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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]

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]

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]

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]

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]

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]

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]

Strategies to develop a functional cure for HIV infection will likely require boosting of effector T cell responses to eliminate reactivated, latently infected cells. We have recently explored an assay for assessing antigen-specific regulation of T cell proliferation, which was related to clinical progression in untreated patients and to vaccine efficacy in two trials of therapeutic Gag-based vaccines. We here expand the same assay to further investigate regulation mediated by various inhibitory pathways. Peripheral blood mononuclear cells from 26 asymptomatic HIV-infected, antiretroviral therapy-naïve patients were stimulated with Gag and Env overlapping peptide panels for 5 days. Monoclonal antibodies (mAbs) blocking inhibitory mediators interleukin (IL) 10, transforming growth factor (TGF) β, programmed death ligand (PD–L) 1 and herpes virus entry mediator (HVEM) were added to parallel cultures. Functional T cell regulation (FTR) was defined as the difference in proliferation between stimulated cultures with and without blocking mAbs. FTR was detected in 54% of patients. Blockade of IL-10/PD-L1 and IL10/TGF-β detected all cases with Gag- and Env-associated FTR, respectively. In accordance with previous findings, isolated Env FTR was associated with higher plasma HIV RNA and lower CD4 counts, while patients with both Gag and Env FTR also had higher Gag- and Env-specific proliferative CD8+ T cell responses. There was no association between FTR and frequencies of activated regulatory T cells. In conclusion, we observed substantial heterogeneity in FTR between patients, inhibitory pathways and HIV antigens. FTR may help to individualize immunomodulation and warrants further assessment in clinical immunotherapy trials. [ABSTRACT FROM AUTHOR]

Resting CD4+ T-cells harboring inducible HIV proviruses are a critical reservoir in antiretroviral therapy (ART)-treated subjects. These cells express little to no viral protein, and thus neither die by viral cytopathic effects, nor are efficiently cleared by immune effectors. Elimination of this reservoir is theoretically possible by combining latency-reversing agents (LRAs) with immune effectors, such as CD8+ T-cells. However, the relative efficacy of different LRAs in sensitizing latently-infected cells for recognition by HIV-specific CD8+ T-cells has not been determined. To address this, we developed an assay that utilizes HIV-specific CD8+ T-cell clones as biosensors for HIV antigen expression. By testing multiple CD8+ T-cell clones against a primary cell model of HIV latency, we identified several single agents that primed latently-infected cells for CD8+ T-cell recognition, including IL-2, IL-15, two IL-15 superagonists (IL-15SA and ALT-803), prostratin, and the TLR-2 ligand Pam3CSK4. In contrast, we did not observe CD8+ T-cell recognition of target cells following treatment with histone deacetylase inhibitors or with hexamethylene bisacetamide (HMBA). In further experiments we demonstrate that a clinically achievable concentration of the IL-15 superagonist ‘ALT-803’, an agent presently in clinical trials for solid and hematological tumors, primes the natural ex vivo reservoir for CD8+ T-cell recognition. Thus, our results establish a novel experimental approach for comparative evaluation of LRAs, and highlight ALT-803 as an LRA with the potential to synergize with CD8+ T-cells in HIV eradication strategies. [ABSTRACT FROM AUTHOR]

Background: Therapeutic HIV vaccines may prove helpful to intensify antiretroviral treatment (ART) efficacy and may be an integral part of future cure strategies. Methods: We examined IFN-gamma ELISpot responses to a panel of 218 HIV clade B consensus-based HIV protease-reverse transcriptase peptides, designed to mimic previously described and predicted cytotoxic T lymphocyte epitopes overlapping drug resistance (DR) positions, that either included the consensus sequence or the DR variant sequence, in 49 ART-naïve HIV-infected individuals. Next generation sequencing was used to assess the presence of minority DR variants in circulating viral populations. Results: Although a wide spectrum of differential magnitudes of response to DR vs. WT peptide pairs was observed, responses to DR peptides were frequent and strong in the study cohort. No difference between the median magnitudes of response to DR vs. WT peptides was observed. Interestingly, of the 22 peptides that were recognized by >15% of the participants, two-thirds (64%) corresponded to DR peptides. When analysing responses per peptide pair per individual, responses to only WT (median 4 pairs/individual) or DR (median 6 pairs/individual) were more common than responses to both WT and DR (median 2 pairs/individual; p<0.001). While the presence of ELISpot responses to WT peptides was frequently associated with the presence of the corresponding peptide sequence in the patient’s virus (mean 68% of cases), responses to DR peptides were generally not associated with the presence of DR mutations in the viral population, even at low frequencies (mean 1.4% of cases; p = 0.0002). Conclusions: Our data suggests that DR peptides are frequently immunogenic and raises the potential benefit of broadening the antigens included in a therapeutic vaccine approach to immunogenic epitopes containing common DR sequences. Further studies are needed to assess the quality of responses elicited by DR peptides. [ABSTRACT FROM AUTHOR]