Short-lived Infected Cells Research Articles

Quantifying the Dynamics of HIV Decline in Perinatally Infected Neonates on Antiretroviral Therapy.

Mathematical modeling has provided important insights into HIV infection dynamics in adults undergoing antiretroviral treatment (ART). However, much less is known about the corresponding dynamics in perinatally infected neonates initiating early ART. From 2014 to 2017, HIV viral load (VL) was monitored in 122 perinatally infected infants identified at birth and initiating ART within a median of 2 days. Pretreatment infant and maternal covariates, including CD4 T cell counts and percentages, were also measured. From the initial cohort, 53 infants demonstrated consistent decline and suppressed VL below the detection threshold (20 copies mL) within 1 year. For 43 of these infants with sufficient VL data, we fit a mathematical model describing the loss of short-lived and long-lived infected cells during ART. We then estimated the lifespans of infected cells and the time to viral suppression, and tested for correlations with pretreatment covariates. Most parameters governing the kinetics of VL decline were consistent with those obtained previously from adults and other infants. However, our estimates of the lifespan of short-lived infected cells were longer than published values. This difference may reflect sparse sampling during the early stages of VL decline, when the loss of short-lived cells is most apparent. In addition, infants with higher pretreatment CD4 percentage or lower pretreatment VL trended toward more rapid viral suppression. HIV dynamics in perinatally infected neonates initiating early ART are broadly similar to those observed in other age groups. Accelerated viral suppression is also associated with higher CD4 percentage and lower VL.

Stability of discrete-time HIV dynamics models with three categories of infected CD4+ T-cells

This paper studies the global stability of two discrete-time HIV infection models. The models integrate (i) latently infected cells, (ii) long-lived chronically infected cells and (iii) short-lived infected cells. The second model generalizes the first one by assuming that the incidence rate of infection as well as the production and removal rates of the HIV particles and cells are modeled by general nonlinear functions. We discretize the continuous-time models by using a nonstandard finite difference scheme. The positivity and boundedness of solutions are established. The basic reproduction number is derived. By using the Lyapunov method, we prove the global stability of the models. Numerical simulations are presented to illustrate our theoretical results.

GLOBAL ANALYSIS OF AN EXTENDED HIV DYNAMICS MODEL WITH GENERAL INCIDENCE RATE

The objective of this work is to investigate the qualitative behavior of an Human Immunodeficiency Virus (HIV) dynamics model with two types of cocirculating target cells and under the effect of anti-viral drug therapy. The model takes into account both short-lived infected cells and long-lived chronically infected cells. In the two types of target cells, the drug efficacy is assumed to be different. The incidence rate of virus infection is given by general functional response. We have derived the basic reproduction number which determines the global dynamics of the model. We have established a set of conditions which are sufficient to investigate the global stability of the equilibria of the model. The global stability analysis of the model has been established using the Lyapunov method. Numerical simulations have been performed for the model with a specific form of the incidence rate function. We have shown that the numerical and theoretical results are consistent.

Global properties of delayed-HIV dynamics models with differential drug efficacy in cocirculating target cells

The objective of this work is to investigate the qualitative behaviors of three HIV dynamical models with two types of cocirculating target cells and intracellular discrete time delay. In the two types of target cells, the drug efficacy is assumed to be different. The models take into account both short-lived infected cells and long-lived chronically infected cells. The incidence rate of infection is given by bilinear and saturation functional response in the first and second model, respectively, while it is given by a general function in the third model. Lyapunov functionals are constructed and LaSalle’s invariance principle is applied to prove the global asymptotic stability of all equilibria of the models. In the first two models, we have derived the basic reproduction number R0. It has been proven that the disease-free equilibrium is globally asymptotically stable (GAS) when R0 ≤ 1, and the endemic equilibrium is GAS when R0 > 1. For the third model, we have derived R0 and established a set of sufficient conditions for global stability of both disease-free and endemic equilibria of the model. At the end theoretical results have been checked by numerical simulations.

Global Stability of Humoral Immunity HIV Infection Models with Chronically Infected Cells and Discrete Delays

We study the global stability of three HIV infection models with humoral immune response. We consider two types of infected cells: the first type is the short-lived infected cells and the second one is the long-lived chronically infected cells. In the three HIV infection models, we modeled the incidence rate by bilinear, saturation, and general forms. The models take into account two types of discrete-time delays to describe the time between the virus entering into an uninfected CD4+T cell and the emission of new active viruses. The existence and stability of all equilibria are completely established by two bifurcation parameters,R0andR1. The global asymptotic stability of the steady states has been proven using Lyapunov method. In case of the general incidence rate, we have presented a set of sufficient conditions which guarantee the global stability of model. We have presented an example and performed numerical simulations to confirm our theoretical results.

Stability of Virus Infection Models with Antibodies and Chronically Infected Cells

Two virus infection models with antibody immune response and chronically infected cells are proposed and analyzed. Bilinear incidence rate is considered in the first model, while the incidence rate is given by a saturated functional response in the second one. One main feature of these models is that it includes both short-lived infected cells and chronically infected cells. The chronically infected cells produce much smaller amounts of virus than the short-lived infected cells and die at a much slower rate. Our mathematical analysis establishes that the global dynamics of the two models are determined by two threshold parametersR0andR1. By constructing Lyapunov functions and using LaSalle's invariance principle, we have established the global asymptotic stability of all steady states of the models. We have proven that, the uninfected steady state is globally asymptotically stable (GAS) ifR0<1, the infected steady state without antibody immune response exists and it is GAS ifR1<1<R0, and the infected steady state with antibody immune response exists and it is GAS ifR1>1. We check our theorems with numerical simulation in the end.

Short-Lived Infected Cells Support Virus Replication in Sooty Mangabeys Naturally Infected with Simian Immunodeficiency Virus: Implications for AIDS Pathogenesis

Sooty mangabeys (SMs) naturally infected with simian immunodeficiency virus (SIV) do not develop AIDS despite high levels of virus replication. At present, the mechanisms underlying this disease resistance are poorly understood. Here we tested the hypothesis that SIV-infected SMs avoid immunodeficiency as a result of virus replication occurring in infected cells that live significantly longer than human immunodeficiency virus (HIV)-infected human cells. To this end, we treated six SIV-infected SMs with potent antiretroviral therapy (ART) and longitudinally measured the decline in plasma viremia. We applied the same mathematical models used in HIV-infected individuals and observed that SMs naturally infected with SIV also present a two-phase decay of viremia following ART, with the bulk (92 to 99%) of virus replication sustained by short-lived cells (average life span, 1.06 days), and only 1 to 8% occurring in longer-lived cells. In addition, we observed that ART had a limited impact on CD4(+) T cells and the prevailing level of T-cell activation and proliferation in SIV-infected SMs. Collectively, these results suggest that in SIV-infected SMs, similar to HIV type 1-infected humans, short-lived activated CD4(+) T cells, rather than macrophages, are the main source of virus production. These findings indicate that a short in vivo life span of infected cells is a common feature of both pathogenic and nonpathogenic primate lentivirus infections and support a model for AIDS pathogenesis whereby the direct killing of infected cells by HIV is not the main determinant of disease progression.

Use of a stochastic model to develop understanding of the impact of different patterns of antiretroviral drug use on resistance development.

To use a stochastic model to gain insights into the consequence for resistance development of different drug use patterns. We consider use of three drugs (A, B and C) where for each drug one and only one viral mutation is associated with ability to replicate (effective reproductive ratio, R > 1) in the presence of that drug as monotherapy. For drug A mutation is a, etc. We define eight populations of short-lived infected cells that live 1 day: Vo with no mutations a, b, c; Va with mutation a only, Vab with mutations a and b, etc. A random number generator was used to determine whether mutations occur in any one round of replication and to sample from a Poisson distribution to determine for each cell the number of cells of the same population created in the next generation, using the R operative at that time. Values of R depended on drug exposure, cost of resistance and availability of target cells. Treatment strategies and the resulting percentage (over 100 runs) developing full "resistance" in 1500 days (Vabc not equal 0) were: (i) ABC 1500 days 0%; (ii) A 300 days, AB 300 days, ABC 900 days 100%; (iii) AB 300 days, ABC 1200 days 33%; (iv) ABC 2/3 1500 days 15%; (v) ABC 1/2 1500 days 100%; (vi) ABC 50 days, no drugs 50 days, for 1500 days 1%, where ABC 2/3 means on-drug for 2 days in every 3, ABC 1/2 represents on-drug for 1 day in every 2, and represents suboptimal adherence. This model helps to develop understanding of key principles concerning development of resistance under different patterns of treatment use.

AIDS pathogenesis: the role of accessory gene mutations, leading to formation of long-lived persistently infected cells and/or apoptosis-inducing HIV-1 particles

Human immunodeficiency virus type 1 (HIV-1) infection indirectly induces activation-dependent apoptosis in bystander immune CD4 + T-cells, a hallmark of AIDS pathogenesis. It is well known that this pathogenetic event is significantly correlated with a high virus load. Active viral replication occurs in HIV-1 asymptomatic carriers throughout all stages of clinical disease. Most of the HIV-1 in plasma is derived from short-lived infected cells with a half life of a few days; however, a minor population of virus is derived from long-lived persistently and latently infected cells. Recently, the importance of such latent reservoirs for HIV-1 has come to the forefront because of studies with potent antiretroviral inhibitors that block only new rounds of infection. An initial large drop in viral load occurs within two weeks as noted by a decrease in plasma viremia. This is then followed by a slower second-phase decay, since only a small fraction of latently infected resting CD4 + T-cells carry replication-competent, integrated provirus. This review highlights the mechanisms of apoptosis induction in bystander immune cells by both protease-defective, gp120-containing HIV-1 particles, as well as by wild-type virus that appears to be derived predominantly from long-lived infected cells. A model involving the NH 2-terminal Nef domain (p7) in this `bystander apoptosis' event is also presented.