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In several publications, the dynamical system of HIV and HTLV mono-infections taking into account diffusion, as well as latently infected cells in cellular transmission has been mathematically analyzed. However, no work has been conducted on HTLV/HIV co-infection dynamics taking both factors into consideration. In this paper, a partial differential equations (PDEs) model of HTLV/HIV dual infection was developed and analyzed, considering the cells' and viruses' spatial mobility. CD 4 + T cells are the primary target of both HTLV and HIV. For HIV, there are three routes of transmission: free-to-cell (FTC), latent infected-to-cell (ITC), and active ITC. In contrast, HTLV transmits horizontally through ITC contact and vertically through the mitosis of active HTLV-infected cells. In the beginning, the well-posedness of the model was investigated by proving the existence of global solutions and the boundedness. Eight threshold parameters that determine the existence and stability of the eight equilibria of the model were obtained. Lyapunov functions together with the Lyapunov–LaSalle asymptotic stability theorem were used to investigate the global stability of all equilibria. Finally, the theoretical results were verified utilizing numerical simulations. [ABSTRACT FROM AUTHOR]

Latently infected CD 4 + T cells represent one of the major obstacles to HIV eradication even after receiving prolonged highly active anti-retroviral therapy (HAART). Long-term use of HAART causes the emergence of drug-resistant virus which is then involved in HIV transmission. In this paper, we develop mathematical HIV models with staged disease progression by incorporating entry inhibitor and latently infected cells. We find that entry inhibitor has the same effect as protease inhibitor on the model dynamics and therefore would benefit HIV patients who developed resistance to many of current anti-HIV medications. Numerical simulations illustrate the theoretical results and show that the virus and latently infected cells reach an infected steady state in the absence of treatment and are eliminated under treatment whereas the model including homeostatic proliferation of latently infected cells maintains the virus at low level during suppressive treatment. Therefore, complete cure of HIV needs complete eradication of latent reservoirs. [ABSTRACT FROM AUTHOR]

The human immunodeficiency virus (HIV) interacts with the immune cells within the human body, where the environment is uncertain and noisy. Stochastic models can successfully encapsulate the effect of such a noisy environment compared to their deterministic counterparts. The human immune system is complex but well-coordinated with various immune cells like C D 4 + T cells, dendritic cells, and cytotoxic T-lymphocyte (CTL) cells, among many others. The CTL can kill the antigenic cells after its recognition. However, the efficacy of CTL in removing the infected C D 4 + T cells is progressively compromised in HIV-infected individuals. This paper considers a noise-induced HIV-immune cell interaction model with immune impairment. A multiplicative white noise is introduced in the infection rate parameter to represent the fluctuations around the average value of the rate parameter as a causative effect of the noise. We analyzed the deterministic and stochastic models and prescribed sufficient conditions for infection eradication and persistence. It is determined under what parametric restrictions the asymptotic solutions of the noise-induced system will be a limiting case of the deterministic solutions. Simulation results revealed that the solutions of the deterministic system either converge to a CTL-dominated interior equilibrium or a CTL-free immunodeficient equilibrium, depending on the initial values of the system. Stochastic analysis divulged that higher noise might be helpful in the infection removal process. The extinction time of infected C D 4 + T cells for some fixed immune impairment gradually decreases with increasing noise intensity and follows the power law. [ABSTRACT FROM AUTHOR]

In this paper, a model of HIV infection taking into account cell-free and cell-to-cell transmissions is investigated under latency. The viral production rate of infectious CD4 T cells and the activation rate of latently infected CD4 T cells play a major role in the evolution of the disease. A system of nonlinear differential equations is derived to capture the dynamics and systematically analyzed thanks to the spectral theory of dynamical systems and a Routh-Hurwitz criterion. In particular, numerical simulations will be performed in order to extract the critical epidemiological features of the solution. [ABSTRACT FROM AUTHOR]

HIV preferentially infects activated CD4+ T cells. Current antiretroviral therapy cannot eradicate the virus. Viral infection of other cells such as macrophages may contribute to viral persistence during antiretroviral therapy. In addition to cell-free virus infection, macrophages can also get infected when engulfing infected CD4+ T cells as innate immune sentinels. How macrophages affect the dynamics of HIV infection remains unclear. In this paper, we develop an HIV model that includes the infection of CD4+ T cells and macrophages via cell-free virus infection and cell-to-cell viral transmission. We derive the basic reproduction number and obtain the local and global stability of the steady states. Sensitivity and viral dynamics simulations show that even when the infection of CD4+ T cells is completely blocked by therapy, virus can still persist and the steady-state viral load is not sensitive to the change of treatment efficacy. Analysis of the relative contributions to viral replication shows that cell-free virus infection leads to the majority of macrophage infection. Viral transmission from infected CD4+ T cells to macrophages during engulfment accounts for a small fraction of the macrophage infection and has a negligible effect on the total viral production. These results suggest that macrophage infection can be a source contributing to HIV persistence during suppressive therapy. Improving drug efficacies in heterogeneous target cells is crucial for achieving HIV eradication in infected individuals. [ABSTRACT FROM AUTHOR]

Recent studies demonstrate that resource competition is an essential component of T-cell proliferation in HIV progression, which can contribute instructively to the disease development. In this paper, we formulate an age-structured within-host HIV model, in the form of a hyperbolic partial differential equation (PDE) for infected target cells coupled with two ordinary differential equations for uninfected T-cells and the virions, to explore the effects of both the T-cell competition and viral shedding variations on the viral dynamics. The basic reproduction number is derived for a general viral production rate which determines the local stability of the infection-free equilibrium. Two special forms of viral production rates, which are extensively investigated in previous literature, the delayed exponential distribution and a step function rate, are further investigated, where the original system can be reduced into systems of delay differential equations. It is confirmed that there exists a unique positive equilibrium for two special viral production rates when the basic reproduction number is greater than one. However, the model exhibits the phenomenon of backward bifurcation, where two positive steady states coexist with the infection-free equilibrium when the basic reproduction number is less than one. [ABSTRACT FROM AUTHOR]

Estimating the time since infection (TI) in newly diagnosed HIV-1 patients is challenging, but important to understand the epidemiology of the infection. Here we explore the utility of virus diversity estimated by next-generation sequencing (NGS) as novel biomarker by using a recent genome-wide longitudinal dataset obtained from 11 untreated HIV-1-infected patients with known dates of infection. The results were validated on a second dataset from 31 patients. Virus diversity increased linearly with time, particularly at 3rd codon positions, with little inter-patient variation. The precision of the TI estimate improved with increasing sequencing depth, showing that diversity in NGS data yields superior estimates to the number of ambiguous sites in Sanger sequences, which is one of the alternative biomarkers. The full advantage of deep NGS was utilized with continuous diversity measures such as average pairwise distance or site entropy, rather than the fraction of polymorphic sites. The precision depended on the genomic region and codon position and was highest when 3rd codon positions in the entire pol gene were used. For these data, TI estimates had a mean absolute error of around 1 year. The error increased only slightly from around 0.6 years at a TI of 6 months to around 1.1 years at 6 years. Our results show that virus diversity determined by NGS can be used to estimate time since HIV-1 infection many years after the infection, in contrast to most alternative biomarkers. We provide the regression coefficients as well as web tool for TI estimation. unfortunately, they only distinguish between recent and long-term infections (concentration of HIV-1-specific antibodies) or are imprecise (immune status as measured by levels of CD4+ T-lymphocytes and viral sequence diversity measured by polymorphisms in Sanger sequences). In this paper, we show that recent advances in sequencing technologies, i.e. the development of next generation sequencing, enable significantly more precise determination of the time since HIV-1 infection, even many years after the infection event. This is a significant advance which could translate into more effective HIV-1 prevention [ABSTRACT FROM AUTHOR]

In this paper, we construct an HIV infection model which includes latent infection, logistic growth for healthy CD4 T-cells, and antiretroviral therapy. We obtain the global asymptotic stability of the uninfected equilibrium by constructing a Lyapunov function, and we give a sufficient condition for the local asymptotic stability of the infected equilibrium. We also use the latin hypercube sampling technique to identify the key parameters in determining the stability of the infected equilibrium. By numerical simulations, we observe that the model without logistic growth would underestimate the number of infectious virions, while the model without latent infection would overestimate the number of infectious virions. [ABSTRACT FROM AUTHOR]

During early human immunodeficiency virus (HIV) infection multiple CD8+ T cell responses are elicited almost simultaneously. These responses exert strong selective pressures on different parts of HIV’s genome, and select for mutations that escape recognition and are thus beneficial to the virus. Some studies reveal that the later these escape mutations emerge, the more slowly they go to fixation. This pattern of escape rate decrease(ERD) can arise by distinct mechanisms. In particular, in large populations with high beneficial mutation rates interference among different escape strains –an effect that can emerge in evolution with asexual reproduction and results in delayed fixation times of beneficial mutations compared to sexual reproduction– could significantly impact the escape rates of mutations. In this paper, we investigated how interference between these concurrent escape mutations affects their escape rates in systems with multiple epitopes, and whether it could be a source of the ERD pattern. To address these issues, we developed a multilocus Wright-Fisher model of HIV dynamics with selection, mutation and recombination, serving as a null-model for interference. We also derived an interference-free null model assuming initial neutral evolution before immune response elicitation. We found that interference between several equally selectively advantageous mutations can generate the observed ERD pattern. We also found that the number of loci, as well as recombination rates substantially affect ERD. These effects can be explained by the underexponential decline of escape rates over time. Lastly, we found that the observed ERD pattern in HIV infected individuals is consistent with both independent, interference-free mutations as well as interference effects. Our results confirm that interference effects should be considered when analyzing HIV escape mutations. The challenge in estimating escape rates and mutation-associated selective coefficients posed by interference effects cannot simply be overcome by improved sampling frequencies or sizes. This problem is a consequence of the fundamental shortcomings of current estimation techniques under interference regimes. Hence, accounting for the stochastic nature of competition between mutations demands novel estimation methodologies based on the analysis of HIV strains, rather than mutation frequencies. [ABSTRACT FROM AUTHOR]

Based on some important biological meanings, we propose a class of HIV infection models incorporating both classical cell-free virus diffusion and direct cell-to-cell transmission. According to recent studies, the direct cell-to-cell transfer of HIV is a significantly more efficient mode of retroviral dissemination. In the first part of our analysis, we show that our model possesses non-negative solutions. Then, we derive sufficient conditions for the asymptotic stability of equilibriums. The analytical solutions are verified by simulation results. At the end of the paper, some important conclusions are given. [ABSTRACT FROM AUTHOR]

In this paper, we study the global properties of two mathematical models which describe the interaction of the human immunodeficiency virus (HIV) with two classes of target cells, CD4+ T cells and macrophages. The incidence rate of virus infection is given by the Crowley-Martin functional response. The first model has two types of discrete delays while the second one incorporates two types of distributed delays to describe the time needed for infection of cell and virus replication. The basic reproduction number R0 is identified which completely determines the global dynamics of the models. By constructing suitable Lyapunov functionals, we have proven that if R0 ≤ 1 then the uninfected steady state is globally asymptotically stable (GAS), and if R0 > 1 then the infected steady state exists and it is GAS. [ABSTRACT FROM AUTHOR]

In this paper, we study the global analysis of virus dynamics models with discrete delay and with distributed delay. The models describe the interaction of the HIV with two classes of target cells, CD4+ T cells and macrophages. The incidence rate of virus infection is given by the Beddington-DeAngelis functional response. The models have two types of discrete time delay or distributed delay describing the time needed for infection of cell and virus replication. The basic reproduction number R0 is identified which completely determines the global dynamics of the models. By constructing suitable Lyapunov functionals, we have proven that if R0 ≤ 1 then the uninfected steady state is globally asymptotically stable (GAS), and if R0 > 1 then the infected steady state exists and it is GAS. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, we sought to identify the CD4+ T-cell dynamics in the course of HIV infection in response to continuous and intermittent intravenous courses of interleukin-2 (IL-2), the principal cytokine responsible for progression of CD4+ T-lymphocytes from the G1 to the S phase of the cell cycle. Based on multivariate regression models, previous literature has concluded that the increase in survival of CD4+ T-cell appears to be the critical mechanism leading to sustained CD4+ T-cell levels in HIV-infected patients receiving intermittent IL-2 therapy. Underscored by comprehensive mathematical modeling, a major finding of the present work is related to the fact that, rather than due to any increase in survival of CD4+ T-cells, the expressive, selective and sustained CD4+ T-cell expansions following IL-2 administration may be related to the role of IL-2 in modulating the dynamics of Fas-dependent apoptotic pathways, such as activation-induced cell death (AICD) or HIV-specific apoptotic routes triggered by viral proteins. [Copyright &y& Elsevier]

In this paper, we introduce ordinary and delay differential equations to describe the interactions between a malignant tumour and the immune systemin vivoin the presence of human immunodeficiency virus (HIV) infection of CD4+T-cells. In the delay model, we take into account the time lags required by the healthy effector cell components to recognize the pathogens and tumour cells. The models consist of four populations: tumour cells, healthy effector cells (CD4+T-cells), effector cells infected by HIVs and free viral particles. The presence of delay term in the model leads to a notable increase in the complexity of the observed behaviour. We investigate the qualitative behaviour of the models and find the conditions that guarantee the asymptotic stability of the steady states. Numerical simulations are provided to illustrate and extend the theoretical results. The obtained results are consistent with the real phenomena and give a better understanding of cancer immunity and viral oncogenesis. [ABSTRACT FROM PUBLISHER]

While antiretroviral drugs can drive HIV to undetectably low levels in the blood, eradication is hindered by the persistence of long-lived, latently infected memory CD4 T cells. Immune activation therapy aims to eliminate this latent reservoir by reactivating these memory cells, exposing them to removal by the immune system and the cytotoxic effects of active infection. In this paper, we develop a mathematical model that investigates the use of immune activation strategies while limiting virus and latent class rebound. Our model considers infection of two memory classes, central and transitional CD4 T cells and the role that general immune activation therapy has on their elimination. Further, we incorporate ways to control viral rebound by blocking activated cell proliferation through anti proliferation therapy. Using the model, we provide insight into the control of latent infection and subsequently into the long term control of HIV infection. [ABSTRACT FROM AUTHOR]

Background: In highly antiretroviral-experienced patients with a multidrug-resistant human immunodeficiency virus (HIV) infection, recommended regimens should preferentially contain 3 active components, including a ritonavir-boosted protease inhibitor (PI/r). Tipranavir/r (TPV/r), a non-peptidic PI, has been specifically developed for patients resistant to the usual antiretroviral classes including PIs. This paper discusses the role of TPV/r in patients experiencing multiple PI resistance. Methods: Virological, immunological, and safety outcomes were collected between 2003 and 2007 at 7 clinical units. Virus resistance assessment was based on 3 different genotypic tests. The 207 patients evaluated had previously received nucleoside reverse transcriptase inhibitors (NRTIs) and PIs. Results: The main drugs co-administered with TPV/r were 1 or 2 NRTIs associated, in half of the patients, with enfuvirtide. After 12 weeks, viral load was <50 copies/ml in 38% of the patients (44% with enfuvirtide), while median CD4 counts had increased from 150 to 250 cells/mm3. Genotypic testing suggested that most of the patients had viruses susceptible to TPV. Lipid and transaminase levels were slightly modified, and less than 10% of treatment discontinuations were due to gastrointestinal events. Conclusion: A regimen including TPV/r associated with at least 1 active component is a valuable option in highly ARV-experienced patients with multi-resistance to the usual ARV classes including PIs. [ABSTRACT FROM AUTHOR]

The major pathway for HIV internalization in CD4+ T cells has been thought to be the direct fusion of virus and cell membranes, because the cell surface is the point of entry of infectious particles. However, the exact contribution of endocytic pathways to the infection of CD4+ T lymphocytes is unknown, and the mechanisms involved in endocytosis of HIV particles are unclear. Recent evidence suggests that endocytosis of cell-free and cell-associated virus particles could lead to effective virus entry and productive infections. Such observations have, in turn, spurred a debate on the relevance of endosomal entry as a mechanism of escape from the immune system and HIV entry inhibitors. In this paper, we review the endocytosis of HIV and discuss its role in HIV infection and pathogenesis. [ABSTRACT FROM AUTHOR]

Cortical F-actin plays important roles during HIV-1 infection. A recent paper in Cell highlights the involvement of F-actin in enhancing dendritic cell (DC)-mediated HIV-1 infection of T cells. Such a critical mechanism of HIV-1 trans -enhancement between human DCs and T cells had not been analyzed in molecular detail before this work. [ABSTRACT FROM AUTHOR]

We present a review and comparison of several recent differential equations models of treatment of HIV-1 infection. We seek to clarify the role of the natural anti-HIV immune response and determine its effect upon optimal treatment schemes. In this paper, we consider systems in which treatment is expressed as a forcing function, as well as those in which we determine optimal treatment via control theoretic techniques. The primary goal of this study is to compare treatment schemes for systems in which a natural nonconstant immune response of the patient is considered explicitly with those that consider implicitly a constant non-specific immune response. We find that when the natural immune response can be boosted sufficiently, drug levels may not need to be as high as previously supposed. This implies that a treatment scenario in which intervals of drug treatment are alternated with some form of immune-boosting therapy may be highly beneficial in terms of reducing toxicity to the patient. Additionally, in developing countries where HIV infection is widespread and sufficient funds are not available to supply rigourous drug regimens, the implications of these models are profound, as they suggest methods of treating HIV at a minimal cost. [ABSTRACT FROM AUTHOR]

In this paper, neglecting the effects of free virus, we consider a simple model of cell-to-cell spread of HIV-1. We discuss the impact of the CD8+ cell non-cytotoxic anti-viral response (CNAR) and cytotoxic T lymphocyte (CTL) activity on infection by HIV-1. Two types of models are considered: the ordinary differential equation (ODE) model and the discrete time delay differential equation (DDE) system. The steady states of the ODE model are globally asymptotically stable respectively under two threshold criteria. In the DDE model, the global stability of the infected steady state of the ODE model becomes only ultimately stable. Moreover, at a certain interval of the time delay, the DDE model will produce Hopf bifurcation or periodic solutions. The introduction of CTL and CNAR will change the values of these steady states and induce fluctuations in the cell concentration. It also affects the critical value of the time delay and is of utility in the interpretation of typical HIV-dynamics data resulting from clinical trials. The DDE model produces sustained infective oscillations in some real parameter values, which is different from the result of the similar cell-free viral spread model with delay. [ABSTRACT FROM AUTHOR]

The requirements for the eradication of HIV in infected individuals are unknown. Intermittent administration of the immune activator interleukin-2 (IL-2) in combination with highly-active anti-retroviral therapy (HAART) has been suggested as an effective strategy to realize long-term control of HIV replication in vivo . However, potential latent virus reservoirs are considered to be a major impediment in achieving this goal. In this paper, a new mathematical model is designed and used to monitor the interactions between HIV, CD4+ T-cells, CD8+ T-cells, productively infected and latently infected CD4+ T-cells, and to evaluate therapeutic strategies during the first 3 years of HIV infection. The model shows that current anti-HIV therapies, including intermittent IL-2 and HAART, are insufficient in achieving eradication of HIV. However, it suggests that the HIV eradication may indeed be theoretically feasible if such therapy is administered continuously (without interruption) under some specified conditions. These conditions may realistically be achieved using an agent (such as a putative anti-HIV vaccine) that brings about a concomitant increase in the proliferation of HIV-specific CD4+ T- and CD8+ T-cells and the differentiation of CD8+ T-cells into anti-HIV cytotoxic T lymphocytes (CTLs). [ABSTRACT FROM AUTHOR]