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]

This paper formulates and analyzes two mathematical models that describe the within-host dynamics of human immunodeficiency virus type 1 (HIV-1) with impairment of both cytotoxic T lymphocytes (CTLs) and B cells. Both viral transmission (VT) and cellular infection (CT) mechanisms are considered. The second model is a generalization of the first model that includes distributed time delays. For the two models, we establish the non-negativity and boundedness of the solutions, find the basic reproductive numbers, determine all possible steady states and establish the global asymptotic stability properties of all steady states by means of the Lyapunov method. We confirm the theoretical results by conducting numerical simulations. We conduct a sensitivity analysis to show the effect of the values of the parameters on the basic reproductive number. We discuss the results, showing that impaired B cells and CTLs, time delay and latent CT have significant effects on the HIV-1 dynamics. [ABSTRACT FROM AUTHOR]

This paper presents and analyzes two mathematical models for the human immunodeficiency virus type-1 (HIV-1) infection with Cytotoxic T Lymphocyte cell (CTL) immune impairment. These models describe the interactions between healthy CD 4 + T cells, latently and actively infected cells, HIV-1 particles, and CTLs. The healthy CD 4 + T cells might be infected when they make contact with: (i) HIV-1 particles due to virus-to-cell (VTC) contact; (ii) latently infected cells due to latent cell-to-cell (CTC) contact; and (iii) actively infected cells due to active CTC contact. Distributed time delays are considered in the second model. We show the nonnegativity and boundedness of the solutions of the systems. Further, we derive basic reproduction numbers ℜ 0 and ℜ ˜ 0 , that determine the existence and stability of equilibria of our proposed systems. We establish the global asymptotic stability of all equilibria by using the Lyapunov method together with LaSalle's invariance principle. We confirm the theoretical results by numerical simulations. The effect of immune impairment, time delay and CTC transmission on the HIV-1 dynamics are discussed. It is found that weak immunity contributes significantly to the development of the disease. Further, we have established that the presence of time delay can significantly decrease the basic reproduction number and then suppress the HIV-1 replication. On the other hand, the presence of latent CTC spread increases the basic reproduction number and then enhances the viral progression. Thus, neglecting the latent CTC spread in the HIV-1 infection model will lead to an underestimation of the basic reproduction number. Consequently, the designed drug therapies will not be accurate or sufficient to eradicate the viruses from the body. These findings may help to improve the understanding of the dynamics of HIV-1 within a host. [ABSTRACT FROM AUTHOR]

In this paper, a reaction–diffusion–chemotaxis HIV-1 model with a cytotoxic T lymphocyte (CTL) immune response and general sensitivity is investigated. We first prove the global classical solvability and L ∞ -boundedness for the considered model in a bounded domain with arbitrary spatial dimensions, which extends the previous existing results. Then, we apply the global existence result to the case with a linear proliferation immune response and an incidence rate. We study the spatiotemporal dynamics about the three types of spatially homogeneous steady states: infection-free steady state S 0 , CTL-inactivated infection steady state S 1 , and CTL-activated infection steady state S ∗. Our analyses indicate that S 0 is globally asymptotically stable if the basic reproduction number R 0 is less than 1; if R 0 is between 1 and a threshold, then S 1 is globally asymptotically stable. However, if R 0 is larger than the threshold, then the chemoattraction and chemorepulsion can destabilize S ∗ , and thus, a spatiotemporal pattern forms as the chemotactic sensitivity crosses certain critical values. We obtain two kinds of important patterns, which are induced by chemotaxis: stationary Turing pattern and irregular oscillatory pattern. We also find that different chemotactic response functions can affect system's dynamics. Based on some empirical parameter values, numerical simulations are given to illustrate the effectiveness of the theoretical predications. [ABSTRACT FROM AUTHOR]

This paper explores the dynamics analysis of a human immunodeficiency virus (HIV) model with saturated cytotoxic T lymphocyte (CTL) immune response and Beddington–DeAngelis infection rate. There are two time delays in the model to describe the time needed for infection of cell and CTL immune response generation, respectively. We obtain two thresholds and three possible equilibria from the model. By analyzing the corresponding characteristic equations, we study the stabilities of equilibrium and the effect of delays on CTL immune response. The results indicate that when immune delay is present, the steady state of equilibrium is disrupted and leads to a Hopf bifurcation. Finally, we use sensitivity analyses to show the effect of parameters on thresholds and numerical simulations to illustrate the theoretical results. [ABSTRACT FROM AUTHOR]

This paper develops a mathematical model to investigate the Human Immunodeficiency Virus (HIV) infection dynamics. The model includes two transmission modes (cell-to-cell and cell-free), two adaptive immune responses (cytotoxic T-lymphocyte (CTL) and antibody), a saturated CTL immune response, and latent HIV infection. The existence and local stability of equilibria are fully characterized by four reproduction numbers. Through sensitivity analyses, we assess the partial rank correlation coefficients of these reproduction numbers and identify that the infection rate via cell-to-cell transmission, the number of new viruses produced by each infected cell during its life cycle, the clearance rate of free virions, and immune parameters have the greatest impact on the reproduction numbers. Additionally, we compare the effects of immune stimulation and cell-to-cell spread on the model's dynamics. The findings highlight the significance of adaptive immune responses in increasing the population of uninfected cells and reducing the numbers of latent cells, infected cells, and viruses. Furthermore, cell-to-cell transmission is identified as a facilitator of HIV transmission. The analytical and numerical results presented in this study contribute to a better understanding of HIV dynamics and can potentially aid in improving HIV management strategies. [ABSTRACT FROM AUTHOR]

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

In the course of reverse transcription, drug-sensitive strain can mutate to a drug-resistant one. Cell-to-cell transmission is proved to be more efficient than virus-to-cell infection. The population of Cytotoxic T Lymphocytes (CTLs) can be divided into CTL precursors and CTL effectors. Naive CTL precursors are those that never have contacted antigen, circulating around the body. Once the host is infected, CTL precursors (CTLp) begin to proliferate and differentiate into CTL effectors (CTLe), which have antiviral activity. In this paper, we study an HIV model with drug-sensitive and drug-resistant mixed strains, CTLp and CTLe, both viral and cellular infections. The basic reproduction ratios for each strain are derived and the stability of each feasible equilibrium is analyzed by using Routh–Hurwitz criteria. The periodic solutions may occur near the equilibrium with CTL immune response via Hopf bifurcation. By using normal form theory, we find more information about the limit cycles, such as the amplitude, phase and stability. [ABSTRACT FROM AUTHOR]

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

The objective of this paper is to study a new mathematical model describing the human immunodeficiency virus (HIV). The model incorporates the impacts of cytotoxic T lymphocyte (CTL) immunity and antibodies with trilinear growth functions. The boundedness and positivity of solutions for non-negative initial data are proved, which is consistent with biological studies. The local stability of the equilibrium is established. Finally, numerical simulations are presented to support our theoretical findings. [ABSTRACT FROM AUTHOR]

Mathematical modeling of human immunodeficiency virus (HIV) and human T-lymphotropic virus type Ⅰ (HTLV-I) mono-infections has received considerable attention during the last decades. These two viruses share the same way of transmission between individuals; through direct contact with certain contaminated body fluids. Therefore, a person can be co-infected with both viruses. In the present paper, we construct and analyze a new HIV/HTLV-I co-infection model under the effect of Cytotoxic T lymphocytes (CTLs) immune response. The model describes the interaction between susceptible CD 4 + 4 + T cells, silent HIV-infected cells, active HIV-infected cells, silent HTLV-infected cells, Tax-expressing (active) HTLV-infected cells, free HIV particles, HIV-specific CTLs and HTLV-specific CTLs. The HIV can spread by two routes of transmission, virus-to-cell (VTC) and cell-to-cell (CTC). Both active and silent HIV-infected cells can infect the susceptible CD 4 + 4 + T cells by CTC mechanism. On the other side, HTLV-I has only one mode of transmission via direct cell-to-cell contact. The well-posedness of the model is established by showing that the solutions of the model are nonnegative and bounded. We calculate all possible equilibria and define the key threshold parameters which govern the existence and stability of all equilibria of the model. We explore the global asymptotic stability of all equilibria by utilizing Lyapunov function and LaSalle's invariance principle. We have discussed the influence of CTL immune response on the co-infection dynamics. We have presented numerical simulations to justify the applicability and effectiveness of the theoretical results. In addition, we evaluate the effect of HTLV-I infection on the HIV dynamics and vice versa. [ABSTRACT FROM AUTHOR]

In this paper, a delayed human immunodeficiency virus (HIV) model with apoptosis of cells has been studied. Both immunological and intracellular delay have been incorporated to make the model more relevant. Firstly, the model has been investigated using local stability analysis. Next, the global stability analysis of steady states has been performed. The stability switch criteria taking the delay as the bifurcating parameter, leading to Hopf bifurcation has been studied. The transition of the system from order to chaos has been explored, and the analytical results have been verified by numerical simulations. The results thus can be used to describe the extensive dynamics exhibited by the model introduced in this article. The effects of apoptosis on viral load has been studied in the model numerically. [ABSTRACT FROM AUTHOR]

Individuals infected by human immunodeficiency virus (HIV) are under oxidative stress due to the imbalance between reactive oxygen species (ROS) production and elimination. This paper presents a mathematical model with the cytotoxic T lymphocytes (CTL) immune response to examine the role of ROS in the dynamics of HIV infection. We classify the equilibria of the model and study the stability of these equilibria. Numerical simulations show that incorporating ROS and CTL immune response into the model leads to very rich dynamics, including bistable phenomena and periodic solutions. Although the current antiretroviral therapy can suppress viral load to the undetectable level, it cannot eradicate the virus. A high level of ROS may be a factor for HIV persistence in patients despite suppressive therapy. These results suggest that oxidative damage and anti-oxidant therapy should be considered in the study of HIV infection and treatment. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) and human T-lymphotropic virus type I (HTLV-I) are two retroviruses that infect the susceptible CD 4 + T cells. It is known that HIV and HTLV-I have in common a way of transmission through direct contact with certain body fluids related to infected individuals. Therefore, it is not surprising that a mono-infected person with one of these viruses can be co-infected with the other virus. In the literature, a great number of mathematical models has been presented to describe the within-host dynamics of HIV or HTLV-I mono-infection. However, the within-host dynamics of HIV/HTLV-I co-infection has not been modeled. In this paper, we develop a new within-host HIV/HTLV-I co-infection model. The model includes the impact of Cytotoxic T lymphocytes (CTLs) immune response, which is important to control the progression of viral co-infection. The model describes the interaction between susceptible CD 4 + T cells, silent HIV-infected cells, active HIV-infected cells, silent HTLV-infected cells, Tax-expressing HTLV-infected cells, free HIV particles, HIV-specific CTLs and HTLV-specific CTLs. We first show the nonnegativity and boundedness of the model's solutions and then we calculate all possible equilibria. We derive the threshold parameters which govern the existence and stability of all equilibria of the model. We prove the global asymptotic stability of all equilibria by utilizing Lyapunov function and LaSalle's invariance principle. We have presented numerical simulations to illustrate the effectiveness of our main results. In addition, we discuss the effect of HTLV-I infection on the HIV-infected patients and vice versa. [ABSTRACT FROM AUTHOR]

In the literature, several mathematical models have been formulated and developed to describe the within-host dynamics of either human immunodeficiency virus (HIV) or human T-lymphotropic virus type I (HTLV-I) monoinfections. In this paper, we formulate and analyze a novel within-host dynamics model of HTLV-HIV coinfection taking into consideration the response of cytotoxic T lymphocytes (CTLs). The uninfected CD 4 + T cells can be infected via HIV by two mechanisms, free-to-cell and infected-to-cell. On the other hand, the HTLV-I has two modes for transmission, (i) horizontal, via direct infected-to-cell touch, and (ii) vertical, by mitotic division of active HTLV-infected cells. It is well known that the intracellular time delays play an important role in within-host virus dynamics. In this work, we consider six types of distributed-time delays. We investigate the fundamental properties of solutions. Then, we calculate the steady states of the model in terms of threshold parameters. Moreover, we study the global stability of the steady states by using the Lyapunov method. We conduct numerical simulations to illustrate and support our theoretical results. In addition, we discuss the effect of multiple time delays on stability of the steady states of the system. [ABSTRACT FROM AUTHOR]

In this paper, a periodic stochastic human immunodeficiency virus (HIV) model with distributed delay and cytotoxic T lymphocytes (CTL) immune response is investigated. First, by It ô's formula, we show that the solution with any positive initial value is global and positive. Then, by the stochastic comparison theorem, we obtain the sufficient conditions guaranteeing the existence and global attractivity of infection‐free periodic solution. Furthermore, we discuss the existence of the infective periodic solution by Has'minskii theory. Finally, numerical examples are given to illustrate the results. [ABSTRACT FROM AUTHOR]

This paper proposes and analyzes a CTL-mediated HIV infection model. The model describes the interaction between healthy CD4+T cells, silent infected cells, active infected cells, free HIV particles, and cytotoxic T lymphocytes (CTLs). The healthy CD4+T cells can be infected when contacted by one of the following: (i) free HIV particles, (ii) silent infected cells, and (iii) active infected cells. The incidence rates of the healthy CD4+T cells with free HIV particles, silent infected cells, and active infected cells are given by general functions. Moreover, the production/proliferation and removal/death rates of all compartments are represented by general functions. The model is an improvement of the existing HIV infection models which have neglected the incidence between the silent infected cells and healthy CD4+T cells. We first show that the model is well posed. The proposed model has three equilibria and their existence is governed by derived two threshold parameters: the basic HIV reproduction number ℜ 0 and the HIV-specific CTL-mediated immunity reproduction number ℜ 1 . Under a set of conditions on the general functions and the parameters ℜ 0 and ℜ 1 , we have proven the global asymptotic stability of all equilibria by using Lyapunov method. We have illustrated the theoretical results via numerical simulations. We have studied the effect of cell-to-cell (CTC) transmission on the dynamical behavior of the system. We have shown that inclusion of CTC transmission decreases the concentration of healthy CD4+T cells and increases the concentrations of infected cells and free HIV particles. [ABSTRACT FROM AUTHOR]

In this paper, we incorporate immune systems into an HIV model, which considers both logistic target-cell proliferation and viral cell-to-cell transmission. We study the dynamics of this model including the existence and stability of equilibria. Based on the existence of equilibria, we focus on the backward bifurcation and forward bifurcation. Considering the stability of equilibria, Hopf bifurcation is discussed by identifying the basic reproduction number R 0 as bifurcation parameter. The direction and stability of Hopf bifurcation are investigated by computing the first Lyapunov exponent. Specially, the effects of immune response on the basic reproduction number R 0 and viral dynamics are addressed by deriving the sensitivity analysis. As a result, we find that the removal rate of infected cells by cytotoxic T lymphocytes (CTLs), γ 1 , is the predominant factor of R 0 . However, we conclude from numerical results that it is unfeasible to decrease R 0 by increasing the value of γ 1 constantly. Numerical simulation is also presented to demonstrate the applicability of the theoretical predictions. These dynamics are investigated by the proposed model to point out the importance and complexity of immune responses in fighting HIV replication. [ABSTRACT FROM AUTHOR]

The dynamics of a model describing the human immunodeficiency virus (HIV) infection with cytotoxic T-lymphocyte (CTL), antibodies and two saturated rates is investigated and studied in this paper. The model includes five nonlinear differential equations describing the evolution of uninfected cells, infected ones, free HIV viruses, CTL immune response and antibodies. This model includes also two treatments that represent the efficiency of drug treatment in inhibiting viral production and preventing new infections. Existence, positivity and boundedness of solutions are given. Existence of the optimal control pair is established and the Pontryagin's maximum principle is used to find an optimal treatment strategy that maximizes the number of uninfected CD4+ T cells as well as cytotoxic T-lymphocyte and antibody immune responses. Finally, the optimality system is derived and solved numerically. Results show that administrating good therapy maximizes the amount of healthy CD4+ T cells and deceases considerably the viral load and the infected cells. [ABSTRACT FROM AUTHOR]

The existence of HIV post-treatment controllers (PTCs) offers hope for an HIV functional cure, and understanding the critical mechanisms determining PTC represents a key step toward this goal. Here, we have studied these mechanisms by analyzing an established mathematical model for HIV viral dynamics. In mathematical models, critical mechanisms are represented by parameters that affect the tipping points to induce qualitatively different dynamics, and in cases with multiple stability, the initial conditions of the system also play a role in determining the fate of the solution. As such, for the tipping points in parameter space, we developed and implemented a sensitivity analysis of the threshold conditions of the associated bifurcations to identify the critical mechanisms for this model. Our results suggest that the infected cell death rate and the saturation parameter for cytotoxic T lymphocyte proliferation significantly affect post-treatment control. For the case with multiple stability, in state space of initial conditions, we first investigated the saddletype equilibrium point to identify its stable manifold, which delimits trapping regions associated to the high and low viral set points. The identified stable manifold serves as a guide for the loads of immune cells and HIV virus at the time of therapy termination to achieve post-treatment control. [ABSTRACT FROM AUTHOR]

A modified mathematical model describing the human immunodeficiency virus (HIV) pathogenesis with cytotoxic T-lymphocytes (CTL) and infected cells in eclipse phase is presented and studied in this paper. The model under consideration also includes a saturated rate describing viral infection. First, the positivity and boundedness of solutions for nonnegative initial data are proved. Next, the global stability of the disease free steady state and the endemic steady states are established depending on the basic reproduction number R0 and the CTL immune response reproduction number RCTL. Moreover, numerical simulations are performed in order to show the numerical stability for each steady state and to support our theoretical findings. Our model based findings suggest that system immunity represented by CTL may control viral replication and reduce the infection. [ABSTRACT FROM AUTHOR]

This paper deals with an optimal control problem for an human immunodeficiency virus (HIV) infection model with cytotoxic T-lymphocytes (CTL) immune response and latently infected cells. The model under con- sideration describes the interaction between the uninfected cells, the latently infected cells, the productively infected cells, the free viruses and the CTL cells. The two treatments represent the efficiency of drug treatment in inhibiting vi- ral production and preventing new infections. Existence of the optimal control pair is established and the Pontryagin's minimum principle is used to charac- terize these two optimal controls. The optimality system is derived and solved numerically using the forward and backward difference approximation. Final-ly, numerical simulations are performed in order to show the role of optimal therapy in controlling the infection severity. [ABSTRACT FROM AUTHOR]

A modified mathematical model of the Human Immunodefficiency Virus (HIV) pathogenesis with cytotoxic T lymphocytes (CTL) is introduced in this paper. This model includes a saturated rate function describing the viral infection. It is shown that the disease free steady state is globally asymptotically stable when the virus basic reproduction number is less than one. The existence of two other infection equilibria is established when the virus basic reproduction number is greater than one. The global stability of these endemic equilibria depends on the basic reproduction number and a CTL immune response reproduction indicator. Numerical simulations are performed to illustrate the behavior of solutions and the effectiveness of CTL cells. Moreover, a comparison of the model fitting with some clinical data sets and its implications are also presented. [ABSTRACT FROM AUTHOR]

In this work, we analyze the capacity of the human body to combat HIV. The model here treated takes into consideration four types of defense of an organism infected by HIV: susceptible defense cells, the infected immune cells, killer T cells, and the HIV-specific killer T cells. This model, therefore, analyzes the interactions between the responses of killer T cells and HIV infections, evidencing how the immune system is attacked and how it defends. An optimal control problem is proposed to derive an optimal sequence of dosages in the standard drug treatment, in such a way as to minimize the side effects. [ABSTRACT FROM AUTHOR]

HIV is known to accumulate escape mutations in the gag gene in response to the immune response from cytotoxic T lymphocytes (CTLs). These mutations can occur within an individual as well as at a population level. The population of Botswana exhibits a high prevalence of HLA*B57 and HLA*B58, which are associated with effective immune control of HIV. In this retrospective cross-sectional investigation, HIV-1 gag gene sequences were analyzed from recently infected participants across two time periods which were 10 years apart: the early time point (ETP) and late time point (LTP). The prevalence of CTL escape mutations was relatively similar between the two time points—ETP (10.6%) and LTP (9.7%). The P17 protein had the most mutations (9.4%) out of the 36 mutations that were identified. Three mutations (A83T, K18R, Y79H) in P17 and T190A in P24 were unique to the ETP sequences at a prevalence of 2.4%, 4.9%, 7.3%, and 5%, respectively. Mutations unique to the LTP sequences were all in the P24 protein, including T190V (3%), E177D (6%), R264K (3%), G248D (1%), and M228L (11%). Mutation K331R was statistically higher in the ETP (10%) compared to the LTP (1%) sequences (p < 0.01), while H219Q was higher in the LTP (21%) compared to the ETP (5%) (p < 0.01). Phylogenetically, the gag sequences clustered dependently on the time points. We observed a slower adaptation of HIV-1C to CTL immune pressure at a population level in Botswana. These insights into the genetic diversity and sequence clustering of HIV-1C can aid in the design of future vaccine strategies. [ABSTRACT FROM AUTHOR]

Background: With the approval of the HIV-1 capsid inhibitor, lenacapavir, capsid sequencing will be required for managing lenacapavir-experienced individuals with detectable viremia. Successful sequence interpretation will require examining new capsid sequences in the context of previously published sequence data. Methods: We analyzed published HIV-1 group M capsid sequences from 21,012 capsid-inhibitor naïve individuals to characterize amino acid variability at each position and influence of subtype and cytotoxic T lymphocyte (CTL) selection pressure. We determined the distributions of usual mutations, defined as amino acid differences from the group M consensus, with a prevalence ≥ 0.1%. Co-evolving mutations were identified using a phylogenetically-informed Bayesian graphical model method. Results: 162 (70.1%) positions had no usual mutations (45.9%) or only conservative usual mutations with a positive BLOSUM62 score (24.2%). Variability correlated independently with subtype-specific amino acid occurrence (Spearman rho = 0.83; p < 1 × 10−9) and the number of times positions were reported to contain an HLA-associated polymorphism, an indicator of CTL pressure (rho = 0.43; p = 0.0002). Conclusions: Knowing the distribution of usual capsid mutations is essential for sequence quality control. Comparing capsid sequences from lenacapavir-treated and lenacapavir-naïve individuals will enable the identification of additional mutations potentially associated with lenacapavir therapy. [ABSTRACT FROM AUTHOR]

Human T-lymphotropic virus type I (HTLV-I) and human immunodeficiency virus (HIV) are two famous retroviruses that share similarities in their genomic organization, and differ in their life cycle as well. It is known that HTLV-I and HIV have in common a way of transmission via direct contact with certain body fluids related to infected patients. Thus, it is not surprising that a single-infected person with one of these viruses can be dually infected with the other virus. In the literature, many researchers have devoted significant efforts for modeling and analysis of HTLV or HIV single infection. However, the dynamics of HTLV/HIV dual infection has not been formulated. In the present paper, we formulate an HTLV/HIV dual infection model. The model includes the impact of the Cytotoxic T lymphocyte (CTLs) immune response, which is important to control the dual infection. The model describes the interaction between uninfected CD 4 + T cells, HIV-infected cells, HTLV-infected cells, free HIV particles, HIV-specific CTLs, and HTLV-specific CTLs. We establish that the solutions of the model are non-negative and bounded. We calculate all steady states of the model and deduce the threshold parameters which determine the existence and stability of the steady states. We prove the global asymptotic stability of all steady states by utilizing the Lyapunov function and Lyapunov–LaSalle asymptotic stability theorem. We solve the system numerically to illustrate the our main results. In addition, we compared between the dynamics of single and dual infections. [ABSTRACT FROM AUTHOR]

The goal of this paper is to study the threshold dynamics of an HIV-1 viral infection model with cell-mediated immune responses and direct cell-to-cell transmission mechanism. The model demonstrates global threshold dynamics with respect to the reproductive numbers for viral infection ℜ 0 and for CTL immune response ℜ 1 . The proofs of main results come from suitable uses of analyzing the characteristic equation and constructing Lyapunov functionals. Specifically, if ℜ 0 < 1, the infection-free equilibrium E 0 is locally and globally asymptotically stable, and the viruses are cleared. If ℜ 1 < 1 < ℜ 0 , the CTL-inactivated equilibrium E 1 is locally and globally asymptotically stable, and the infection becomes chronic but without persistent CTLs response. If ℜ 1 > 1, the CTL-activated equilibrium E 2 is locally and globally asymptotically stable, and the infection is chronic with persistent CTLs response. Numerical simulations are performed to support our results. [ABSTRACT FROM AUTHOR]

Efforts to cure HIV have focused on reactivating latent proviruses to enable elimination by CD8+ cytotoxic T-cells. Clinical studies of latency reversing agents (LRA) in antiretroviral therapy (ART)-treated individuals have shown increases in HIV transcription, but without reductions in virologic measures, or evidence that HIV-specific CD8+ T-cells were productively engaged. Here, we show that the SARS-CoV-2 mRNA vaccine BNT162b2 activates the RIG-I/TLR – TNF – NFκb axis, resulting in transcription of HIV proviruses with minimal perturbations of T-cell activation and host transcription. T-cells specific for the early gene-product HIV-Nef uniquely increased in frequency and acquired effector function (granzyme-B) in ART-treated individuals following SARS-CoV-2 mRNA vaccination. These parameters of CD8+ T-cell induction correlated with significant decreases in cell-associated HIV mRNA, suggesting killing or suppression of cells transcribing HIV. Thus, we report the observation of an intervention-induced reduction in a measure of HIV persistence, accompanied by precise immune correlates, in ART-suppressed individuals. However, we did not observe significant depletions of intact proviruses, underscoring challenges to achieving (or measuring) HIV reservoir reductions. Overall, our results support prioritizing the measurement of granzyme-B-producing Nef-specific responses in latency reversal studies and add impetus to developing HIV-targeted mRNA therapeutic vaccines that leverage built-in LRA activity. Here, the authors show in a cohort of people with HIV, COVID mRNA vaccination is followed by a transient boost in a particular profile of HIV-specific T-cell responses and a corresponding decrease in residual HIV RNA – suggesting productive immune engagement with infected cells. [ABSTRACT FROM AUTHOR]

Programmed death-1 (PD-1) blockade during chronic Simian immunodeficiency virus (SIV) infection results in restoration of CD8 T-cell function and enhances viral control. Here, we tested the therapeutic benefits of PD-1 blockade administered soon after antiretrovial therapy (ART) interruption (ATI) by treating SIV-infected and ARTsuppressed macaques with either an anti-PD-1 antibody (n = 7) or saline (n = 4) at 4 wk after ATI. Following ATI, the plasma viremia increased rapidly in all animals, and the frequency of SIV-specific CD8 T cells also increased in some animals. PD-1 blockade post ATI resulted in higher proliferation of total memory CD8 and CD4 T cells and natural killer cells. PD-1 blockade also resulted in higher proliferation of SIVspecific CD8 T cells and promoted their differentiation toward better functional quality. Importantly, four out of the seven anti-PD-1 antibody-treated animals showed a rapid decline in plasma viremia by 100-to 2300-fold and this was observed only in animals that showed measurable SIV-specific CD8 T cells post PD-1 blockade. These results demonstrate that PD-1 blockade following ATI can significantly improve the function of anti-viral CD8 T cells and enhance viral control and strongly suggests its potential synergy with other immunotherapies that induce functional CD8 T-cell response under ART. These results have important implications for HIV cure research. [ABSTRACT FROM AUTHOR]

Recently, hematopoietic stem cell (HSC) based therapy is being discussed as a possible treatment for HIV infection. The main advantage of this approach is that it limits the immune impairing effect of infection by introducing an independent influx of antigen-specific cytotoxic T lymphocytes (CTL). In this paper, we present a mathematical approach to predict the dynamics of HSC based therapy. We use a modification of a basic mathematical model for virus induced impairment of help to study how virus – immune system dynamics can be influenced by a single injection of CD8+ T lymphocytes derived from hematopoietic stem cells. Our mathematical and numerical results indicate that a single, large enough dose of genetically derived CTL may lead to restoration of the cellular immune response and result in long-term control of infection. [ABSTRACT FROM AUTHOR]

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

The rising global HIV-1 burden urgently requires vaccines capable of providing heterologous protection. Here, we developed a clade C HIV-1 vaccine consisting of priming with modified vaccinia Ankara (MVA) and boosting with cyclically permuted trimeric gp120 (CycP-gp120) protein, delivered either orally using a needle-free injector or through parenteral injection. We tested protective efficacy of the vaccine against intrarectal challenges with a pathogenic heterologous clade C SHIV infection in rhesus macaques. Both routes of vaccination induced a strong envelope-specific IgG in serum and rectal secretions directed against V1V2 scaffolds from a global panel of viruses with polyfunctional activities. Envelope-specific IgG showed lower fucosylation compared with total IgG at baseline, and most of the vaccine-induced proliferating blood CD4+ T cells did not express CCR5 and α4β7, markers associated with HIV target cells. After SHIV challenge, both routes of vaccination conferred significant and equivalent protection, with 40% of animals remaining uninfected at the end of six weekly repeated challenges with an estimated efficacy of 68% per exposure. Induction of envelope-specific IgG correlated positively with G1FB glycosylation, and G2S2F glycosylation correlated negatively with protection. Vaccine-induced TNF-α+ IFN-γ+ CD8+ T cells and TNF-α+ CD4+ T cells expressing low levels of CCR5 in the rectum at prechallenge were associated with decreased risk of SHIV acquisition. These results demonstrate that the clade C MVA/CycP-gp120 vaccine provides heterologous protection against a tier2 SHIV rectal challenge by inducing a polyfunctional antibody response with distinct Fc glycosylation profile, as well as cytotoxic CD8 T cell response and CCR5-negative T helper response in the rectum. A clade C HIV-1 vaccine: Clade C HIV-1 infections are responsible for a large proportion of global HIV-1 burden, and a vaccine is urgently required. Sahoo et al. created a clade C HIV-1 vaccination regimen that they tested in rhesus macaques, consisting of priming with modified vaccinia Ankara (MVA) and boosting with cyclically permuted trimeric gp120 (CycP-gp120). To assess delivery methods, vaccines were administered by parenteral injection or oral administration using a needle-free injector. Both routes of MVA/CycP-gp120 administration provided equivalent protection against mucosal SHIV infection. Reduced risk of infection correlated with distinct env-specific IgG Fc glycosylation profiles, as well as with vaccine-induced TNF-α+ IFN-γ+ CD8+ T cells and TNF-α+ CCR5lo CD4+ T cells. These findings demonstrate that the MVA/CycP-gp120 immunization regimen provides significant protection against heterologous SHIV infection. [ABSTRACT FROM AUTHOR]

Unlike many other viruses, HIV-1 is highly variable. The structure of the viral envelope changes as the infection progresses and is one of the biggest obstacles in developing an HIV-1 vaccine. HIV-1 infection can cause the production of various natural autoantibodies, including catalytic antibodies hydrolyzing DNA, myelin basic protein, histones, HIV-integrase, HIV-reverse transcriptase, β-casein, serum albumin, and some other natural substrates. Currently, there are various directions for the development of HIV-1 vaccines: stimulation of the immune response on the mucous membranes; induction of cytotoxic T cells, which lyse infected cells and hold back HIV-infection; immunization with recombinant Env proteins or vectors encoding Env; mRNA-based vaccines and some others. However, despite many attempts to develop an HIV-1 vaccine, none have been successful. Here we review the entire spectrum of antibodies found in HIV-infected patients, including neutralizing antibodies specific to various viral epitopes, as well as antibodies formed against various autoantigens, catalytic antibodies against autoantigens, and some viral proteins. We consider various promising targets for developing a vaccine that will not produce unwanted antibodies in vaccinated patients. In addition, we review common problems in the development of a vaccine against HIV-1. [ABSTRACT FROM AUTHOR]

• A new HIV/HTLV-I co-infection model with latency and Cytotoxic T lymphocytes (CTLs) immune response is developed and rigorously analyzed. • Both silent and active infected cells have been considered. • Well-possedness of the model and existence of equilibria are established. • Global stability of the equilibria are established by means of Lyapunov functions. • We have presented numerical simulations to illustrate the effectiveness of our main results. Human immunodeficiency virus (HIV) and human T-lymphotropic virus type I (HTLV-I) are two retroviruses that attack the immune cells and impair their functions. Both HIV and HTLV-I can be transmitted between individuals through direct contact with certain body fluids from infected individuals. Therefore, a person can be co-infected with both viruses. HIV causes acquired immunodeficiency syndrome, while HTLV-I is the causative agent for adult T-cell leukemia and HTLV-I-associated myelopathy/tropical spastic paraparesis. Several mathematical models have been developed in the literature to describe the within-host dynamics of HIV and HTLV-I mono-infections. However, modeling a within-host dynamics of HIV/HTLV-I co-infection has not been involved. In the present paper, we are concerned to formulate and analyze a new HIV/HTLV co-infection model under the effect of Cytotoxic T lymphocytes (CTLs) immune response. The model describes the interaction between susceptible CD4+T cells, silent HIV-infected cells, active HIV-infected cells, silent HTLV-infected cells, Tax-expressing HTLV-infected cells, free HIV particles, HIV-specific CTLs and HTLV-specific CTLs. The HIV can spread by two routes of transmission, virus-to-cell and cell-to-cell. On the other side, HTLV-I has two modes of transmission, (i) horizontal transmission via direct cell-to-cell contact, and (ii) vertical transmission through mitotic division of Tax-expressing HTLV-infected cells. The well-posedness of the model is established by showing that the solutions of the model are nonnegative and bounded. We define a set of threshold parameters which govern the existence and stability of all equilibria of the model. We explore the global asymptotic stability of all equilibria by utilizing Lyapunov function and LaSalle's invariance principle. We have presented numerical simulations to justify the applicability and effectiveness of the theoretical results. In addition, we evaluate the effect of HTLV-I infection on the HIV dynamics and vice versa. [ABSTRACT FROM AUTHOR]

Human leukocyte antigen (HLA) class I allotypes vary in their ability to present peptides in the absence of tapasin, an essential component of the peptide loading complex. We quantified tapasin dependence of all allotypes that are common in European and African Americans (n = 97), which revealed a broad continuum of values. Ex vivo examination of cytotoxic T cell responses to the entire HIV-1 proteome from infected subjects indicates that tapasin-dependent allotypes present a more limited set of distinct peptides than do tapasin-independent allotypes, data supported by computational predictions. This suggests that variation in tapasin dependence may impact the strength of the immune responses by altering peptide repertoire size. In support of this model, we observed that individuals carrying HLA class I genotypes characterized by greater tapasin independence progress more slowly to AIDS and maintain lower viral loads, presumably due to increased breadth of peptide presentation. Thus, tapasin dependence level, like HLA zygosity, may serve as a means to restrict or expand breadth of the HLA-I peptide repertoire across humans, ultimately influencing immune responses to pathogens and vaccines. [ABSTRACT FROM AUTHOR]

Nef is an HIV-encoded accessory protein that enhances pathogenicity by down-regulating major histocompatibility class I (MHC-I) expression to evade killing by cytotoxic T lymphocytes (CTLs). A potent Nef inhibitor that restores MHC-I is needed to promote immune-mediated clearance of HIV-infected cells. We discovered that the plecomacrolide family of natural products restored MHC-I to the surface of Nef-expressing primary cells with variable potency. Concanamycin A (CMA) counteracted Nef at sub nanomolar concentrations that did not interfere with lysosomal acidification or degradation and were nontoxic in primary cell cultures. CMA specifically reversed Nef-mediated down-regulation of MHC-I, but not CD4, and cells treated with CMA showed reduced formation of the Nef:MHC-I:AP-1 complex required for MHC-I down-regulation. CMA restored expression of diverse allotypes of MHC-I in Nef expressing cells and inhibited Nef alleles from divergent clades of HIV and simian immunodeficiency virus, including from primary patient isolates. Lastly, we found that restoration of MHC-I in HIV infected cells was accompanied by enhanced CTL-mediated clearance of infected cells comparable to genetic deletion of Nef. Thus, we propose CMA as a lead compound for therapeutic inhibition of Nef to enhance immune-mediated clearance of HIV-infected cells. [ABSTRACT FROM AUTHOR]

HIV-1 positive elite controllers or suppressors control viral replication without antiretroviral therapy, likely via CTL-mediated elimination of infected cells, and therefore represent a model of an HIV-1 functional cure. Efforts to cure HIV-1 accordingly rely on the existence or generation of antigen-specific cytotoxic T lymphocytes (CTL) to eradicate infected cells upon reversal of latency. Detecting and quantifying these HIV-1-specific CTL responses will be crucial for developing vaccine and T cell-based immunotherapies. A recently developed assay, called MANAFEST, uses T cell receptor (TCR) Vβ sequencing of peptide-stimulated cultures followed by a bioinformatic pipeline to identify neoantigen-specific T cells in cancer patients. This assay is more sensitive than conventional immune assays and therefore has the possibility to identify HIV-1 antigenic targets that have not been previously explored for vaccine or T cell immunotherapeutic strategies. Here we show that a modified version of the MANAFEST assay, called ViraFEST, can identify memory CD8+ T cell responses against autologous HIV-1 Gag and Nef epitope variants in an elite suppressor. Nine TCR Vβ clonotypes were identified and 6 of these were cross-reactive for autologous variants or known escape variants. Our findings are a proof of principle that the ViraFEST assay can be used to detect and monitor these responses for downstream use in immunotherapeutic treatment approaches. [ABSTRACT FROM AUTHOR]

Cytolytic CD4+ T cells play a prominent role in chronic viral infection. CD4+ CTLs clones specific for HIV-1 Nef and Gag are capable of killing HIV-1 infected CD4+ T cells and macrophages. Additionally, HIV-specific cytolytic CD4+ T cell responses in acute HIV infection are predictive of disease progression. CD57 expression on CD4s identifies cytolytic cells. These cells were dramatically increased in chronic HIV infection. CD57 expression correlated with cytolytic granules, granzyme B and perforin expression. They express lower CCR5 compared to CD57– cells, have less HIV total DNA, and were a minor component of the HIV reservoir. A small percentage of CD57+ CD4+ CTLs from EC were HIV-specific, could upregulate IFNγ with Gag peptide stimulation, express cytolytic granule markers and maintain TbethighEomes+ transcription factor phenotype. This was not observed in viraemic controllers. The maintenance of HIV-specific CD4 cytolytic function in Elite controllers together with CD8 CTLs may be important for the control of HIV viraemia and of potential relevance to cure strategies. [ABSTRACT FROM AUTHOR]

Euphorbia umbellata (E. umbellata) belongs to Euphorbiaceae family, popularly known as Janauba, and its latex contains a combination of phorbol esters with biological activities described to different cellular protein kinase C (PKC) isoforms. Here, we identified deoxi-phorbol esters present in E. umbellata latex alcoholic extract that are able to increase HIV transcription and reactivate virus from latency models. This activity is probably mediated by NF-kB activation followed by nuclear translocation and binding to the HIV LTR promoter. In addition, E. umbellata latex extract induced the production of pro inflammatory cytokines in vitro in human PBMC cultures. This latex extract also activates latent virus in human PBMCs isolated from HIV positive patients as well as latent SIV in non-human primate primary CD4+ T lymphocytes. Together, these results indicate that the phorbol esters present in E. umbellata latex are promising candidate compounds for future clinical trials for shock and kill therapies to promote HIV cure and eradication. [ABSTRACT FROM AUTHOR]

Thirty-eight years after the first reports of HIV infection and the start of the AIDS pandemic ([1]), HIV is now a manageable condition. However, the clear message that toxicities and side-effects of Immune Checkpoint (IC) molecules may undermine any positive effects is not lost on the authors, and it is clear that future HIV treatment strategies need to be safe as well as effective. Although they were able to find evidence of CD32 expression in analysis of cells that contained HIV DNA, there was no correlation with total or integrated HIV DNA levels (or time to rebound on stopping ART), consistent with subsequent findings that CD32 may in fact be a marker of T cell - B cell doublets that have survived flow cytometry gating ([10]), but this remains a contentious area. Our current best treatment strategies are highly effective and have revolutionized the course of HIV infection. [Extracted from the article]

High usage of progestin-only injectable contraceptives, which include the intramuscular injectables depo-medroxyprogesterone acetate (DMPA-IM, Depo-Provera) and norethisterone (NET) enanthate (NET-EN or Nur-Isterate), correlates worldwide with areas of high HIV-1 prevalence. Epidemiological data show a significant association between usage of DMPA-IM and increased HIV-1 acquisition but no such association from limited data for NET-EN. Whether MPA and NET have similar effects on HIV-1 acquisition and pathogenesis, and the relationship between these effects and the dose of MPA, are critical issues for women’s health and access to suitable and safe contraceptives. We show for the first time that MPA, unlike NET, significantly increases HIV-1 replication in peripheral blood mononuclear cells (PBMCs) and a cervical cell line model. The results provide novel evidence for a biological mechanism whereby MPA, acting via the glucocorticoid receptor (GR), increases HIV-1 replication by at least in part increasing expression of the CCR5 HIV-1 coreceptor on target T-lymphocytes. MPA, unlike NET, also increases activation of T-cells and increases the CD4/CD8 ratio, suggesting that multiple mechanisms are involved in the MPA response. Our data offer strong support for different biological mechanisms for MPA versus NET, due to their differential GR activity. The dose-dependence of the MPA response suggests that significant effects are observed within the range of peak serum levels of progestins in DMPA-IM but not NET-EN users. Dose-response results further suggest that effects of contraceptives containing MPA on HIV-1 acquisition and disease progression may be critically dependent on dose, time after injection and intrinsic factors that affect serum concentrations in women. [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocytes (CTLs) have been suggested to play an important role in controlling human immunodeficiency virus (HIV-1 or simply HIV) infection. HIV, due to its high mutation rate, can evade recognition of T cell responses by generating escape variants that cannot be recognized by HIV-specific CTLs. Although HIV escape from CTL responses has been well documented, factors contributing to the timing and the rate of viral escape from T cells have not been fully elucidated. Fitness costs associated with escape and magnitude of the epitope-specific T cell response are generally considered to be the key in determining timing of HIV escape. Several previous analyses generally ignored the kinetics of T cell responses in predicting viral escape by either considering constant or maximal T cell response; several studies also considered escape from different T cell responses to be independent. Here, we focus our analysis on data from two patients from a recent study with relatively frequent measurements of both virus sequences and HIV-specific T cell response to determine impact of CTL kinetics on viral escape. In contrast with our expectation, we found that including temporal dynamics of epitope-specific T cell response did not improve the quality of fit of different models to escape data. We also found that for well-sampled escape data, the estimates of the model parameters including T cell killing efficacy did not strongly depend on the underlying model for escapes: models assuming independent, sequential, or concurrent escapes from multiple CTL responses gave similar estimates for CTL killing efficacy. Interestingly, the model assuming sequential escapes (i.e., escapes occurring along a defined pathway) was unable to accurately describe data on escapes occurring rapidly within a shorttime window, suggesting that some of model assumptions must be violated for such escapes. Our results thus suggest that the current sparse measurements of temporal CTL dynamics in blood bear little quantitative information to improve predictions of HIV escape kinetics. More frequent measurements using more sensitive techniques and sampling in secondary lymphoid tissues may allow to better understand whether and how CTL kinetics impacts viral escape. [ABSTRACT FROM AUTHOR]

HIV is adept at avoiding naturally generated T cell responses; therefore, there is a need to develop HIV-specific T cells with greater potency for use in HIV cure strategies. Starting with a CD4-based chimeric antigen receptor (CAR) that was previously used without toxicity in clinical trials, we optimized the vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains to determine which components augmented the ability of T cells to control HIV replication. This re-engineered CAR was at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR, or a TCR-based approach, and substantially better than broadly neutralizing antibody-based CARs. A humanized mouse model of HIV infection demonstrated that T cells expressing optimized CARs were superior at expanding in response to antigen, protecting CD4 T cells from infection, and reducing viral loads compared to T cells expressing the original, clinical trial CAR. Moreover, in a humanized mouse model of HIV treatment, CD4 CAR T cells containing the 4-1BB costimulatory domain controlled HIV spread after ART removal better than analogous CAR T cells containing the CD28 costimulatory domain. Together, these data indicate that potent HIV-specific T cells can be generated using improved CAR design and that CAR T cells could be important components of an HIV cure strategy. [ABSTRACT FROM AUTHOR]

In order to inform the rational design of HIV-1 preventive and cure interventions it is critical to understand the events occurring during acute HIV-1 infection (AHI). Using viral deep sequencing on six participants from the early capture acute infection RV217 cohort, we have studied HIV-1 evolution in plasma collected twice weekly during the first weeks following the advent of viremia. The analysis of infections established by multiple transmitted/founder (T/F) viruses revealed novel viral profiles that included: a) the low-level persistence of minor T/F variants, b) the rapid replacement of the major T/F by a minor T/F, and c) an initial expansion of the minor T/F followed by a quick collapse of the same minor T/F to low frequency. In most participants, cytotoxic T-lymphocyte (CTL) escape was first detected at the end of peak viremia downslope, proceeded at higher rates than previously measured in HIV-1 infection, and usually occurred through the exploration of multiple mutational pathways within an epitope. The rapid emergence of CTL escape variants suggests a strong and early CTL response. Minor T/F viral strains can contribute to rapid and varied profiles of HIV-1 quasispecies evolution during AHI. Overall, our results demonstrate that early, deep, and frequent sampling is needed to investigate viral/host interaction during AHI, which could help identify prerequisites for prevention and cure of HIV-1 infection. [ABSTRACT FROM AUTHOR]

In an effort to make affordable vaccines suitable for the regions most affected by HIV-1, we have constructed stable vaccines that express an HIV-1 subtype C mosaic Gag immunogen (BCG-GagM, MVA-GagM and DNA-GagM). Mosaic immunogens have been designed to address the tremendous diversity of this virus. Here we have shown that GagM buds from cells infected and transfected with MVA-GagM and DNA-GagM respectively and forms virus-like particles. Previously we showed that a BCG-GagM prime MVA-GagM boost generated strong cellular immune responses in mice. In this study immune responses to the DNA-GagM and MVA-GagM vaccines were evaluated in homologous and heterologous prime-boost vaccinations. The DNA homologous prime boost vaccination elicited predominantly CD8+ T cells while the homologous MVA vaccination induced predominantly CD4+ T cells. A heterologous DNA-GagM prime MVA-GagM boost induced strong, more balanced Gag CD8+ and CD4+ T cell responses and that were predominantly of an effector memory phenotype. The immunogenicity of the mosaic Gag (GagM) was compared to a naturally occurring subtype C Gag (GagN) using a DNA homologous vaccination regimen. DNA-GagN expresses a natural Gag with a sequence that was closest to the consensus sequence of subtype C viruses sampled in South Africa. DNA-GagM homologous vaccination induced cumulative HIV-1 Gag-specific IFN-γ ELISPOT responses that were 6.5-fold higher than those induced by the DNA-GagN vaccination. Similarly, DNA-GagM vaccination generated 7-fold higher levels of cytokine-positive CD8+ T cells than DNA-GagN, indicating that this subtype C mosaic Gag elicits far more potent immune responses than a consensus-type Gag. Cells transfected and infected with DNA-GagM and MVA-GagM respectively, expressed high levels of GagM and produced budding virus-like particles. Our data indicates that a heterologous prime boost regimen using DNA and MVA vaccines expressing HIV-1 subtype C mosaic Gag is highly immunogenic in mice and warrants further investigation in non-human primates. [ABSTRACT FROM AUTHOR]

Virus spreading in tissues is determined by virus transport, virus multiplication in host cells and the virus-induced immune response. Cytotoxic T cells remove infected cells with a rate determined by the infection level. The intensity of the immune response has a bell-shaped dependence on the concentration of virus, i.e., it increases at low and decays at high infection levels. A combination of these effects and a time delay in the immune response determine the development of virus infection in tissues like spleen or lymph nodes. The mathematical model described in this work consists of reaction-diffusion equations with a delay. It shows that the different regimes of infection spreading like the establishment of a low level infection, a high level infection or a transition between both are determined by the initial virus load and by the intensity of the immune response. The dynamics of the model solutions include simple and composed waves, and periodic and aperiodic oscillations. The results of analytical and numerical studies of the model provide a systematic basis for a quantitative understanding and interpretation of the determinants of the infection process in target organs and tissues from the image-derived data as well as of the spatiotemporal mechanisms of viral disease pathogenesis, and have direct implications for a biopsy-based medical testing of the chronic infection processes caused by viruses, e.g. HIV, HCV and HBV. [ABSTRACT FROM AUTHOR]

The depletion of mucosal CD4+ T-cells occurs early in HIV infection and despite years on antiretroviral treatment (ART), this population never reconstitutes to pre-HIV infection levels. In an effort to understand the effect of ART initiation and different ART regimens on the reconstitution of mucosal T cells within the gut associated lymphoid tissue (GALT), we quantified the frequency of CD4+ and CD8+ T cells expressing the gut homing receptors CCR9 and β7 in peripheral blood (PB) of HIV infected individuals naive to ART and treated individuals on both short-term (less than a year) and long-term ART (more than 2 years). We found that the gut homing CD4+ T cells were depleted in ART-naive individuals and increased after ART initiation but levels were not comparable to HIV uninfected individuals. Gut homing CD4+ T cell activation decreased after ART initiation whilst gut homing CD8+ T cell activation remained elevated in ART experienced individuals, especially in those individuals taking protease inhibitors. Our findings provide new insights into the effects of ART initiation and ART regimens on the frequency and immune status of gut homing CD4+ and CD8+ T cells. [ABSTRACT FROM AUTHOR]

We, and others, have reported that in the HIV-negative settings, regulatory CD4+CD25highFoxP3+ T cells (Treg) exert differential effects on CD8 subsets, and maintain the memory / effector CD8+ T cells balance, at least in part through the PD-1/PD-L1 pathway. Here we investigated Treg–mediated effects on CD8 responses in chronic HIV infection. As compared to Treg from HIV negative controls (Treg/HIV-), we show that Treg from HIV infected patients (Treg/HIV+) did not significantly inhibit polyclonal autologous CD8+ T cell function indicating either a defect in the suppressive capacity of Treg/HIV+ or a lack of sensitivity of effector T cells in HIV infection. Results showed that Treg/HIV+ inhibited significantly the IFN-γ expression of autologous CD8+ T cells stimulated with recall CMV/EBV/Flu (CEF) antigens, but did not inhibit HIV-Gag–specific CD8+ T cells. In cross-over cultures, we show that Treg/HIV- inhibited significantly the differentiation of either CEF- or Gag-specific CD8+ T cells from HIV infected patients. The expression of PD-1 and PD-L1 was higher on Gag-specific CD8+ T cells as compared to CEF-specific CD8+ T cells, and the expression of these markers did not change significantly after Treg depletion or co-culture with Treg/HIV-, unlike on CEF-specific CD8+ T cells. In summary, we show a defect of Treg/HIV+ in modulating both the differentiation and the expression of PD-1/PD-L1 molecules on HIV-specific CD8 T cells. Our results strongly suggest that this particular defect of Treg might contribute to the exhaustion of HIV-specific T cell responses. [ABSTRACT FROM AUTHOR]