering two kinds of delays accounting, respectively, for (i) a latent period between the time target cells are contacted by the virus particles and the time the virions enter the cells and (ii) a virus production period for new virions to be produced within and released from the infected cells, we develop and analyze a mathematical model for HIV-1 therapy by fighting a virus with another virus. For the different values of the basic reproduction number and the second basic reproduction number, we investigate the stability of the infection-free equilibrium, the single-infection equilibrium and the double-infection equilibrium. We conclude that increasing delays will decrease the values of the basic reproduction number and the second basic reproduction number. Our results have potential applications in HIV-1 therapy. The approach we use here is a combination of analysis of characteristic equations, Fluctuation Lemma and Lyapunov function.     

Modeling sexual transmission of HIV/AIDS in Jiangsu province,China

HIV transmission by sexual activities exhibits a substantial increase and has become a primary transmission mode in China recently. A mathematical model is formulated so as to identify the key processes and parameters that could explain the quick increase in the proportion of heterosexual transmission and further to assist in suggesting control measures urgently. On the basis of surveillance data on a number of people living with HIV/AIDS in Jiangsu province, we parameterize the model and estimate the reproduction number by using the least squares method. The basic reproduction number was estimated to be R₀ = 3.52 for the therapy scenario of heterosexual transmission. The model predicts that the epidemic will peak in 2020. New infections are sensitive to the transmission coefficient, dependent on condom use rate, and the risky activities during the early period, whereas are sensitive to the recruitment rate in the late period of the transmission respectively. Antiviral therapy can either increase or decrease the new infections depending on both the extended life span of treated individuals and the infectiousness of the treated individuals. Hence, effective control measures during different transmission periods can be suggested, and antiretroviral therapy is a contentious issue for disease control. Copyright © 2012 John Wiley & Sons, Ltd.     

System Dynamic simulation of treatment policies to address colliding epidemics of tuberculosis,drug resistant tuberculosis and injecting drug users driven HIV in Russia

The explosive increase in the number of people infected with tuberculosis (TB),multi drug resistant tuberculosis (MDRTB), and injecting drug users (IDU)HIV/AIDS has become a serious public health challenge in Russia. The WorldHealth Organization is recommending policies including simultaneous use ofhighly active antiretroviral therapy (HAART) to treat HIV/AIDS and second linedrugs to treat MDRTB. We developed a System Dynamics simulation model torepresent the dynamic transmission of TB, MDRTB and human immunodeficiency virus(HIV). The model simulated scenarios regarding MDRTB cure rate and HAARTcoverage, that is the HIV/AIDS population covered by HAART. The results over a20-year period indicate that reduction in TB and HIV-associated TB deaths wouldbe negligible for HAART coverage up to 50%. The reduction is onlysignificant for HAART coverage of 70% and above. Similarly, high MDRTBcure rate reduces significantly deaths from TB and MDRTB and this reduction ismore important as the HAART coverage is increased.     

Modeling and dynamics of HIV transmission among high-risk groups in Guangzhou city, China

In this paper, a multicompartmental model is formulated to study how HIV is transmitted among different HIV high-risk groups, including MSM (men who have sex with men), FRs (foreigner residents), FSWs (female sex workers), and IDUs (injection drug users). The explicit expression for the basic reproduction number is obtained via the next generation matrix approach. We show that the disease free equilibrium is locally as well as globally asymptotically stable (the disease goes to extinction) when the basic reproduction number is less than unity, and the disease is always present when the basic reproduction number is larger than unity. As an illustration of our theoretical results, we conduct numerical simulations. We also conduct a case study where model parameters are estimated from the demographic and epidemiological data from Guangzhou. Using the parameter estimates, we predict the HIV/AIDS trend for each high-risk group. Furthermore, our study suggests that reducing the transmission routes of the disease and increasing condom use will be useful for control of HIV transmission.     

Dynamics of an HIV‐1 virus model with both virus‐to‐cell and cell‐to‐cell transmissions,general incidence rate,intracellular delay,and CTL immune responses

Direct cell‐to‐cell transmission of HIV‐1 is a more efficient means of virus infection than virus‐to‐cell transmission. In this paper, we incorporate both these transmissions into an HIV‐1 virus model with nonlinear general incidence rate, intracellular delay, and cytotoxic T lymphocyte (CTL) immune responses. This model admits three types of equilibria: infection‐free equilibrium, CTL‐inactivated equilibrium, and CTL‐activated equilibrium. By using Lyapunov functionals and LaSalle invariance principle, it is verified that global threshold dynamics of the model can be explicitly described by the basic reproduction numbers.     

Bayesian segmental growth mixture Tobit models with skew distributions

This paper presents an extension of the standard Tobit to simultaneously address segmental phases, subpopulation heterogeneity, lower limit of detection, and skewness in outcomes of human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) longitudinal data. A major problem often encountered in an HIV/AIDS research is the development of drug resistance to antiretroviral (ARV) drug or therapy. For dealing with drug resistance problem, estimating the time at which drug resistance would develop is usually sought. Following ARV treatment, the profile of each subject’s viral load tends to follow a ‘broken stick’ like growth trajectory, indicating multiple phases of decline and increase in viral loads. Such multiple phases with multiple change-points are captured by subject-specific random parameters of growth curve models. To account subpopulation heterogeneity of drug resistance among patients, the turning-points are also allowed to differ by latent classes of patients on the basis of trajectories of observed viral loads. These features of viral longitudinal data are jointly modeled in a unified framework of segmental growth mixture Tobit mixed-effects models with skew distributions for a response variable with left censoring and skewness under the Bayesian approach. The proposed methods are illustrated using real data from an AIDS clinical study.