Model Of HIV Infection Research Articles

Development of HIV-Resistant CAR T Cells by CRISPR/Cas-Mediated CAR Integration into the CCR5 Locus

Adoptive immunotherapy using chimeric antigen receptor (CAR) T cells has been highly successful in treating B cell malignancies and holds great potential as a curative strategy for HIV infection. Recent advances in the use of anti-HIV broadly neutralizing antibodies (bNAbs) have provided vital information for optimal antigen targeting of CAR T cells. However, CD4+ CAR T cells are susceptible to HIV infection, limiting their therapeutic potential. In the current study, we engineered HIV-resistant CAR T cells using CRISPR/Cas9-mediated integration of a CAR cassette into the CCR5 locus. We used a single chain variable fragment (scFv) of the clinically potent bNAb 10-1074 as the antigen-targeting domain in our anti-HIV CAR T cells. Our anti-HIV CAR T cells showed specific lysis of HIV-infected cells in vitro. In a PBMC humanized mouse model of HIV infection, the anti-HIV CAR T cells expanded and transiently limited HIV infection. In conclusion, this study provides proof-of-concept for developing HIV-resistant CAR T cells using CRISPR/Cas9 targeted integration.

Global stability of a delayed HIV-1 dynamics model with saturation response with cure rate, absorption effect and two time delays

In this paper, we proposed a new HIV-1 infection model with saturation infection rate by incorporating, cure rate, absorption effect, and two-time delays namely intracellular time delay that representing the time viral passage into a target cell and creation of new infectious particles and maturation time delay representing the required time for newly produce virus to mature and the infect the susceptible cell. The mathematical investigation shows that the basic reproduction number R0 of the model totally decides the steadiness properties. Utilizing the characteristic equation of the model and Routh-Hurwitz steadiness basis, we affirmed that the infection-free equilibrium and the chronic disease equilibrium are locally asymptotically steady in case R0 ≤ 1 and R0 > 1, individually. If R0 ≤ 1, using the appropriate Lyapunov functions and LaSalle’s invariance principle, it has been shown that the infection-free equilibrium of the model is globally asymptotically stable. If R0 > 1 the model is persistent. Conversely, if R0 > 1, the infection-free equilibrium is unstable and a unique chronic infection equilibrium exists. We show that, if R0 > 1, the chronic infection is globally asymptotically stable. Moreover, numerical simulations are performed to verify the theoretical results.

Dynamics of an HIV infection model with two time delays

In this paper, a mathematical model for HIV-1 infection and immune response is considered, involving two discrete time delays in the intracellular as well as in activation of immune response. Using a recently developed geometric method for studying a class of transcendental equation with two time delays and delay dependent coefficients, we obtain the stability and bifurcation results at the non-trivial equilibrium. In particular, the crossing curves on the two-delays parameter plane can be completely characterized, on which Hopf and double-Hopf bifurcation will take place. In the case of Hopf bifurcation, there exist stability switches, and the direction and stability of delay induced Hopf-bifurcation can be determined using normal form theory and center manifold theorem. These results imply the model will exhibit complex temporal dynamics, such as period oscillations, quasi-periodic solutions, etc. Numerical examples are also carried out to verify these results.

Analysis of a fractional order HIV-1 infection model with saturated immune response

Analysis of a fractional order HIV-1 infection model with saturated immune response

Analysis of HIV-1 mathematical model using Taylor’s series method

The main objective of this study is the use of Taylor?s series method for approximate solution of HIV-1 infection model. This method explores to solve a system of ODE expressed as an infinite series. These series components are easily determined. The presented method?s effectiveness and reliability are shown using a numerical example, and the consequences are evaluated to those acquired from different techniques in the research using tables and graphs. The proposed method has no assumptions about small or large parameters, and the technique?s accuracy increases when the order of approximation is increased. The results reveal that the approximate solution obtained through the use of Taylor's series method is more reliable and accurate.

Modified Bernoulli wavelets functional matrix approach for the HIV infection of CD4+ T cells model

In this study, we generated a novel functional matrix using Bernoulli wavelets. Also, we developed a novel technique called the Bernoulli wavelets collocation method to obtain reasonably accurate solutions for the HIV-infection model of CD4+ T cells. This mathematical model is in the form of a system of a nonlinear ordinary differential equation (ODE). This approach obtains the solution for this model by transforming it into a system of nonlinear algebraic equations by expanding through Bernoulli wavelets with unknown coefficients. The collocation scheme is used to calculate these unknown coefficients. The consistency and proficiency of the developed approach are demonstrated through tables and graphs. Obtained results reveal that the current approach is more accurate than other methods in the literature. All computations have been made with the help of Mathematica software. Some properties of Bernoulli wavelets are discussed in terms of theorems.

A simple model for viral decay dynamics and the distribution of infected cell life spans in SHIV-infected infant rhesus macaques

The dynamics of HIV viral load following the initiation of antiretroviral therapy is not well-described by simple, single-phase exponential decay. Several mathematical models have been proposed to describe its more complex behavior, the most popular of which is two-phase exponential decay. The underlying assumption in two-phase exponential decay is that there are two classes of infected cells with different lifespans. However, with the exception of CD4+ T cells, there is not a consensus on all of the cell types that can become productively infected, and the fit of the two-phase exponential decay to observed data from SHIV.C.CH505 infected infant rhesus macaques was relatively poor. Therefore, we propose a new model for viral decay, inspired by the Gompertz model where the decay rate itself is a dynamic variable. We modify the Gompertz model to include a linear term that modulates the decay rate. We show that this simple model performs as well as the two-phase exponential decay model on HIV and SIV data sets, and outperforms it for the infant rhesus macaque SHIV.C.CH505 infection data set. We also show that by using a stochastic differential equation formulation, the modified Gompertz model can be interpreted as being driven by a population of infected cells with a continuous distribution of cell lifespans, and estimate this distribution for the SHIV.C.CH505-infected infant rhesus macaques. Thus, we find that the dynamics of viral decay in this model of infant HIV infection and treatment may be explained by a distribution of cell lifespans, rather than two distinct cell types.

Anatomical and physiological aspects of the HIV infection pathogenesis in animal models

Understanding the entire pathogenesis of HIV infection, from penetration at the gates of infection to the induction of severe immunodeficiency, is an essential tool for the development of new treatment methods. Less than 40 years of research into the mechanisms of HIV infection that lead to the development of acquired immunodeficiency syndrome have accumulated a huge amount of information, but HIV's own unique variability identifies new whitespaces.
 Despite the constant improvement of the protocols of antiretroviral therapy and the success of its use, it has not yet been possible to stop the spread of HIV infection. The development of new protocols and the testing of new groups of antiretroviral drugs is possible, first of all, due to the improvement of animal models of the HIV infection pathogenesis. Their relevance, undoubtedly increases, but still depends on specific research tasks, since none of the in vivo models can comprehensively simulate the mechanism of the infection pathology in humans which leads to multi-organ damage.
 The aim of the review was to provide up-to-date information on known animal models of HIV infection, focusing on the method of their infection and anatomical, physiological and pathological features.

A therapeutic vaccine strategy to prevent Pneumocystis pneumonia in an immunocompromised host in a non-human primate model of HIV and Pneumocystis co-infection.

Pneumocystis is a ubiquitous fungal pathogen that causes pneumonia (PCP) and pulmonary sequelae in HIV-infected individuals and other immunocompromised populations. With the success of anti-retroviral therapy for HIV-infected individuals the frequency of PCP in that population has decreased, however, PCP remains a significant cause of morbidity and mortality in individuals with hematologic and solid malignancies, and in individuals treated with immunosuppressive therapies for autoimmune diseases, and following bone marrow and solid organ transplantation. Despite the clinical need, there is no approved vaccine to prevent PCP in vulnerable populations. The ultimate goal of the field is to develop an effective vaccine that can overcome immune deficits in at risk populations and induce long-lasting protective immunity to Pneumocystis. Toward this goal, our laboratory has established a model of PCP co-infection in simian immunodeficiency virus (SIV)-infected non-human primates (NHP) and identified a recombinant protein sub-unit vaccine, KEX1, that induces robust anti-Pneumocystis immunity in immune-competent macaques that is durable and prevents PCP following simian immunodeficiency virus (SIV)-induced immunosuppression. Type I, or invariant natural killer T (iNKT) cells have the potential to provide B cell help under conditions of reduced CD4+ T cell help. In the present study, we used the SIV model of HIV infection to address whether therapeutic vaccination with the iNKT cell-activating adjuvant α-galactosylceramide (α-GC) and KEX1 (α-GC+KEX1) can effectively boost anti-Pneumocystis humoral immunity following virus-induced immunosuppression. Immunization of antigen-experienced NHPs with α-GC+KEX1 during the early chronic phase of SIV-infection significantly boosted anti-Pneumocystis humoral immunity by increasing memory B cells and antibody titers, and enhanced titer durability during SIV-induced immunosuppression. This therapeutic vaccination strategy boosted anti-Pneumocystis immune responses during SIV-infection and contributed to protection against Pneumocystis co-infection in KEX1-vaccinated macaques. These studies present a novel strategy for stimulating durable anti-Pneumocystis humoral immunity in the context of complex, chronic SIV-induced immunosuppression and may be further applied to immunization of other immunosuppressed populations, and toward other common recall antigens.

HIV-1 infected humanized DRAGA mice develop HIV-specific antibodies despite lack of canonical germinal centers in secondary lymphoid tissues.

A major barrier in the use of humanized mice as models of HIV-1 (HIV) infection is the inadequate generation of virus-specific antibody responses. Humanized DRAGA (hDRAGA) mice generate antigen-specific class switched antibodies to several pathogens, but whether they do so in HIV infection and the extent to which their secondary lymphoid tissues (sLT) support germinal center responses is unknown. hDRAGA mice were evaluated for their ability to support HIV replication, generate virus-specific antibody responses, develop splenocyte subsets, and organize sLT architecture. hDRAGA mice supported persistent HIV replication and developed modest levels of gp41-specific human IgM and IgG. Spleens from uninfected and HIV infected hDRAGA mice contained differentiated B and CD4+ T cell subsets including germinal center (GC) B cells and T follicular helper cells (TFH); relative expansions of TFH and CD8+ T cells, but not GC B cells, occurred in HIV-infected hDRAGA mice compared to uninfected animals. Immunofluorescent staining of spleen and mesenteric lymph node sections demonstrated atypical morphology. Most CD4+ and CD8+ T cells resided within CD20hi areas. CD20hi areas lacked canonical germinal centers, as defined by staining for IgD-Ki67+cells. No human follicular dendritic cells (FDC) were detected. Mouse FDC were distributed broadly throughout both CD20hi and CD20lo regions of sLT. HIV RNA particles were detected by in situ hybridization within CD20+ areas and some co-localized with mouse FDC. Viral RNA+ cells were more concentrated within CD20hi compared to CD20lo areas of sLT, but differences were diminished in spleen and eliminated in mesenteric lymph nodes when adjusted for CD4+ cell frequency. Thus, hDRAGA mice recapitulated multiple aspects of HIV pathogenesis including HIV replication, relative expansions in TFH and CD8+ T cells, and modest HIV-specific antibody production. Nevertheless, classical germinal center morphology in sLT was not observed, which may account for the inefficient expansion of GC B cells and generation of low titer human antibody responses to HIV-1 in this model.

On analysis of fractional order HIV infection model with the adaptive immune response under Caputo operator

On analysis of fractional order HIV infection model with the adaptive immune response under Caputo operator

Dynamics analysis of an HIV infection model with latent reservoir, delayed CTL immune response and immune impairment

In this paper, we propose an HIV model with latent reservoir, delayed CTL immune response and immune impairment in which both virus-to-cell infection and cell-to-cell viral transmission are considered. By using Lyapunov functionals and LaSalle's invariance principle, it is verified that when time delay is equal to zero, the global threshold dynamics of the model is determined by the basic reproduction ratio. With the help of uniform persistence theory for infinite dimensional systems, we obtain the uniform persistence when the basic reproduction ratio is greater than unity. By choosing time delay τ as a bifurcation parameter and analyzing the corresponding characteristic equation of the system, we establish the existence of Hopf bifurcation at the chronic-infection equilibrium. Numerical simulations are carried out to illustrate the corresponding theoretical results.

Buprenorphine reverses neurocognitive impairment in EcoHIV infected mice: A potential therapy for HIV-NCI.

Thirty-eight million people worldwide are living with HIV, PWH, a major public health problem. Antiretroviral therapy (ART) revolutionized HIV treatment and significantly increased the lifespan of PWH. However, approximately 15-50% of PWH develop HIV associated neurocognitive disorders (HIV-NCI), a spectrum of cognitive deficits, that negatively impact quality of life. Many PWH also have opioid use disorder (OUD), and studies in animal models of HIV infection as well as in PWH suggest that OUD can contribute to HIV-NCI. The synthetic opioid agonist, buprenorphine, treats OUD but its effects on HIV-NCI are unclear. We reported that human mature inflammatory monocytes express the opioid receptors MOR and KOR, and that buprenorphine reduces important steps in monocyte transmigration. Monocytes also serve as HIV reservoirs despite effective ART, enter the brain, and contribute to HIV brain disease. Using EcoHIV infected mice, an established model of HIV infection and HIV-NCI, we previously showed that pretreatment of mice prior to EcoHIV infection reduces mouse monocyte entry into the brain and prevents NCI. Here we show that buprenorphine treatment of EcoHIV infected mice with already established chronic NCI completely reverses the disease. Disease reversal was associated with a significant reduction in brain inflammatory monocytes and reversal of dendritic injury in the cortex and hippocampus. These results suggest that HIV-NCI persistence may require a continuing influx of inflammatory monocytes into the brain. Thus, we recommend buprenorphine as a potential therapy for mitigation of HIV brain disease in PWH with or without OUD.

Single-cell analysis of immune cell transcriptome during HIV-1 infection and therapy

BackgroundCellular immune responses are phenotypically and functionally perturbed during HIV-1 infection, with the majority of function restored upon antiretroviral therapy (ART). Despite ART, residual inflammation remains that can lead to HIV-related co-morbidities and mortality, indicating that ART does not fully restore normal immune cell function. Thus, understanding the dynamics of the immune cell landscape during HIV-1 infection and ART is critical to defining cellular dysfunction that occurs during HIV-1 infection and imprints during therapy.ResultsHere, we have applied single-cell transcriptome sequencing of peripheral blood immune cells from chronic untreated HIV-1 individuals, HIV-1-infected individuals receiving ART and HIV-1 negative individuals. We also applied single-cell transcriptome sequencing to a primary cell model of early HIV-1 infection using CD4+ T cells from healthy donors. We described changes in the transcriptome at high resolution that occurred during HIV-1 infection, and perturbations that remained during ART. We also determined transcriptional differences among T cells expressing HIV-1 transcripts that identified key regulators of HIV-1 infection that may serve as targets for future therapies to block HIV-1 infection.ConclusionsThis work identified key molecular pathways that are altered in immune cells during chronic HIV-1 infection that could remain despite therapy. We also identified key genes that are upregulated during early HIV-1 infection that provide insights on the mechanism of HIV-1 infection and could be targets for future therapy.

Dynamics of a Stochastic HIV Infection Model with Logistic Growth and CTLs Immune Response under Regime Switching

Considering the influences of uncertain factors on the reproduction of virus in vivo, a stochastic HIV model with CTLs’ immune response and logistic growth was developed to research the dynamics of HIV, where uncertain factors are white noise and telegraph noise. which are described by Brownian motion and Markovian switching, respectively. We show, firstly, the existence of global positive solutions of this model. Further, by constructing suitable stochastic Lyapunov functions with regime switching, some sufficient conditions for the existence and uniqueness of the stationary distribution and the conditions for extinction are obtained. Finally, the main results are explained by some numerical examples. Theoretical analysis and numerical simulation show that low-intensity white noise can maintain the persistence of the virus, and high intensity white noise can make the virus extinct after a period of time with multi-states.

Oscillatory, crossover behavior and chaos analysis of HIV-1 infection model using piece-wise Atangana–Baleanu fractional operator: Real data approach

There are many fatal diseases which are caused by virus. Different types of viruses cause different infections. One of them is HIV-1 infection which caused by retrovirus. HIV-1 infection is a hazardous disease that can lead to cancer, AIDS, and other serious illnesses. Several mathematical models have been proposed in the field and examined using various methods. In this manuscript, the newly suggested piece-wise (PW) Atangana–Baleanu (AB) fractional operator is used to examine HIV-1 infection. Some theorems related to the existence of the solution to the examined model are proved through fixed point results. The Ulam–Hyers (UH) stability and its different forms are presented for the proposed PW HIV-1 infection model. The considered model’s numerical results are attained via the Newton interpolation method. The results are graphically illustrated via MATLAB software to show the behavior of the considered model. Oscillatory and complex dynamics are obtained for some fractional orders and show the crossover behavior of the proposed model. The model’s simulation of infected class is fitted with the real data taken for six different countries. It proves the validity and accuracy of the suggested approach.

Modelling of HIV viral load and 2-LTR dynamics during high active antiretroviral therapy in a heterogeneous environment

This paper is concerned with a diffusive HIV infection model with space-dependent parameters, different infection stages and different classes of antiretroviral drugs, in which the cells are assumed to be comparatively immobile and the viruses obey Fickian diffusion in a continuous bounded domain with a smooth boundary. The aim of this paper is twofold: first, to investigate the combined effect of spatial heterogeneity, viral diffusion and high active antiretroviral therapy on the long-term dynamics of the model; second, to evaluate the effect of treatment intensification with the integrase inhibitor raltegravir on the viral load and 2-LTR dynamics in patients with uninterrupted antiretroviral therapy in a spatially heterogeneous environment. Through mathematical analysis, the basic reproduction ratio is explicitly calculated and determined as a threshold to predict whether the infection is cleared up in the cases of spatial heterogeneity and homogeneity. Besides, the results of numerical simulations show that: (i) both spatial heterogeneity and viral diffusion affect the basic reproduction ratio and the time evolution of viral load at each location; (ii) protease inhibitors may be more effective in reducing viral load than reverse transcriptase inhibitors, although both have the same effect on the basic reproduction ratio; (iii) treatment intensification with raltegravir induces a very minor decrease in viral load and a minor increase in 2-LTR, which implies that ongoing viral replication may not be the source of the persistence of low-level viral load.

Molecular insights into antibody-mediated protection against the prototypic simian immunodeficiency virus

SIVmac239 infection of macaques is a favored model of human HIV infection. However, the SIVmac239 envelope (Env) trimer structure, glycan occupancy, and the targets and ability of neutralizing antibodies (nAbs) to protect against SIVmac239 remain unknown. Here, we report the isolation of SIVmac239 nAbs that recognize a glycan hole and the V1/V4 loop. A high-resolution structure of a SIVmac239 Env trimer-nAb complex shows many similarities to HIV and SIVcpz Envs, but with distinct V4 features and an extended V1 loop. Moreover, SIVmac239 Env has a higher glycan shield density than HIV Env that may contribute to poor or delayed nAb responses in SIVmac239-infected macaques. Passive transfer of a nAb protects macaques from repeated intravenous SIVmac239 challenge at serum titers comparable to those described for protection of humans against HIV infection. Our results provide structural insights for vaccine design and shed light on antibody-mediated protection in the SIV model.

Mitoquinone mesylate attenuates brain inflammation in humanized mouse model of chronic HIV infection.

Mitoquinone mesylate attenuates brain inflammation in humanized mouse model of chronic HIV infection.

Healthy dynamics of CD4 T cells may drive HIV resurgence in perinatally-infected infants on antiretroviral therapy

In 2019 there were 490,000 children under five living with HIV. Understanding the dynamics of HIV suppression and rebound in this age group is crucial to optimizing treatment strategies and increasing the likelihood of infants achieving and sustaining viral suppression. Here we studied data from a cohort of 122 perinatally-infected infants who initiated antiretroviral treatment (ART) early after birth and were followed for up to four years. These data included longitudinal measurements of viral load (VL) and CD4 T cell numbers, together with information regarding treatment adherence. We previously showed that the dynamics of HIV decline in 53 of these infants who suppressed VL within one year were similar to those in adults. However, in extending our analysis to all 122 infants, we find that a deterministic model of HIV infection in adults cannot explain the full diversity in infant trajectories. We therefore adapt this model to include imperfect ART adherence and natural CD4 T cell decline and reconstitution processes in infants. We find that individual variation in both processes must be included to obtain the best fits. We also find that infants with faster rates of CD4 reconstitution on ART were more likely to experience resurgences in VL. Overall, our findings highlight the importance of combining mathematical modeling with clinical data to disentangle the role of natural immune processes and viral dynamics during HIV infection.