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In this paper, we study a model that enhances our understanding of cytokine-influenced HIV-1 infection. The impact of adaptive immune response (cytotoxic T lymphocytes (CTLs) and antibodies) and time delay on HIV-1 infection is included. The model takes into account two types of distributional delays, (i) the delay in the HIV-1 infection of CD4+T cells and (ii) the maturation delay of new virions. We first investigated the fundamental characteristics of the system, then found the system's equilibria. We derived five threshold parameters, ℜ i , i = 0, 1,..., 4, which completely determine the existence and stability of the equilibria. The Lyapunov method was used to prove the global asymptotic stability for all equilibria. We illustrate the theoretical results by performing numerical simulations. We also performed a sensitivity analysis on the basic reproduction number ℜ 0 and identified the most-sensitive parameters. We found that pyroptosis contributes to the number ℜ 0 , and then, neglecting it will make ℜ 0 underevaluated. Necrosulfonamide and highly active antiretroviral drug therapy (HAART) can be effective in preventing pyroptosis and at reducing viral replication. Further, it was also found that increasing time delays can effectively decrease ℜ 0 and, then, inhibit HIV-1 replication. Furthermore, it is shown that both CTLs and antibody immune responses have no effect on ℜ 0 , while this can result in less HIV-1 infection. [ABSTRACT FROM AUTHOR]

In this paper, the dynamical behaviors of a multiple delayed HIV-1 infection model which describes the interactions of humoral, cytotoxic T lymphocyte (CTL) immune responses, and two modes of transmission that are the classical virus-to-cell infection and the direct cell-to-cell transmission are investigated. The model incorporates three delays, including the delays of cell infection, virus production and activation of immune response. We first prove the well-posedness of the model, and calculate the biological existence of equilibria and the reproduction numbers, which contain virus infection, humoral immune response, CTL immune response, CTL immune competition, and humoral immune competition. Further, the threshold conditions for the local and global stability of the equilibria for infection-free, immune-free, antibody response, CTL response, and interior are established by utilizing linearization method and the Lyapunov functionals. The existence of Hopf bifurcation with immune delay as a bifurcation parameter is investigated by using the bifurcation theory. Numerical simulations are carried out to illustrate the theoretical results and reveal the effects of some key parameters on viral dynamics. [ABSTRACT FROM AUTHOR]

The time fractional-order nonlinear model of HIV-1 infection of T-cells with and without the rate of virus-producing cells’ death is very important in mathematical modeling. This paper presents proofs of the existence and uniqueness theorems using the Banach fixed point theorem, along with new approximate analytical solutions to two nonlinear fractional Equationuations characterizing HIV-1 infection in $CD{4^ + }$CD4+ T-cells. We use a combination of two methods, namely the natural transform method to deal with the linear terms and the Adomian decomposition method to deal with the nonlinear terms. There are two nonlinear numerical examples presented in this work, namely, we find approximate solutions to the time fractional-order nonlinear model of HIV-1 infection of T cells with and without the rate of virus-producing cells’ death using an effective method called the Adomian natural decomposition method (ANDM). The present approach, which has numerous applications in the science and engineering fields, is a great alternative to the many existing methods for solving systems of differential Equationuations. It also holds great promise for additional real-world applications. The Mathematica 12 package is used to carry out some of the nonlinear term calculations and the graphs presented in this work. [ABSTRACT FROM AUTHOR]

It is well known that dynamical systems are very useful tools to study viral diseases such as HIV, HBV, HCV, Ebola and Influenza. This paper focuses on a mathematical model of the cell-to-cell and the cell-free spread of HIV with both linear and nonlinear functional responses and logistic target cell growth. The reproduction number of each mode of transmission has been calculated and their sum has been considered as the basic reproduction number. Based on the values of the reproduction number, the local and global stabilities of the rest points are investigated. Choosing a suitable bifurcation parameter, some conditions for the occurrence of Hopf bifurcation are also obtained. Moreover, numerical simulations are presented to support the analytical results. Finally, to study the effect of the drug on the disease process, some control conditions are determined. Since two modes of transmission and both linear and nonlinear functional responses have been included in this manuscript, our obtained results are a generalization of those in the literature. Moreover, the results are obtained with weaker assumptions in comparison with the previous ones. [ABSTRACT FROM AUTHOR]

In this paper, we incorporate immune systems containing Cytotoxic T lymphocyte and humoral immunity into a general human immunodeficiency viruses infection model, which also considers logistic growth for target cells and both modes of spread, cell-to-cell and cell-free represents, by linear functions. We derive five threshold parameters which are used to study the existence of equilibria. By considering the characteristic equations, the local stability of disease-free and immune-free equilibria is investigated. Lyapunov functions and LaSalle's invariance are constructed to prove the global stability of all steady states. Global dynamics of the human immunodeficiency viruses model can be accurately expressed by threshold parameters; also the existence of Hopf bifurcation is discussed and the results are expressed in the form of a proposition. Furthermore, numerical simulations confirm the corresponding theoretical results. [ABSTRACT FROM AUTHOR]

In recent decades, AIDS has been one of the main challenges facing the medical community around the world. Due to the large human deaths of this disease, researchers have tried to study the dynamic behaviors of the infectious factor of this disease in the form of mathematical models in addition to clinical trials. In this paper, we study a new mathematical model in which the dynamics of CD 4 + T-cells under the effect of HIV-1 infection are investigated in the context of a generalized fractal-fractional structure for the first time. The kernel of these new fractal-fractional operators is of the generalized Mittag-Leffler type. From an analytical point of view, we first derive some results on the existence theory and then the uniqueness criterion. After that, the stability of the given fractal-fractional system is reviewed under four different cases. Next, from a numerical point of view, we obtain two numerical algorithms for approximating the solutions of the system via the Adams-Bashforth method and Newton polynomials method. We simulate our results via these two algorithms and compare both of them. The numerical results reveal some stability and a situation of lacking a visible order in the early days of the disease dynamics when one uses the Newton polynomial. [ABSTRACT FROM AUTHOR]

The two-drug regimen dolutegravir plus lamivudine demonstrated durable efficacy for up to 3 years in phase III studies and a high barrier to resistance in treatment-naive and virologically suppressed people with HIV (PWH). This systematic literature review summarizes real-world evidence evaluating effectiveness and safety of dolutegravir plus lamivudine. We searched Ovid MEDLINE®, Embase®, PubMed, Cochrane library, and relevant international conference proceedings from 2013 to 2020. Qualitative synthesis of virologic suppression at Week 48, treatment-emergent resistance, discontinuation rates, and comorbidities was undertaken, with no statistical analyses conducted. Linked publications and potential for duplication in reporting of outcomes for cohorts and populations were identified, and the publication reporting the highest number of PWH receiving dolutegravir plus lamivudine was included in the analysis. Thirty-four studies reporting on cohorts of PWH not suspected to be linked or to include duplicate data receiving dolutegravir plus lamivudine were identified (N = 5017). Of 3744 virologically suppressed PWH who switched to dolutegravir plus lamivudine, 603 (16%) reported history of virologic failure. Nineteen studies included effectiveness data (n = 3558), four of which included data from treatment-naive PWH (n = 69). In studies with > 100 PWH, high rates of virologic suppression (Week 48, 97–100%) were maintained with dolutegravir plus lamivudine, with low rates of virologic failure (0–3.3 per 100 person-years of follow-up); one instance of emergent integrase strand transfer inhibitor resistance was reported in a complex treatment-experienced individual. Rates of discontinuation due to adverse events were low and consistent with previously observed trial data. Dolutegravir plus lamivudine minimally impacted renal function and had minimal impact on or improved lipid profiles and bone mineral density. This systematic review demonstrates that effectiveness and safety of dolutegravir plus lamivudine in clinical practice support data from randomized controlled trials with regard to high rates of virologic response, low rates of discontinuation, and a high barrier to resistance. [ABSTRACT FROM AUTHOR]

The paper is focused on stochastic modelling of the process of transition of infected cells and virions of HIV-1 infection between two lymph nodes. The model is based on the following assumptions: (1) the duration of transition of infected cells and virions between two lymph nodes is set using a time-dependent function, (2) infected cells produce virions in the process of transition between two lymph nodes, (3) infected cells and virions may die when moving between two lymph nodes. The methods of the theory of branching random processes are used to study analytically the model variables. An algorithm for statistical modelling of the number of infected cells and virions in the second lymph node is presented. The results of computational experiments studying the distribution law of the number of virions produced by one infected cell depending on the duration of movement between two lymph nodes are presented. [ABSTRACT FROM AUTHOR]

In this paper, we propose and analyse a delayed HIV-1 model with both viral and cellular transmissions and virus waning. We obtain the threshold dynamics of the proposed model, characterized by the basic reproduction number R 0 . If R 0 < 1 , the infection-free steady state is globally asymptotically stable; whereas if R 0 > 1 , the system is uniformly persistent. When the delays are positive, we show that the intracellular delays in both viral and cellular infections may lead to stability switches of the infected steady state. Both analytical and numerical results indicate that if the effect of cell-to-cell transmission is ignored, then the risk of HIV-1 infection will be underestimated. Moreover, the viral load of model without virus waning is higher than the one of model with virus waning. These results highlight the important role of two ways of viral transmission and virus waning on HIV-1 infection. [ABSTRACT FROM AUTHOR]

Summary: In this paper, we consider a four‐dimensional version of a human immunodeficiency virus (HIV) infection model, which is an extension of some previous three‐dimensional models. We approach the treatment problem by adding two controls u1 and u2 to the system for inhibiting viral production and preventing new infections. In fact, u1 is added to components of uninfected and infected cells to represent the effect of chemotherapy on the interaction of uninfected CD4+ T cells with infected cells. u2 is considered in the effector immune component as immunotherapy. The purpose of this work is to control the progress of the disease in a steady state. Hence, first, we obtain a relation between the two controls u1 and u2 such that a Hopf bifurcation occurs. Next, the Pontryagin minimum principle will be applied to derive the optimal therapy for HIV. At the end, numerical results are presented. [ABSTRACT FROM AUTHOR]

Highly active antiretroviral therapy (HAART) reduces the viral burden in human immunodeficiency virus type 1 (HIV-1) infected patients. The paper addresses the problem of controlling the predator-prey like model of the interaction among CD4+T-cell, CD8+ T-cell, and HIV-1 by an external drug agency. By exploring the dynamic properties of the system, the original system is first regrouped into two subsystems, then a nonlinear global controller is presented by designing two controllers over two complementary zones: a local controller on a finite region and a global controller over its complement. The local controller is designed to guarantee nonnegativty, and avoids the problem of control singularity within the neighborhood of the origin Il. The complementary controller is designed via back stepping for both subsystems over the complementary region. The closed-loop system is globally stable at nominal values through the introduction of a novel bridging virtual control, and the resulting controller is singularity free and guarantees nonnegativity. In this paper, simulations are conducted in discrete-time with sampling time Ts to show the effectiveness of the proposed method. [ABSTRACT FROM AUTHOR]

HIV-associated neurocognitive disorders (HAND) persist under antiretroviral therapy as a complex pathology that has been difficult to study in cellular and animal models. Therefore, we generated an ex vivo human brain slice model of HIV-1 infection from surgically resected adult brain tissue. Brain slice cultures processed for flow cytometry showed >90% viability of dissociated cells within the first three weeks in vitro, with parallel detection of astrocyte, myeloid, and neuronal populations. Neurons within brain slices showed stable dendritic spine density and mature spine morphologies in the first weeks in culture, and they generated detectable activity in multi-electrode arrays. We infected cultured brain slices using patient-matched CD4+ T-cells or monocyte-derived macrophages (MDMs) that were exposed to a GFP-expressing R5-tropic HIV-1 in vitro. Infected slice cultures expressed viral RNA and developed a spreading infection up to 9 days post-infection, which were significantly decreased by antiretrovirals. We also detected infected myeloid cells and astrocytes within slices and observed minimal effect on cellular viability over time. Overall, this human-centered model offers a promising resource to study the cellular mechanisms contributing to HAND (including antiretroviral toxicity, substance use, and aging), infection of resident brain cells, and new neuroprotective therapeutics. [ABSTRACT FROM AUTHOR]

In this paper, following a previous paper ([32] Permanence and extinction of a non-autonomous HIV-1 model with two time delays, preprint) on the permanence and extinction of a delayed non-autonomous HIV-1 within-host model, we introduce and investigate a delayed HIV-1 model including maximum homeostatic proliferation rate of CD4+ T-cells and varying coefficients. By applying the asymptotic analysis theory and oscillation theory, we show: (i) the system will be permanent when the threshold value R* > 1, and for this case we also obtain the explicit estimate of the eventual lower bound of the HIV-1 virus load; (ii) the threshold value R* < 1 implies the extinction of the virus. Furthermore, we obtain that the threshold dynamics is in agreement with that of the corresponding autonomous system, which extends the classic results for the system with constant coefficients. Numerical simulations are also given to illustrate our main results, and in particular, some sensitivity test of R* is established. [ABSTRACT FROM AUTHOR]

The modern antiretroviral treatment of human immunodeficiency virus (HIV-1) infection has considerably lowered the incidence of opportunistic infections. With the exception of the most severe dementia manifestations, the incidence and prevalence of HIV-associated neurocognitive disorders (HAND) have not decreased, and HAND continues to be relevant in daily clinical practice. Now, HAND occurs in earlier stages of HIV infection, and the clinical course differs from that before the widespread use of combination antiretroviral treatment (cART). The predominant clinical feature is a subcortical dementia with deficits in the domains concentration, attention, and memory. Motor signs such as gait disturbance and impaired manual dexterity have become less prominent. Prior to the advent of cART, the cerebral dysfunction could at least partially be explained by the viral load and by virus-associated histopathological findings. In subjects where cART has led to undetectable or at least very low viral load, the pathogenic virus-brain interaction is less direct, and an array of poorly understood immunological and probably toxic phenomena are discussed. This paper gives an overview of the current concepts in the field of HAND and provides suggestions for the diagnostic and therapeutic management. [ABSTRACT FROM AUTHOR]

In this paper, we consider a four dimensional model of the human immunodeficiency virus-1 (HIV-1) with delay, which is an extension of some three dimensional models. We approach the treatment problem by adding two controllers to the system for inhibiting viral production. The optimal controller $$u_{1}$$ is considered for vaccine and $$u_{2}$$ for the drug. The Pontryagin maximum principle with delay is used to characterize these optimal controls. At the end, numerical results are presented to illustrate the optimal solutions. The validity of the model was confirmed by proper semi-quantitative simulation of some clinical data. The model was used to predict the possible beneficial effects of vaccine and anti-retroviral drug administration in HIV-1 disease. [ABSTRACT FROM AUTHOR]

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HIV infection is one of the most serious causes of death throughout the world. CD4+ T cells which play an important role in immune protection, are the primary targets for HIV infection. The hallmark of HIV infection is the progressive loss in population of CD4+ T cells. However, the pathway causing this slow T cell decline is poorly understood [16]. This paper studies a discontinuous mathematical model for HIV-1 infection, to investigate the effect of pyroptosis on the disease. For this purpose, we use the theory of discontinuous dynamical systems. In this way, we can better analyze the dynamical behavior of the HIV-1 system. Especially, considering the dynamics of the system on its discontinuity boundary enables us to obtain more comprehensive results rather than the previous researches. A stability region for the system, corresponding to its equilibria on the discontinuity boundary, will be determined. In such a parametric region, the trajectories of the system will be trapped on the discontinuity manifold forever. It is also shown that in the obtained stability region, the disease can lead to a steady state in which the population of uninfected T cells and viruses will preserve at a constant level of cytokines. This means that the pyroptosis will be restricted and the disease cannot progress for a long time. Some numerical simulations based on clinical and experimental data are given which are in good agreement with our theoretical results. [ABSTRACT FROM AUTHOR]

In this paper, a delayed human immunodeficiency virus (HIV)-1 infection model with absorption and cytotoxic T lymphocytes (CTL) immune response is studied. By using suitable Lyapunov functionals and LaSalle's invariance principle, it is proved that if the basic reproductive ratio is less than unity, the infection-free equilibrium is globally asymptotically stable; if the immune response reproductive ratio is less than unity and the basic reproductive ratio is greater than unity, sufficient conditions are derived for the global stability of the CTL-inactivated infection equilibrium; if the immune response reproductive ratio is greater than unity, sufficient conditions are obtained for the global stability of the CTL-activated infection equilibrium. Numerical simulations are carried out to illustrate the theoretical results. [ABSTRACT FROM PUBLISHER]

In this paper, we introduce the stochasticity into an HIV-1 infection model with cytotoxic T lymphocytes (CTLs) immune response via the technique of parameter perturbation. We show that there is a positive solution as desired in any population dynamics. Then we analyze the long time behavior of this model. We obtain a sufficient condition for the stochastic asymptotic stability in the large of the infection-free equilibrium and give the conditions for the solution fluctuating around the two infection equilibria (one without CTLs being activated and the other with). Finally, we make simulations to conform to our analytical results. [ABSTRACT FROM AUTHOR]

In this paper, an attempt has been made to study the global dynamical behavior of a viral dynamics model incorporating both the lytic and nonlytic immune responses. The global stability of the model is analyzed in terms of two threshold parameters, namely, basic reproduction number, R 0 and immune response reproduction number, R 1. The obtained results signify that the infection dies out if R 0 ≤ 1 and persists if R 0 > 1. We establish that the global dynamic behavior of the model has no concern with the efficacy of the nonlytic component. Numerical simulations are performed to support our theoretical findings and to investigate the effects of lytic and nonlytic components on the viral dynamics model. A comparison of two different viral infection models has been performed to illustrate the effect of viral replication inhibition through nonlytic effector mechanism on the infection dynamics. Moreover, a case study of HIV-1 infected humanized mice is presented and the result manifests that the model can fairly demonstrate the chronic stage of HIV-1 infection in humanized mice. • A viral dynamic model with lytic and nonlytic immune responses has been presented. • Global stability of the model is independent of the efficacy of nonlytic strength. • Inhibition of viral replication reduces the level of infected cells and virions. • The model fairly demonstrates the chronic HIV-1 infection in humanized mice. [ABSTRACT FROM AUTHOR]

In this paper, a mathematical model for HIV-1 infection with intracellular delay and Beddington-DeAngelis functional response is investigated. We obtain a necessary and sufficient condition for the global stability of the infection-free equilibrium and give some sufficient conditions for the local stability of the infected equilibrium. [ABSTRACT FROM AUTHOR]

In this paper, we consider a more realistic model than a previous one (Lou et al. in Math Biosci Eng 3:313, 2006) for an HIV-1 dynamical model incorporating the AIDS-related cancer cells in tissue cultures. In order to improve the description of the phenomenon, we have taken into account also the time delay for the incubation phase when the target cells are infected. The model involves three cell populations: cancer cells, healthy and infected CD4+ T lymphocytes and we verify that there exists up to six steady states. We discuss the existence, the stability properties and the biological meanings of the steady states, focusing in particular on the positive one: cancer- HIV-healthy cells steady state. We find Hopf bifurcation of the positive steady state, leading to periodic solutions and chaos. By means of numerical simulations the effect of the delay is analyzed and we find that the existence of infected quiescent memory T cells is one of the important reasons for which the HIV-1 infected individual develops AIDS. [ABSTRACT FROM AUTHOR]

The oral cavity is rarely reported to be a site of human immunodeficiency virus (HIV) transmission, despite detectable virus in saliva and relatively frequent prevalence of periodontal disease in HIV-infected persons yielding increased excretion of mononuclear-cell-enriched gingival fluid. To search for possible sources of HIV in saliva, and using the polymerase chain-reaction technique, we sought the presence and shedding patterns of proviral HIV-1 DNA in gingival crevicular fluid in a group of patients previously determined as HIV-1-seropositive. Periodontal status at the collection sites was monitored by several clinical parameters, including Plaque Index, Gingival Index, probing depth, and clinical attachment loss. Gingival crevicular fluid samples were collected by means of paper points. Proviral HIV-1 DNA was detected in the gingival fluid of 17 out of 35 HIV-1-infected patients. Its detection correlated significantly with higher plasma HIV-1 RNA viral load (p =0.03) and not with peripheral blood CD4+ cell count, the presence of blood in gingival fluid, or oral lesions. There was a significant correlation between clinical attachment loss at the sites of fluid collection and plasma HIV-l RNA viral load (p =0.002), and borderline correlation between the latter and probing depth (p =0.54) in the group of patients harboring proviral HIV-l DNA in gingival crevicular fluid. The results of our study suggest that mononuclear cells present in gingival crevicular fluid and harboring proviral HIV-1 DNA could represent a potential source of HIV-1 in the presence or absence of local bleeding, especially in persons with advanced HIV infection and increased loss of clinical attachment. [ABSTRACT FROM AUTHOR]

HIV-1 has evolved a plethora of strategies to overcome the cytoskeletal barrier (i.e., actin and intermediate filaments (AFs and IFs) and microtubules (MTs)) to achieve the viral cycle. HIV-1 modifies cytoskeletal organization and dynamics by acting on associated adaptors and molecular motors to productively fuse, enter, and infect cells and then traffic to the cell surface, where virions assemble and are released to spread infection. The HIV-1 envelope (Env) initiates the cycle by binding to and signaling through its main cell surface receptors (CD4/CCR5/CXCR4) to shape the cytoskeleton for fusion pore formation, which permits viral core entry. Then, the HIV-1 capsid is transported to the nucleus associated with cytoskeleton tracks under the control of specific adaptors/molecular motors, as well as HIV-1 accessory proteins. Furthermore, HIV-1 drives the late stages of the viral cycle by regulating cytoskeleton dynamics to assure viral Pr55Gag expression and transport to the cell surface, where it assembles and buds to mature infectious virions. In this review, we therefore analyze how HIV-1 generates a cell-permissive state to infection by regulating the cytoskeleton and associated factors. Likewise, we discuss the relevance of this knowledge to understand HIV-1 infection and pathogenesis in patients and to develop therapeutic strategies to battle HIV-1. [ABSTRACT FROM AUTHOR]

In this research work, we suggest two mathematical models that take into account (i) two categories of target cells, CD 4 + T cells and macrophages, and (ii) two modes of infection transmissions, the direct virus-to-cell (VTC) method and cell-to-cell (CTC) infection transmission, where CTC is an effective method of spreading human immunodeficiency virus type-1 (HIV-1), as with the VTC method. The second model incorporates four time delays. In both models, the presence of a bounded and positive solution of the biological model is investigated. The existence conditions of all equilibria are established. The basic reproduction number R 0 that identifies a disease index is obtained. Lyapunov functions are utilized to verify the global stability of all equilibria. The theoretical findings are verified through numerical simulations. According to the outcomes, the trajectories of the solutions approach the infection-free equilibrium and infection-present equilibrium when R 0 ≤ 1 and R 0 > 1 , respectively. Further, we study the sensitivity analysis to investigate how the values of all the parameters of the suggested model affect R 0 for given data. We discuss the impact of the time delay on HIV-1 progression. We find that a longer time delay results in suppression of the HIV-1 infection and vice versa. [ABSTRACT FROM AUTHOR]

This paper study the dynamical behavior of a general HIV-1 infection model under the effect of Highly active antiretroviral therapies (HAART). The model includes three types of infected cells (i) long-lived productively infected cells which live for long time and creat small amount of HIV-1 particles, (ii) latently infected cells which do not creat HIV-1 until they have been activated (iii) short-lived productively infected cells which live for long time and creat large amount of HIV-1. The model incorporates humoral immune response and general nonlinear forms for the incidence rate of infection, the generation and removal rates of all compartments. The nonnegativity and boundedness of the solutions of the model as well as global stability of the steady states are studied. The global stability are established using Lyapunov method. Using MATLAB we conduct some numerical simulations to confirm our results. [ABSTRACT FROM AUTHOR]

The aim of this paper is to determine the differences of fertility between HIV 1 infected and uninfected women in Abidjan, Cote d Ivoire, using data available in an observational study conducted in 1995 and 1996 in 2 antenatal care centres in the district of Yopougon, Abidjan, within an intervention programme to reduce mother to child HIV 1 transmission DITRAME project, ANRS 049 . Fertility indicators have been constructed from retrospective data on pregnancies and births, and univariate and multivariate analyses have been performed on these indicators and stratified by age groups to compare HIV 1 positive and HIV negative populations. The main outcome measures were the number of pregnancies, the number of miscarriages, the risk of miscarriage and the proportion of primigravida. Four thousand, three hundred and ninety six women agreed to HIV testing: 12.1 were found to be HIV 1 infected. HIV 1 positive women had significantly fewer pregnancies than HIV negatives in age groups 25-29 P =0.05 and 30-34 P =0.008 . The risk of having had at least one abortion or stillbirth was significantly higher for HIV 1 infected women than for HIV negatives OR=1.28, 95 CI: 1.02-1.60 , when controlling for social and demographic factors. This study suggests that HIV 1 infection has deleterious consequences on female fertility, with lower fertility rates and more frequent adverse pregnancy outcomes. Family planning and antenatal care services should consider antenatal HIV counselling and testing in women in areas of high HIV prevalence. [ABSTRACT FROM AUTHOR]

This paper reports the results of the cross-sectional phase of a long-term follow-up investigation, carried out on a sample representative of the broad population of HIV-1 infected patients, with the objective of evaluating the possible neurocognitive effects of zidovudine and 2′, 3′-dideoxyinosine, compared to a group of people who refused antiretroviral therapy. The sample was composed of 88 people, 42 of whom were treated with ZDV at a daily dose of 500–600 mg, 19 with ddI at a daily dose of 400 mg, and 27 with no therapy. To assess the relevance of different antiretroviral therapies on cognitive performance adjusting for demographic and clinical characteristics, a stepwise logistic regression analysis was performed with neuropsychological performance as the dependent variable and age, education, sex, at-risk behaviour, CD4 count, presence of prominent depressive and anxious symptoms, HIV-1 serostatus and type of antiretroviral treatment as independent variables. The results confirm that people with AIDS and AIDS-related complex treated with ZDV and ddI show a better neuropsychological performance when compared to non-treated patients. By examining the mean performance on each of the previous neuropsychological tests, we found that the most impaired functions in untreated patients were related to short-term memory, long-term memory, vocational competence, and ultimate adjustment. [ABSTRACT FROM AUTHOR]

The chemokine receptor CXCR4 and its ligand CXCL12 regulate leukocyte trafficking, homeostasis and functions and are potential therapeutic targets in many diseases such as HIV-1 infection and cancers. Here, we identified new CXCR4 ligands in the CERMN chemical library using a FRET-based high-throughput screening assay. These are bis-imidazoline compounds comprising two imidazole rings linked by an alkyl chain. The molecules displace CXCL12 binding with submicromolar potencies, similarly to AMD3100, the only marketed CXCR4 ligand. They also inhibit anti-CXCR4 mAb 12G5 binding, CXCL12-mediated chemotaxis and HIV-1 infection. Further studies with newly synthesized derivatives pointed out to a role of alkyl chain length on the bis-imidazoline properties, with molecules with an even number of carbons equal to 8, 10 or 12 being the most potent. Interestingly, these differ in the functions of CXCR4 that they influence. Site-directed mutagenesis and molecular docking predict that the alkyl chain folds in such a way that the two imidazole groups become lodged in the transmembrane binding cavity of CXCR4. Results also suggest that the alkyl chain length influences how the imidazole rings positions in the cavity. These results may provide a basis for the design of new CXCR4 antagonists targeting specific functions of the receptor. [ABSTRACT FROM AUTHOR]

In this paper, we study a model that enhances our understanding of cytokine-influenced HIV-1 infection. The impact of adaptive immune response (cytotoxic T lymphocytes (CTLs) and antibodies) and time delay on HIV-1 infection is included. The model takes into account two types of distributional delays, (i) the delay in the HIV-1 infection of CD4+T cells and (ii) the maturation delay of new virions. We first investigated the fundamental characteristics of the system, then found the system’s equilibria. We derived five threshold parameters, ℜi, i = 0, 1,…, 4, which completely determine the existence and stability of the equilibria. The Lyapunov method was used to prove the global asymptotic stability for all equilibria. We illustrate the theoretical results by performing numerical simulations. We also performed a sensitivity analysis on the basic reproduction number ℜ0 and identified the most-sensitive parameters. We found that pyroptosis contributes to the number ℜ0, and then, neglecting it will make ℜ0 underevaluated. Necrosulfonamide and highly active antiretroviral drug therapy (HAART) can be effective in preventing pyroptosis and at reducing viral replication. Further, it was also found that increasing time delays can effectively decrease ℜ0 and, then, inhibit HIV-1 replication. Furthermore, it is shown that both CTLs and antibody immune responses have no effect on ℜ0, while this can result in less HIV-1 infection.

A mathematical model is presented that describes the dynamics of the population of CD4 T-lymphocytes in a single lymph node. The model is based on a high-dimensional system of nonlinear delay differential equations supplemented with initial data. The equations of the model are given, and their well-posedness is investigated. The results of computational experiments with the model illustrating the characteristic cell population dynamics under the conditions of antigen-specific stimulation of the cell reproduction process for cells of various types are presented. [ABSTRACT FROM AUTHOR]

RNA plays an important role in biology, and more than 170 RNA modifications have been identified so far. Post-transcriptional modification of RNA in cells plays a crucial role in the regulation of its stability, transport, processing, and gene expression. So far, the research on RNA modification and the exact role of its enzymes is becoming more and more comprehensive. Human immunodeficiency virus 1 (HIV-1) is an RNA virus and the causative agent of acquired immunodeficiency syndrome (AIDS), which is one of the most devastating viral pandemics in history. More and more studies have shown that HIV has RNA modifications and regulation of its gene expression during infection and replication. This review focuses on several RNA modifications and their regulatory roles as well as the roles that different RNA modifications play during HIV-1 infection, in order to find new approaches for the development of anti-HIV-1 therapeutics. [ABSTRACT FROM AUTHOR]

The transactive response DNA-binding protein (TARDBP/TDP-43) influences the processing of diverse transcripts, including that of histone deacetylase 6 (HDAC6). Here, we assessed TDP-43 activity in terms of regulating CD4+ T-cell permissivity to HIV-1 infection. We observed that overexpression of wt-TDP-43 increased both mRNA and protein levels of HDAC6, resulting in impaired HIV-1 infection independently of the viral envelope glycoprotein complex (Env) tropism. Consistently, using an HIV-1 Env-mediated cell-to-cell fusion model, the overexpression of TDP-43 levels negatively affected viral Env fusion capacity. Silencing of endogenous TDP-43 significantly decreased HDAC6 levels and increased the fusogenic and infection activities of the HIV-1 Env. Using pseudovirus bearing primary viral Envs from HIV-1 individuals, overexpression of wt-TDP-43 strongly reduced the infection activity of Envs from viremic non-progressors (VNP) and rapid progressors (RP) patients down to the levels of the inefficient HIV-1 Envs observed in long-term non-progressor elite controllers (LTNP-EC). On the contrary, silencing endogenous TDP-43 significantly favored the infectivity of primary Envs from VNP and RP individuals, and notably increased the infection of those from LTNP-EC. Taken together, our results indicate that TDP-43 shapes cell permissivity to HIV-1 infection, affecting viral Env fusion and infection capacities by altering the HDAC6 levels and associated tubulin-deacetylase anti-HIV-1 activity. [ABSTRACT FROM AUTHOR]

Highlights: [•] We proposed new nonlinear stochastic control of HIV infection. [•] The proposed method is based on new nonlinear convex function as controller that their parameter tunes by genetic algorithm. [•] In evaluating long periods, the total amount of drugs increases slightly, but rebound risks for viral load are minimized. [•] The result of our paper is drudge dosage management method for control of HIV. [ABSTRACT FROM AUTHOR]

Introduction: The purpose of the study was to assess hepcidin levels and iron metabolism in otherwise healthy human immunodeficiency virus-1 (HIV-1)-infected males and the influence of antiretroviral therapy on hepcidin production, as data in this group are scarce. Methods: A total of 89 HIV-1-infected males, 42 on effective antiretroviral therapy (ART)—group A, 47 treatment-naïve—group B, and 27 healthy controls—group C, were enrolled. Erythrocytes parameters, iron metabolism parameters, hepcidin, highly sensitive C-reactive protein (hsCRP), interleukin 6 (IL-6), and soluble transferrin receptor (sTfR) levels were assessed. Conditions related to inflammatory activity, systemic metabolic diseases and iron supplementation were exclusion criteria. Convenience sampling was used. Results: Median age in HIV-1 group was 33 years, and 27 years in the control group. Median CD4+ T-cell count was 724 cells/μl in group A, and 488 cells/μl in group B (p = 0.0000). Nadir CD4+ T-cell count was 397 cells/μl in group A and 475 cells/μl in group B (p = 0.0001). Median value of HIV-1 viral load (VL) in group B was 16 900 copies/mL. The hepcidin value was lower in group A than in groups B (p = 0.0008) or C (p = 0.0004), without differences between groups B and C. The hepcidin value correlated with ferritin in groups A (r2 = 0.16; p = 0.008) and B (r2 = 0.39; p = 0.000), but not in group C (r2 = 0.11; p = 0.09). In group A, the hepcidin value correlated with current CD4+ count (r = 0.48, p = 0.0012), but there was no correlation in group B. There were no correlations of hepcidin values with CD4+ T cell nadir in group A (p = 0.371) or in group B (p = 0.477); ART period (p = 0.614); VL in group B (p = 0.71). No abnormalities of iron metabolism, hsCRP, IL-6, or sTfR were noted. Conclusions: Asymptomatic HIV-1 infection does not cause clinically important iron metabolism alterations or increased hepcidin production. Hepcidin values decrease on effective antiretroviral therapy. [ABSTRACT FROM AUTHOR]

This paper presents an algorithm for nonlinear adaptive control of the viral load in HIV-1 infection. The infection model considered is a reduced complexity nonlinear state-space model with two state variables, that represent the plasma concentration of uninfected and infected CD4+ T-cells of the human immune system. The viral load is assumed to be proportional to the concentration of infected cells. First, a change of variables that exactly linearizes the system is obtained. For the resulting linear system the manipulated variable is obtained by state feedback. To compensate for the uncertainty in the infection parameter of the model an estimator based on a Control Lyapunov Function is designed. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, an HIV-1 infection model with distributed intracellular delays is investigated, where the intracellular delays account for the time the target cells are contacted by the virus particles and the time the contacted cells become actively infected meaning that the contacting virions enter cells and the time the virus has penetrated into a cell and the time the new virions are created within the cell and are released from the cell, respectively. By analyzing the characteristic equations, the local stability of an infection-free equilibrium and a chronic-infection equilibrium of the model is established. By using suitable Lyapunov functionals and LaSalle’s invariance principle, it is proved that if the basic reproduction ratio is less than unity, the infection-free equilibrium is globally asymptotically stable; and if the basic reproduction ratio is greater than unity, the chronic-infection equilibrium is globally asymptotically stable. [Copyright &y& Elsevier]

Abstract: In this paper, an HIV-1 infection model with a saturation infection rate and an intracellular delay accounting for the time between viral entry into a target cell and the production of new virus particles is investigated. By analyzing the characteristic equations, the local stability of an infection-free equilibrium and a chronic-infection equilibrium of the model is established. By using suitable Lyapunov functionals and the LaSalle invariant principle, it is proved that if the basic reproduction ratio is less than unity, the infection-free equilibrium is globally asymptotically stable; if the basic reproduction ratio is greater than unity, the chronic-infection equilibrium is globally asymptotically stable. [Copyright &y& Elsevier]

Abstract: Based on some important biological meanings, a class of more general HIV-1 infection models with time delay is proposed in the paper. In the HIV-1 infection model, time delay is used to describe the time between infection of uninfected target cells and the emission of viral particles on a cellular level as proposed by Herz et al. [A.V.M. Herz, S. Bonhoeffer, R.M. Anderson, R.M. May, M.A. Nowak, Viral dynamics in vivo: Limitations on estimates of intracellular delay and virus decay, Proc. Natl. Acad. Sci. USA 93 (1996) 7247–7251]. Then, the effect of time delay on stability of the equilibria of the HIV-1 infection model has been studied and sufficient criteria for local asymptotic stability of the infected equilibrium and global asymptotic stability of the viral free equilibrium are given. [Copyright &y& Elsevier]

In this paper, we propose and analyse a delayed HIV-1 model with both viral and cellular transmissions and virus waning. We obtain the threshold dynamics of the proposed model, characterized by the basic reproduction number $R_0 $. If $R_0 \lt 1 $, the infection-free steady state is globally asymptotically stable; whereas if $R_0 \gt 1 $, the system is uniformly persistent. When the delays are positive, we show that the intracellular delays in both viral and cellular infections may lead to stability switches of the infected steady state. Both analytical and numerical results indicate that if the effect of cell-to-cell transmission is ignored, then the risk of HIV-1 infection will be underestimated. Moreover, the viral load of model without virus waning is higher than the one of model with virus waning. These results highlight the important role of two ways of viral transmission and virus waning on HIV-1 infection.