Search

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]

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]

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]

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]

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]

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.

In this paper, we investigate a delayed HIV-1 infection model with immune response. Though a logistic growth is incorporated in the growth of the target cells, our focus is on the effect of delays on the infection dynamics. We first study the existence of steady states, which depends on the basic reproduction number $R_0$. When $R_0\le 1$, there is only the infection-free steady state, which is globally asymptotically stable if $R_0 < 1$. When $R_0> 1$, besides the unstable infection-free steady state, there is a unique infected steady state. We then study the local stability of the infected steady state and local Hopf bifurcation at it. The theoretical analysis indicates that the dynamics scenario is complicated. For example, there can be three sequences of critical values, stability switches and double Hopf bifurcation can occur. Some of the theoretical results are also illustrated with numerical simulations.

Human specific immunity consists of two branches: humoral immunity and cellular immunity. To protect us from pathogens, cell-mediated and humoral immune responses work together to provide the strongest degree of efficacy. In this paper, we propose an HIV-1 model with cell-mediated and humoral immune responses, in which both virus-to-cell infection and cell-to-cell transmission are considered. Five reproduction ratios, namely, immunity-inactivated reproduction ratio, cell-mediated immunity-activated reproduction ratio, humoral immunity-activated reproduction ratio, cell-mediated immunity-competed reproduction ratio and humoral immunity-competed reproduction ratio, are calculated and verified to be sharp thresholds determining the local and global properties of the virus model. Numerical simulations are carried out to illustrate the corresponding theoretical results and reveal the effects of some key parameters on viral dynamics.

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 CD4+ 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.

HIV-1 employs a rich arsenal of viral factors throughout its life cycle and co-opts intracellular trafficking pathways. This exquisitely coordinated process requires precise manipulation of the host microenvironment, most often within defined subcellular compartments. The virus capitalizes on the host by modulating cell-surface proteins and cleverly exploiting nuclear import pathways for post entry events, among other key processes. Successful virus–cell interactions are indeed crucial in determining the extent of infection. By evolving defenses against host restriction factors, while simultaneously exploiting host dependency factors, the life cycle of HIV-1 presents a fascinating montage of an ongoing host–virus arms race. Herein, we provide an overview of how HIV-1 exploits native functions of the host cell and discuss recent findings that fundamentally change our understanding of the post-entry replication events. [ABSTRACT FROM AUTHOR]

Over the past decade, a series of observations linking α4β7, the principal gut‐homing integrin, with various aspects of HIV‐1 infection have generated considerable interest in the field of HIV‐1 research. After the initial report that the major HIV‐1 envelope glycoprotein, gp120, can bind to α4β7, intensive research efforts have been focused on the role of α4β7 as a key factor in HIV‐1 pathogenesis and as a potential target for prevention and treatment. The interaction between α4β7 and its natural ligand, MAdCAM‐1, directs infected CD4+ T cells and HIV‐1 virions carrying incorporated α4β7 to the gut mucosa, which may facilitate HIV‐1 seeding and replication in the intestinal compartment during the early stages of infection. In addition, cells that express high levels of α4β7, such as Th17 cells, represent preferential targets for infection, and their frequency in the circulation was shown to correlate with susceptibility to HIV‐1 infection and disease progression. A number of in vivo studies in nonhuman primates have investigated whether blockage of α4β7 may affect SIV transmission and pathogenesis. Administration of a primatized anti‐α4β7 antibody that blocks MAdCAM‐1 binding to α4β7 was reported to reduce SIV mucosal transmission in rhesus macaques. However, the mechanism responsible for such a protective effect is still undefined, and conflicting results have been reported on the effects of the same antibody, in combination with ART, during the early chronic phase of SIV infection. Thus, despite a series of tantalizing results accrued over the past decade, the jury is still out on the role of α4β7 in HIV‐1 infection. [ABSTRACT FROM AUTHOR]

We consider a mathematical model that describes a viral infection of HIV-1 with both virus-tocell and cell-to-cell transmission, CTL response immune and four distributed delays, describing intracellular delays and immune response delay. One of the main features of the model is that it includes a constant production rate of CTLs export from thymus, and an immune response delay. We derive the basic reproduction number and show that if the basic reproduction number is less than one, then the infection free equilibrium is globally asymptotically stable; whereas, if the basic reproduction number is greater than one, then there exist a chronic infection equilibrium, which is globally asymptotically stable in absence of immune response delay. Furthermore, for the special case with only immune response delay, we determine some conditions for stability switches of the chronic infection equilibrium. Numerical simulations indicate that the intracellular delays and immune response delay can stabilize and/or destabilize the chronic infection equilibrium. [ABSTRACT FROM AUTHOR]

Bone deficits are frequent in HIV-1-infected patients. We report here that osteoclasts, the cells specialized in bone resorption, are infected by HIV-1 in vivo in humanized mice and ex vivo in human joint biopsies. In vitro, infection of human osteoclasts occurs at different stages of osteoclastogenesis via cell-free viruses and, more efficiently, by transfer from infected T cells. HIV-1 infection markedly enhances adhesion and osteolytic activity of human osteoclasts by modifying the structure and function of the sealing zone, the osteoclast-specific bone degradation machinery. Indeed, the sealing zone is broader due to F-actin enrichment of its basal units (i.e., the podosomes). The viral protein Nef is involved in all HIV-1-induced effects partly through the activation of Src, a regulator of podosomes and of their assembly as a sealing zone. Supporting these results, Nef-transgenic mice exhibit an increased osteoclast density and bone defects, and osteoclasts derived from these animals display high osteolytic activity. Altogether, our study evidences osteoclasts as host cells for HIV-1 and their pathological contribution to bone disorders induced by this virus, in part via Nef. [ABSTRACT FROM AUTHOR]

Background: Gait and balance deficits are reported in adults with HIV infection and are associated with reduced quality of life. Current research suggests an increased fall-incidence in this population, with fall rates among middle-aged adults with HIV approximating that in seronegative elderly populations. Gait and postural balance rely on a complex interaction of the motor system, sensory control, and cognitive function. However, due to disease progression and complications related to ongoing inflammation, these systems may be compromised in people with HIV. Consequently, locomotor impairments may result that can contribute to higher-than-expected fall rates. The aim of this review was to synthesize the evidence regarding objective gait and balance impairments in adults with HIV, and to emphasize those which could contribute to increased fall risk.Methods: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. An electronic search of published observational studies was conducted in March 2016. Methodological quality was assessed using the NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Narrative synthesis of gait and balance outcomes was performed, and meta-analyses where possible.Results: Seventeen studies were included, with fair to low methodological quality. All studies used clinical tests for gait-assessment. Gait outcomes assessed were speed, initiation-time and cadence. No studies assessed kinetics or kinematics. Balance was assessed using both instrumented and clinical tests. Outcomes were mainly related to center of pressure, postural reflex latencies, and timed clinical tests. There is some agreement that adults with HIV walk slower and have increased center of pressure excursions and -long loop postural reflex latencies, particularly under challenging conditions.Conclusions: Gait and balance impairments exist in people with HIV, resembling fall-associated parameters in the elderly. Impairments are more pronounced during challenging conditions, might be associated with disease severity, are not influenced by antiretroviral therapy, and might not be associated with peripheral neuropathy. Results should be interpreted cautiously due to overall poor methodological quality and heterogeneity. Locomotor impairments in adults with HIV are currently insufficiently quantified. Future research involving more methodological uniformity is warranted to better understand such impairments and to inform clinical decision-making, including fall-prevention strategies, in this population. [ABSTRACT FROM AUTHOR]

Background: The rapid replication rate of HIV-1, coupled with a high mutation rate and recombination, is the underlying force driving its genetic diversity. In the infected individual, a population of highly related but nonidentical strains exists. At the population level, multiple subtypes often cocirculate, leading to the generation of intersubtype recombinant forms. As a result, the geographic distribution of subtypes and recombinant forms is complex and uneven. Genetic subtyping of HIV-1 isolates has been shown to be helpful for understanding the genetic evolution, the worldwide spread of the virus, and the evaluation of drug resistance. Materials and methods: We determined the genetic heterogeneity of HIV-1 group M in southwestern Greece. Protease and partial reverse-transcriptase sequences were generated from 150 HIV-1-infected individuals attending the Division of Infectious Diseases of Patras University Hospital, Greece, from 2006 to 2012, and analyzed using online subtyping tools and phylogenetic methods. Results: The majority of the infected individuals were male (77%). HIV-1 subtype A1 was responsible for 51.3% of infections, followed by subtypes B (34%), G (4%), F1 (2%), and the circulating recombinant forms 02_AG (2.7%), 14_BG (1.3%), 35_AD (1.3%), and 01_AE (0.7%). Additionally, we identified three cases with a recombinant B/CRF02_AG strain (2%) and one with a recombinant G/GRF_AG strain. Sexual transmission was responsible for 96.3% of cases. Heterosexual transmission was responsible for 70.2% of subtype-A1 infections, whereas subtype B was transmitted by men who have sex with men in 75.5% of cases. Protease substitutions I13V, E35D, M36I, R57K, H69K, and L89M, which serve as drug-resistance support mutations in subtype B, were present in the majority of subtype-A1 sequences of the population. Conclusion: HIV-1 infection in southwestern Greece is sexually transmitted and highly heterogeneous. Subtype A1 has surpassed subtype B, and is the most prevalent strain. In the population studied, subtype A1 exhibited certain polymorphisms in the protease region, which may serve as drug-resistance support mutations in subtype B. [ABSTRACT FROM AUTHOR]