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• We present a detailed protocol for a novel triplex dPCR assay for the quantification of the intact HIV-1 DNA reservoir. • We assessed and evaluated the performance of these assays on HIV-1 control cell line material and HIV-1 patient samples. • The triplex assays were implemented on the Naica dPCR platform (Stilla). The development of an HIV-1 cure is hampered by the existence of a persistent (latent) reservoir that contains a small proportion of replication-competent intact proviruses which refuels viral replication upon treatment discontinuation. Therefore, an accurate evaluation and quantification of these (intact) proviruses is essential to determine the efficacy of HIV-1 cure strategies which aim to eliminate this reservoir. Here, we present two triplex digital PCR assays which resulted from a combination of two existing methods, the IPDA (a 2-colour digital PCR based method) and Q4PCR assays (4 colour qPCR method), and tested the functionality on a three-colour digital PCR platform. In the present paper, we provide a step-by-step experimental protocol for these triplex digital PCR assays and validate their performance on a latently infected Jurkat cell-line model and HIV-1 patient samples. Our data demonstrates the potential and flexibility of increasing the number of subgenomic regions of HIV-1 within the IPDA to acquire sensitive detection of the HIV-1 reservoir while benefitting from the advantages of a dPCR setup. [ABSTRACT FROM AUTHOR]

Epigenetics, a field of study focused on cellular gene regulation independent of DNA sequence alterations, encompasses DNA methylation, histone modification and microRNA modification. Epigenetics processes play a pivotal role in governing the life cycles of viruses, enabling their transmission, persistence, and maintenance with in host organisms. This review examines the epigenetics regulation of diverse virus including orthomoxyviruses, coronavirus, retroviridae, mononegavirales, and poxviruses among others. The investigation encompasses ten representative viruses from these families. Detailed exploration of the epigenetic mechanisms underlying each virus type, involving miRNA modification, histone modification and DNA methylation, sheds light on the intricate and multifaceted epigenetic interplay between viruses and their hosts. Furthermore, this review investigates the influence of these epigenetic processes on infection cycles, emphasizing the utilization of epigenetics by viruses such as Epstein-Barr virus and Human immunodeficiency virus (HIV) to regulate gene expression during chronic or latent infections, control latency, and transition to lytic infection. Finally, the paper explores the novel treatments possibilities stemming from this epigenetic understanding. • Epigenetics consist of DNA methylation, histone modification and microRNA modification and play a very crucial role in controlling the life cycles of viruses. • This review focus on the epigenetics regulation of members of orthomoxy viruses, corona viruses, retroviridae, mononegavirales and poxviruses etc. Ten different viruses from various families are included and their detail epigenetics mechanisms is discussed. • Complex epigenetic relations between virus and host and their affect on infection cycle and control of latency and changeover to lytic infection and novel treatment options based on this epigenetic information. [ABSTRACT FROM AUTHOR]

Abstract Human Immunodeficiency Virus (HIV) infection continues to have major adverse public health and clinical consequences despite the effectiveness of combination Antiretroviral Therapy (cART) in reducing HIV viral load and improving immune function. As successfully treated individuals with HIV infection age, their cognition declines faster than reported for normal aging. This phenomenon underlines the importance of improving long-term care, which requires a better understanding of the impact of HIV on the brain. In this paper, automated identification of patients and brain regions affected by HIV infection are modeled as a classification problem, whose solution is determined in two steps within our proposed Chained-Regularization framework. The first step focuses on selecting the HIV pattern (i. e., the most informative constellation of brain region measurements for distinguishing HIV infected subjects from healthy controls) by constraining the search for the optimal parameter setting of the classifier via group sparsity ( ℓ 2,1 -norm). The second step improves classification accuracy by constraining the parameterization with respect to the selected measurements and the Euclidean regularization ( ℓ 2 -norm). When applied to the cortical and subcortical structural Magnetic Resonance Images (MRI) measurements of 65 controls and 65 HIV infected individuals, this approach is more accurate in distinguishing the two cohorts than more common models. Finally, the brain regions of the identified HIV pattern concur with the HIV literature that uses traditional group analysis models. [ABSTRACT FROM AUTHOR]

Highlights • A model within-host viral evolution with immune response is suggested. • The model is mechanistic and is a development of an earlier suggested model of RNA virus (HIV) evolution without immune response. • Three principal scenarios of evolution are possible for this model framework, namely (i) the development of immune resistance, (ii) evolutionary escape without the development of immune resistance, and (iii) increasing Darwinian fitness. (Please note that scenario (iii) can progress without immune response at all; evolution towards decreasing virulence of adaptation to a specific host are examples). • Impact of immune response on viral evolution in scenario (iii) is considered (Scenarios (i) and (ii) are left out of the scope). Simulations show that immune response is able to accelerate evolution in scenario (iii). • HIV is a case study. Abstract The objectives of this paper are to explore the impact of immune response on within-host viral evolution towards higher Darwinian fitness and, in particular, to verify a hypothesis that immune response, which is insufficient to annihilate a viral infection, can accelerate this evolution. To address this issue, a model of within-host viral evolution with immune response is formulated. This model is an extension of a continuous phenotype space model of viral evolution that was earlier suggested by A. Korobeinikov and C. Dempsey, which incorporates strain-specific immune response with cross-immunity. The model is based upon Nowak–May and Wodarz models of within-host HIV dynamics and is mechanistic (based upon first principles); this allows straightforward interpretation of the model’s parameters and simulation results, as well as its further developments. In order to make the simulation results and conclusions robust and reliable and to ensure that they do not depend on the particularities of an immune response model, four different mathematical models of cell-mediated immune response are considered with the proposed model. Simulations confirmed that immune response, when it is unable to eliminate viruses, accelerates viral evolution. [ABSTRACT FROM AUTHOR]

Abstract: In this paper we analyse a stochastic model representing HIV internal virus dynamics. The stochasticity in the model is introduced by parameter perturbation which is a standard technique in stochastic population modelling. We show that the model established in this paper possesses non-negative solutions as this is essential in any population dynamics model. We also carry out analysis on the asymptotic behaviour of the model. We approximate one of the variables by a mean reverting process and find out the mean and variance of this process. Numerical simulations conclude the paper. [Copyright &y& Elsevier]

Abstract: In this paper we introduce stochasticity into a model of AIDS and condom use via the technique of parameter perturbation which is standard in stochastic population modelling. We show that the model established in this paper possesses non-negative solutions as desired in any population dynamics. We also carry out a detailed analysis on asymptotic stability both in probability one and in pth moment. Our results reveal that a certain type of stochastic perturbation may help to stabilise the underlying system. [Copyright &y& Elsevier]

Despite years of combined antiretroviral therapy (cART), HIV persists in infected individuals. The virus also rebounds after the cessation of cART. The sources contributing to viral persistence and rebound are not fully understood. When viral rebound occurs, what affects the time to rebound and how to delay the rebound remain unclear. In this paper, we started with the data fitting of an HIV infection model to the viral load data in treated and untreated humanized myeloid-only mice (MoM) in which macrophages serve as the target of HIV infection. By fixing the parameter values for macrophages from the MoM fitting, we fit a mathematical model including the infection of two target cell populations to the viral load data from humanized bone marrow/liver/thymus (BLT) mice, in which both CD4+ T cells and macrophages are the target of HIV infection. Data fitting suggests that the viral load decay in BLT mice under treatment has three phases. The loss of infected CD4+ T cells and macrophages is a major contributor to the first two phases of viral decay, and the last phase may be due to the latent infection of CD4+ T cells. Numerical simulations using parameter estimates from the data fitting show that the pre-ART viral load and the latent reservoir size at treatment cessation can affect viral growth rate and predict the time to viral rebound. Model simulations further reveal that early and prolonged cART can delay the viral rebound after cessation of treatment, which may have implications in the search for functional control of HIV infection. • A macrophage infection model is fit to humanized myeloid-only (MoM) mouse data. • A model with two targets of HIV infection is fit to humanized BLT mouse data. • We studied the viral load decay dynamics in BLT mice under treatment. • We evaluated what might cause a rapid viral rebound after treatment cessation. [ABSTRACT FROM AUTHOR]

This paper is devoted to developing a nonlocal dispersal HIV infection dynamical model. The existence of travelling wave solutions is investigated by employing Schauder's fixed point theorem. That is, we study the existence of travelling wave solutions for R 0 > 1 and each wave speed c > c ⁎ . In addition, the boundary asymptotic behaviour of travelling wave solutions at +∞ is obtained by constructing suitable Lyapunov functions and employing Lebesgue dominated convergence theorem. By employing a limiting argument, we investigate the existence of travelling wave solutions for R 0 > 1 and c = c ⁎ . The main difficulties are that the semiflow generated by the model does not have the order-preserving property and the solutions lack of regularity. [ABSTRACT FROM AUTHOR]

The current COVID-19 pandemic and the likelihood of future viral pandemics demonstrate a need for strategic prevention campaigns that integrate biomedical, structural, and behavioral interventions within larger scale comprehensive public health initiatives. In Human Immunodeficiency Virus (HIV) prevention, community-based efforts have resulted in reductions in transmission rates, increases in testing, increases in biomedical prevention uptake, and increased engagement in secondary and tertiary prevention efforts. In this paper, we review three community-based strategies (health communication, accessible screening, and accessible prevention resources) that have demonstrated effectiveness in HIV prevention and offer recommendations for utilizing these strategies in the COVID-19 pandemic. For example, health communication strategies have positively influenced HIV testing behavior, sex communication, and condom use among HIV negative individuals and treatment initiation, treatment adherence, and retention in care among people living with HIV. In addition, studies have shown that improving accessibility of HIV screening and prevention resources in community venues such as schools, pharmacies, mobile-testing sites, churches, hair salons, and bars is useful for increasing the uptake of HIV testing, especially among disproportionately affected populations and those deemed hard to reach. Despite differences in modes of transmission, it is plausible that a synergistic multilevel response with emphasis on community-based efforts could lead to similar outcomes for the current COVID-19 pandemic and future viral pandemics. Community-based prevention strategies offer an opportunity to integrate, and bolster disconnected and siloed initiatives that achieve limited impacts independently. [ABSTRACT FROM AUTHOR]

Vpu is one of four accessory proteins encoded by human immunodeficiency virus type I (HIV-1). Vpu modulates the expression of several cellular restriction factors within the HIV-1 infected cell including CD4, CD74, the bone marrow stromal antigen 2 (BST-2) and NK-T-and-B antigen. The interaction of HIV-1 Vpu with these proteins interferes with the innate immune response directed against HIV-1; thereby promoting viral persistence. The involvement of HIV-1 Vpu in manipulating the cellular environment in ways that favor viral replication makes it an attractive target for anti-HIV drug intervention. This paper describes the over-expression and purification of a soluble HIV-1 Vpu from inclusion bodies by ion-exchange chromatography, allowing production of 6 mg of highly purified protein (>95% purity) per 10 mg of pelleted cells obtained from 1 L of bacterial culture. Far-UV circular dichroism showed that the recombinant protein is folded and retained its secondary structure. Moreover, using ELISA, known HIV-1 Vpu binding partners, BST-2 and CD74, showed that the refolded purified protein is functional or at least assumes a conformation that is capable of binding these putative binding partners. To our knowledge, this is the first report of the purification and successful solubilization of full-length, wild-type HIV-1 Vpu from inclusion bodies in Escherichia coli . [ABSTRACT FROM AUTHOR]

This paper investigates bifurcations and stability of an HIV model that incorporates the immune responses. The conditions for the global stability of infection-free equilibrium and infection equilibrium are respectively established by the Lyapunov method and the geometric approach. The backward bifurcation from the infection-free equilibrium is examined by analytical analysis. More interestingly, with the aid of mathematical analysis, we find a new type of bifurcations from an infection equilibrium, where a backward bifurcation curve emerges and can be continued to the place where the basic reproduction number is less than unity. By numerical simulations, we find a variety of dynamical behaviors of the model, which reveal the importance and complexity of immune responses in fighting HIV replication. [ABSTRACT FROM AUTHOR]

In biomedical studies on HIV RNA dynamics, viral loads generate repeated measures that are often subjected to upper and lower detection limits, and hence these responses are either left- or right-censored. Linear and non-linear mixed-effects censored (LMEC/NLMEC) models are routinely used to analyze these longitudinal data, with normality assumptions for the random effects and residual errors. However, the derived inference may not be robust when these underlying normality assumptions are questionable, especially the presence of outliers and thick-tails. Motivated by this, Matos et al. (2013) recently proposed an exact EM-type algorithm for LMEC/NLMEC models using a multivariate Student’s- t distribution, with closed-form expressions at the E-step. In this paper, we develop influence diagnostics for LMEC/NLMEC models using the multivariate Student’s- t density, based on the conditional expectation of the complete data log-likelihood. This partially eliminates the complexity associated with the approach of Cook (1977, 1986) for censored mixed-effects models. The new methodology is illustrated via an application to a longitudinal HIV dataset. In addition, a simulation study explores the accuracy of the proposed measures in detecting possible influential observations for heavy-tailed censored data under different perturbation and censoring schemes. [ABSTRACT FROM AUTHOR]

Patients with HIV infection are at increased risk of developing non-Hodgkin lymphoma and Hodgkin lymphoma. While the pathogenesis of these lymphomas is incompletely understood, evidence indicates that immune deregulation, genetic alterations and cytokine production play an important role in HIV lymphomagenesis. The lymphoma microenvironment in this heterogeneous group of lymphomas plays an equally critical role in their development, growth and progression. Important components of the microenvironment in HIV-related lymphomas include EBV and/or HHV-8 coinfection, reactive inflammatory cells, tumor microvasculature, and soluble factors. This paper provides a brief overview of HIV-related lymphomas and focuses on their lymphomagenesis and microenvironment. [ABSTRACT FROM AUTHOR]

The pattern recognition molecules of the lectin complement pathway are important components of the innate immune system with known functions in host-virus interactions. This paper summarizes current knowledge of how these intriguing molecules, including mannose-binding lectin (MBL), Ficolin-1, -2 and -3, and collectin-11 (CL-11) may influence HIV-pathogenesis. It has been demonstrated that MBL is capable of binding and neutralizing HIV and may affect host susceptibility to HIV infection and disease progression. In addition, MBL may cause variations in the host immune response against HIV. Ficolin-1, -2 and -3 and CL-11 could have similar functions in HIV infection as the ficolins have been shown to play a role in other viral infections, and CL-11 resembles MBL and the ficolins in structure and binding capacity. [ABSTRACT FROM AUTHOR]

Men who have sex with men and women (MSMW) compose a subset of men who have sex with men (MSM) and represent an estimated 35% of MSM. Research on the HIV risk behaviors of MSMW has largely focused on their behaviors in comparison to men who have sex with men only (MSMO). Results suggest that compared to MSMO, MSMW are less likely to have ever had an HIV test, are at greater risk of being unaware of their HIV infection and are less likely to have encountered HIV prevention activities or materials. Additional research is needed to provide a more comprehensive understanding of the unique sexual behaviors and lived experience of MSMW as a group in order to better inform HIV prevention efforts. The purpose of this paper is to summarize existing data and discuss strategies to reduce HIV acquisition and transmission among MSMW. [ABSTRACT FROM AUTHOR]

Abstract: The reconstruction of phylogenetic trees based on viral genetic sequence data sequentially sampled from an epidemic provides estimates of the past transmission dynamics, by fitting epidemiological models to these trees. To our knowledge, none of the epidemiological models currently used in phylogenetics can account for recovery rates and sampling rates dependent on the time elapsed since transmission, i.e. age of infection. Here we introduce an epidemiological model where infectives leave the epidemic, by either recovery or sampling, after some random time which may follow an arbitrary distribution. We derive an expression for the likelihood of the phylogenetic tree of sampled infectives under our general epidemiological model. The analytic concept developed in this paper will facilitate inference of past epidemiological dynamics and provide an analytical framework for performing very efficient simulations of phylogenetic trees under our model. The main idea of our analytic study is that the non-Markovian epidemiological model giving rise to phylogenetic trees growing vertically as time goes by can be represented by a Markovian “coalescent point process” growing horizontally by the sequential addition of pairs of coalescence and sampling times. As examples, we discuss two special cases of our general model, described in terms of influenza and HIV epidemics. Though phrased in epidemiological terms, our framework can also be used for instance to fit macroevolutionary models to phylogenies of extant and extinct species, accounting for general species lifetime distributions. [Copyright &y& Elsevier]

Abstract: The HIV gp41 protein catalyzes fusion between viral and target cell membranes. Although the ~20-residue N-terminal fusion peptide (FP) region is critical for fusion, the structure of this region is not well characterized in large gp41 constructs that model the gp41 state at different times during fusion. This paper describes solid-state NMR (SSNMR) studies of FP structure in a membrane-associated construct (FP-Hairpin), which likely models the final fusion state thought to be thermostable trimers with six-helix bundle structure in the region C-terminal of the FP. The SSNMR data show that there are populations of FP-Hairpin with either α helical or β sheet FP conformation. For the β sheet population, measurements of intermolecular 13C-13C proximities in the FP are consistent with a significant fraction of intermolecular antiparallel β sheet FP structure with adjacent strand crossing near L7 and F8. There appears to be negligible in-register parallel structure. These findings support assembly of membrane-associated gp41 trimers through interleaving of N-terminal FPs from different trimers. Similar SSNMR data are obtained for FP-Hairpin and a construct containing the 70 N-terminal residues of gp41 (N70), which is a model for part of the putative pre-hairpin intermediate state of gp41. FP assembly may therefore occur at an early fusion stage. On a more fundamental level, similar SSNMR data are obtained for FP-Hairpin and a construct containing the 34 N-terminal gp41 residues (FP34) and support the hypothesis that the FP is an autonomous folding domain. [Copyright &y& Elsevier]

Abstract: Privacy is a much discussed and politically charged topic in contemporary healthcare. Yet, studying the actual privacy practices of healthcare professionals and patients remains extremely challenging. In this paper we reflect on our experiences using qualitative methods in two projects on HIV care, the first researching internet use by a particular group of patients, and the second looking at issues of information technology integration in hospitals. Our aim in doing so is to highlight some of the opportunities and challenges involved in including an explicit focus on ‘context’ in qualitative privacy research in healthcare. We suggest that adopting a more reflexive approach to the way methods are used in relation to ‘context’ in privacy-related HCI research provides opportunities for understanding how different ‘privacy contexts’ are enacted in and through our research practices in different environments. [Copyright &y& Elsevier]

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]

Abstract: Previously we proposed two simplified models of early HIV-1 evolution. Both showed that under a model of neutral evolution and exponential growth, the mean Hamming distance (HD) between genetic sequences grows linearly with time. In this paper we describe a more realistic continuous-time, age-dependent mathematical model of infection and viral replication, and show through simulations that even in this more complex description, the mean Hamming distance grows linearly with time. This remains unchanged when we introduce recombination, though the confidence intervals of the mean HD obtained ignoring recombination are overly conservative. [Copyright &y& Elsevier]

Abstract: The HIV-1 has evolved swiftly and the scenario of HIV-1 genetic diversity is constantly changing. In South America, recombinant forms of subtypes B, F1, and BF1 have historically driven the HIV-1 epidemic. In recent years, however, infection with subtype C has gained prominence as its prevalence increased in Southern Brazil as well as neighboring countries. Current studies point to a single introduction of closely related strains as the beginning of the Brazilian subtype C epidemic. However, the place of origin of these strains, date, and route of introduction are under continuous debate as well as the clinical outcomes of the emergence of subtype C. Therefore, this paper reviews the history of the HIV-1 subtype C in Brazil, particularly in the Southern region, covering its demographic and evolutionary history and the possible implications to the Brazilian AIDS epidemic as well as to neighboring countries. [Copyright &y& Elsevier]

Abstract: The strategies of structured treatment interruptions (STIs) of antiretroviral therapies have been proposed for clinical management of HIV infected patients, but clinical studies on STIs failed to achieve a consistent conclusion for this strategy. To evaluate the STI strategies, in particular, CD4+ T cell count-guided STIs, and explain these controversial conclusions from different clinical studies, in this paper we propose to use piecewise HIV virus dynamic models to quantitatively explore the STI strategies and investigate their dynamic behaviors. Our analysis results indicate that CD4+ T cell counts can be maintained above a safe level using the STI with a single threshold or a threshold window. Numerical simulations show that the CD4+ T cell counts either fluctuate or approach a stable level for a patient, depending on the prescribed upper or lower threshold values. In particular, the CD4+ T cell counts can be stabilized at a desired level if the threshold policy control is applied. The durations of drug-on and drug-off are very sensitive to the prescribed upper or lower threshold levels, which possibly explains why the on–off strategy with fixed schedule or an STI strategy with frequent switches are associated with the high rate of failure. Our findings suggest that it is critical to carefully choose the thresholds of CD4+ T cell count and individualize the STIs for each individual patient based on initial CD4+ T cell counts. [Copyright &y& Elsevier]

Abstract: In this paper, we propose and discuss a possible mechanism, which, via continuous mutations and evolution, eventually enables HIV to break from immune control. In order to investigate this mechanism, we employ a simple mathematical model, which describes the relationship between evolving HIV and the specific CTL response and explicitly takes into consideration the role of CD4+T cells (helper T cells) in the activation of the CTL response. Based on the assumption that HIV evolves towards higher replication rates, we quantitatively analyze the dynamical properties of this model. The model exhibits the existence of two thresholds, defined as the immune activation threshold and the immunodeficiency threshold, which are critical for the activation and persistence of the specific cell-mediated immune response: the specific CTL response can be established and is able to effectively control an infection when the virus replication rate is between these two thresholds. If the replication rate is below the immune activation threshold, then the specific immune response cannot be reliably established due to the shortage of antigen-presenting cells. Besides, the specific immune response cannot be established when the virus replication rate is above the immunodeficiency threshold due to low levels of CD4+T cells. The latter case implies the collapse of the immune system and beginning of AIDS. The interval between these two thresholds roughly corresponds to the asymptomatic stage of HIV infection. The model shows that the duration of the asymptomatic stage and progression of the disease are very sensitive to variations in the model parameters. In particularly, the rate of production of the naive lymphocytes appears to be crucial. [Copyright &y& Elsevier]

Abstract: In this paper we analyze the demographic fluctuations and correlations present in within-host populations of viruses and their target cells during the early stages of infection. In particular, we present an exact treatment of a discrete-population, stochastic, continuous-time master equation description of HIV or similar retroviral infection dynamics, employing Monte Carlo simulations. The results of calculations employing Gillespie''s direct method clearly demonstrate the importance of considering the microscopic details of the interactions which constitute the macroscopic dynamics. We then employ the approach to study the statistical characteristics of infections involving realistic absolute numbers of within-host viral and cellular populations, before going on to investigate the effect that initial viral population size plays on these characteristics. Our main conclusion is that cross-correlations between infected cell and virion populations alter dramatically over the course of the infection. We suggest that these statistical correlations offer a novel and robust signature for the acute phase of retroviral infection. [Copyright &y& Elsevier]

Abstract: In this paper, we investigate an HIV model incorporating the effect of an ARV regimen. Since drug concentration varies during dose intervals, which results in periodic variation of the drug efficacy, our model is then a periodic time-dependent system. We get a threshold value between the extinction and the uniform persistence of the disease by applying the persistence theory. Our main results show that the disease goes to extinction if the threshold value is less than unity, whilst the disease persists if the threshold value is larger than unity. We also prove that there exists a positive periodic solution which is globally asymptotically stable. The threshold dynamics is in agreement with that for the system with constant coefficients, which extends the classic results for the corresponding autonomous model. [Copyright &y& Elsevier]

Abstract: Analysis and control of human immunodeficiency virus (HIV) infection have attracted the interests of mathematicians and control engineers during the recent years. Several mathematical models exist and adequately explain the interaction of the HIV infection and the immune system up to the stage of clinical latency, as well as viral suppression and immune system recovery after treatment therapy. However, none of these models can completely exhibit all that is observed clinically and account the full course of infection. Besides model inaccuracies that HIV models suffer from, some disturbances/uncertainties from different sources may arise in the modelling. In this paper we study the basic properties of a 6-dimensional HIV model that describes the interaction of HIV with two target cells, CD4+ T cells and macrophages. The disturbances are modelled in the HIV model as additive bounded disturbances. Highly Active AntiRetroviral Therapy (HAART) is used. The control input is defined to be dependent on the drug dose and drug efficiency. We developed treatment schedules for HIV infected patients by using robust multirate Model Predictive Control (MPC)-based method. The MPC is constructed on the basis of the approximate discrete-time model of the nominal model. We established a set of conditions, which guarantee that the multirate MPC practically stabilizes the exact discrete-time model with disturbances. The proposed method is applied to the stabilization of the uninfected steady state of the HIV model. The results of simulations show that, after initiation of HAART with a strong dosage, the viral load drops quickly and it can be kept under a suitable level with mild dosage of HAART. Moreover, the immune system is recovered with some fluctuations due to the presence of disturbances. [Copyright &y& Elsevier]

Abstract: Previously we reported a broadly HIV-1 neutralizing mini-antibody (Fab 3674) of modest potency that was derived from a human non-immune phage library by panning against the chimeric gp41-derived construct NCCG-gp41. This construct presents the N-heptad repeat of the gp41 ectodomain as a stable, helical, disulfide-linked trimer that extends in helical phase from the six-helix bundle of gp41. In this paper, Fab 3674 was subjected to affinity maturation against the NCCG-gp41 antigen by targeted diversification of the CDR-H2 loop to generate a panel of Fabs with diverse neutralization activity. Three affinity-matured Fabs selected for further study, Fabs 8060, 8066 and 8068, showed significant increases in both potency and breadth of neutralization against HIV-1 pseudotyped with envelopes of primary isolates from the standard subtype B and C HIV-1 reference panels. The parental Fab 3674 is 10–20-fold less potent in monovalent than bivalent format over the entire B and C panels of HIV-1 pseudotypes. Of note is that the improved neutralization activity of the affinity-matured Fabs relative to the parental Fab 3674 was, on average, significantly greater for the Fabs in monovalent than bivalent format. This suggests that the increased avidity of the Fabs for the target antigen in bivalent format can be partially offset by kinetic and/or steric advantages afforded by the smaller monovalent Fabs. Indeed, the best affinity-matured Fab (8066) in monovalent format (∼50 kDa) was comparable in HIV-1 neutralization potency to the parental Fab 3674 in bivalent format (∼120 kDa) across the subtype B and C reference panels. [Copyright &y& Elsevier]

Abstract: Non-specifically bound nucleic acid contaminants are an unwanted feature of recombinant RNA-binding proteins purified from Escherichia coli (E. coli). Removal of these contaminants represents an important step for the proteins’ application in several biological assays and structural studies. The method described in this paper is a one-step protocol which is effective at removing tightly bound nucleic acids from overexpressed tagged HIV-1 Rev in E. coli. We combined affinity chromatography under denaturing conditions with subsequent on-column refolding, to prevent self-association of Rev while removing the nucleic acid contaminants from the end product. We compare this purification method with an established, multi-step protocol involving precipitation with polyethyleneimine (PEI). As our tailored protocol requires only one-step to simultaneously purify tagged proteins and eliminate bound cellular RNA and DNA, it represents a substantial advantage in time, effort, and expense. [Copyright &y& Elsevier]

Abstract: In this paper, we develop an HIV model that considers the dependence of HIV/AIDS progress on infection age (duration since infection), chronological age and impulsive antiretroviral treatment. The analytical results show that there exists a globally asymptotically stable infection-free state when the impulsive period and drug-treatment proportion satisfy . The numerical simulation results indicate that there exist and such that . Due to pulses, it would be difficult to obtain the optimal pulse interval in the age distribution of population. However, our results demonstrate the effect of the impulsive drug-treatment strategy on the dynamics of HIV/AIDS. [Copyright &y& Elsevier]

Abstract: Opioids were originally discovered because of their ability to induce analgesia, but further investigation has shown that the opioids regulate the function of cells involved in the immune response. We suggest that the regulation of cytokine, chemokine, and cytokine receptor expression is a critical component of the immunomodulatory activity of the opioids. In this paper we review the literature dealing with the regulation of cytokine and cytokine receptor expression by agonists for the three major opioid receptor types (μ, κ, and δ), and nociceptin, the natural agonist for the orphanin FQ/nociceptin receptor. Although the opioid receptors share a high degree of sequence homology, opposing roles between the kappa opioid receptor (KOR) and the mu opioid receptor (MOR) have become apparent. We suggest that activation of the KOR induces an anti-inflammatory response through the down-regulation of cytokine, chemokine and chemokine receptor expression, while activation of the MOR favors a pro-inflammatory response. Investigation into the opioid receptor-like (ORL1)/nociceptin system also suggests a role for this receptor as a down-regulator of immune function. These effects suggest a broad role for opioids in the modulation of the function of the immune system, and suggest possible targets for the development of new therapeutics for inflammatory and infectious diseases. [Copyright &y& Elsevier]

Abstract: Simian immunodeficiency virus (SIV) has been shown to evolve from a relatively slowly replicating and mildly cytopathic virus early in the infection (SIVMneCL8) to a faster replicating and more cytopathic virus at later stages of the infection (SIVMne170). It has recently been demonstrated that the early and mildly cytopathic variant SIVMneCL8 out-competed the late and highly cytopathic strain SIVMne170 in cell culture experiments, because the fitness disadvantage derived from the higher cytopathicity was not matched by a sufficient increase in the viral replication rate. However, in another set of experiments where the life span of cells in culture was artificially limited, the late and more cytopathic virus won the competition, because under this condition cytopahticity was not an important determinant of viral fitness. It was hypothesized that the limited life span experiment reflected the immune-mediated high turnover environment in vivo more accurately, and that the presence of immune responses accounts for the selection of the cytopathic strain SIVmne170 during later stages of the infection. This paper investigates the effect of immune responses, in particular cytotoxic T lymphocyte (CTL) responses, on the competition dynamics between these two SIV strains with the help of mathematical models. Model analysis and parameter estimates derived from previously published data on SIV growth kinetics suggest that the SIV-specific CTL response might not be the driving force that leads to the selection of the cytopathic strain SIVMne170 during later stages of the infection. This implies that more complex evolutionary mechanisms might have to be invoked in order to explain the emergence of these strains in vivo. One possibility is that the ability of multiple virus particles to infect the same cell (coinfection) might be a pre-requisite for the emergence of the cytopathic strain SIVMne170 as the disease progresses. [Copyright &y& Elsevier]

Abstract: It is well known that the mathematical models provide very important information for the research of human immunodeficiency virus-type 1 and hepatitis C virus (HCV). However, the infection rate of almost all mathematical models is linear. The linearity shows the simple interaction between the T cells and the viral particles. In this paper, we consider the classical mathematical model with saturation response of the infection rate. By stability analysis we obtain sufficient conditions on the parameters for the global stability of the infected steady state and the infection-free steady state. We also obtain the conditions for the existence of an orbitally asymptotically stable periodic solution. Numerical simulations are presented to illustrate the results. [Copyright &y& Elsevier]

Abstract: CXCR4 belongs to the family of G protein-coupled receptors and mediates the various developmental and regulatory effects of the chemokine SDF-1α. In addition, CXCR4 acts as a co-receptor along with CD4 for the HIV-1 viral glycoprotein gp120. Recently, there has also been a small molecule described that antagonizes both SDF-1 and gp120 binding to CXCR4. The structural and mechanistic basis for this dual recognition ability of CXCR4 is unknown largely due to the technical challenges of biochemically producing the components of the various complexes. We expressed the human CXCR4 receptor using a modified baculovirus expression vector that facilitates a single step antibody affinity purification of CXCR4 to >80% purity from Hi5 cells. The recombinant receptor undergoes N-linked glycosylation, tyrosine sulfation and is recognized by the 12G5 conformation specific antibody against human CXCR4. We are able to purify CXCR4 alone as well as complexed with its endogenous ligand SDF-1, its viral ligand gp120, and a small molecule antagonist AMD3100 by ion-exchange chromatography. We anticipate that the expression and purification scheme described in this paper will facilitate structure–function studies aimed at elucidating the molecular basis for CXCR4 recognition of its endogenous chemokine and viral ligands. [Copyright &y& Elsevier]

Abstract: This paper describes the development of a SYBR Green-based multiplex real time RT-PCR for the simultaneous detection of HCV and HIV-1 genomes in plasma samples. Viral genomes were identified in the same sample by their distinctive melting temperature (Tm) which are 81.6 and 86.5°C for HIV-1 gag 142bp amplicon and HCV 5′-NCR region 226bp amplicon, respectively. Analysis of known scalar concentrations of reference plasma indicated that the multiplex procedure detects at least 500copies/ml of both HIV-1 and HCV. In addition, we also assayed HIV-1 and HCV viral load in 30 co-infected patients and in 15 blood donors, confirming the sensitivity and specificity of the assay. This method may represent a useful alternative method for the detection of HIV-1/HCV co-infection, reliable for a rapid and relatively inexpensive screening of blood donors. [Copyright &y& Elsevier]

Abstract: The viral macrophage inflammatory protein-II (vMIP-II) encoded by Kaposi’s sarcoma-associated herpesvirus has unique biological activities in that it blocks the cell entry by several different human immunodeficiency virus type 1 (HIV-1) strains via chemokine receptors including CXCR4 and CCR5. In this paper, we report the solution structure of all-d-amino acid peptides derived from the N-terminus of vMIP-II, which have been shown to have strong CXCR4 binding activity and potently inhibit HIV-1 entry via CXCR4, by using long mixing time two-dimensional nuclear Overhauser enhancement spectroscopy experiments. Both of all-d-peptides vMIP-II (1–10) and vMIP-II (1–21), which are designated as DV3 and DV1, respectively, have higher CXCR4 binding ability than their l-peptide counterparts. They are partially structured in aqueous solution, displaying a turn-like structure over residues 5–8. The small temperature coefficients of His-6 amide proton for both peptides also suggest the formation of a small hydrophobic pocket centered on His-6. The structural features of DV3 are very similar to the reported solution structure of all-l-peptide vMIP-II (1–10) [M.P. Crump, E. Elisseeva, J. Gong, I. Clark-Lewis, B.D. Sykes, Structure/function of human herpesvirus-8 MIP-II (1–71) and the antagonist N-terminal segment (1–10), FEBS Lett. 489 (2001) 171], which is consistent with the notion that d- and l-enantiomeric peptides can adopt mirror image conformations. The NMR structures of the d-peptides provide a structural basis to understand their mechanism of action and design new peptidomimetic analogs to further explore the structure–activity relationship of d-peptide ligand binding to CXCR4. [Copyright &y& Elsevier]

Abstract: Entry of lentiviruses, such as human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV), requires folding of two heptad repeat regions (HR1 and HR2) of gp41 into a trimer-of-hairpins, which subsequently brings virus and cell membrane into fusion. This motif is a generalized feature of viral fusion proteins and has been exploited in generating antiviral fusion agents. In the present paper, we report structural characters of Env protein from another lentivirus, bovine immunodeficiency virus (BIV), which contributes to a good animal model of HIV. BIV HR1 and HR2 regions are predicted by two different programs and expressed separately or conjointly in Escherichia coli. Biochemical and biophysical analyses show that the predicted HRs of BIV Env can form a stable trimer-of-hairpins or six-helix bundle just like that formed by feline immunodeficiency virus Env. Cell fusion assay demonstrates that the HR2 peptide of BIV can efficiently inhibit the virus-mediated cell fusion. [Copyright &y& Elsevier]

This paper argues for a broader interdisciplinary conceptualization of research on psychosocial risk factors and disease that relies on epidemiology, human laboratory-based studies, animal studies, in vitro and other mechanistic studies and intervention research. A model is proposed that includes the isolation of the active ingredients in the proposed psychological or social contributing factor, and a determination of their neural substrates, peripheral neurophysiological and pathophysiological correlates, and clinical disease outcomes. Research in HIV-1 pathogenesis provides examples of these kinds of studies. The HIV section highlights research that focuses on specific cognitive representations of stressful life experiences as active ingredients that shape the affective and neurophysiological impact of events. Links between these cognitive states and HIV progression, as well as the potential neurophysiologic, virologic, and immunologic mediators of these relationships are described. Implications and extensions of this model are derived for research on psychosocial factors and cancer. [Copyright &y& Elsevier]

Women with HIV bear a significant burden of Human Papillomavirus (HPV) related cervical disease, and a have a higher risk of dying from cervical cancer should it occur. WLH have increased acquisition of HPV and decreased clearance, leading to persistent HPV infection: a risk for cervical cancer. The greatest burden of HIV in women occurs in sub-Saharan Africa where diagnostic and treatment services for cervical disease are limited. This paper will describe the epidemiology of HPV related cervical disease in women living with HIV (WLH) and the efforts to treat precursor lesions in HIV treatment programs supported by the President's Emergency Plan for AIDS Relief (PEPFAR. [ABSTRACT FROM AUTHOR]

Abstract: This paper outlines a commentary response to an article published by Young and colleagues in Preventive Medicine that evaluated the feasibility of using Twitter as a surveillance and monitoring took for HIV. We draw upon the broader literature on disease surveillance and public health prevention using social media and broader considerations of epidemiological and surveillance methods to provide readers with necessary considerations for using social media in epidemiology and surveillance. [Copyright &y& Elsevier]

• A mathematical model of HIV multiple infection is developed. • The model includes both sequential virus infection and cell-to-cell transmission. • The model is fit to the distribution data of proviral viral genomes in infected cells. • Cell-to-cell transmission is shown to play a role in multiple infection formation. • Relative contributions from different routes of infection are evaluated. Multiple infection of target cells by human immunodeficiency virus (HIV) may lead to viral escape from host immune responses and drug resistance to antiretroviral therapy, bringing more challenges to the control of infection. The mechanisms underlying HIV multiple infection and their relative contributions are not fully understood. In this paper, we develop and analyze a mathematical model that includes sequential cell-free virus infection (i.e. one virus is transmitted each time in a sequential infection of target cells by virus) and cell-to-cell transmission (i.e. multiple viral genomes are transmitted simultaneously from infected to uninfected cells). By comparing model prediction with the distribution data of proviral genomes in HIV-infected spleen cells, we find that multiple infection can be well explained when the two modes of viral transmission are both included. Numerical simulation using the parameter estimates from data fitting shows that the majority of T cell infections are attributed to cell-to-cell transmission and this transmission mode also accounts for more than half of cell's multiple infections. These results suggest that cell-to-cell transmission plays a critical role in forming HIV multiple infection and thus has important implications for HIV evolution and pathogenesis. [ABSTRACT FROM AUTHOR]

PML, also known as TRIM19, belongs to the family of tripartite motif (TRIM) proteins. Like some other TRIM proteins, PML exerts a broad antiviral activity. PML is mainly expressed in the nucleus, where it forms dynamic structures known as PML nuclear bodies that recruit many proteins, such as Sp100 and Daxx. It was reported that HIV-1 infection induces the translocation of PML from the nucleus to the cytoplasm (Turelli et al., 2001). This paper also suggested that PML could interfere with HIV-1 infection but this was later contradicted (Berthoux et al., 2003). We sought to re-evaluate the implication of PML during HIV-1 infection. We show that infection by HIV-1 but also other retroviruses triggers the formation of PML cytoplasmic bodies, as early as 30 min post-infection. PML re-localization was blocked by reverse-transcription inhibitors and was not observed following infection with unrelated viruses, suggesting it is specifically triggered by retroviral reverse-transcription. Furthermore, we show that PML interferes with an early step of retroviral infection since PML knockdown dramatically increases RT efficiency. However, the effect of PML on retroviral infection was found to be indirect and to operate through the stabilization of one of its well-characterized partners, Daxx. In the presence of PML, Daxx inhibits an early step of reverse-transcription thereby interfering with HIV-1 infection. Like PML, Daxx is an interferon-inducible protein that provides intrinsic immunity against various viruses. Our study unravels for the first time its capacity to inhibit an early step of HIV-1 replication. [ABSTRACT FROM AUTHOR]