Modeling the dynamics of viral–host interaction during treatment of productively infected cells and free virus involving total immune response

Virus dynamics models are useful in interpreting and predicting the change in viral load over the time and the effect of treatment in emerging viral infections like HIV/AIDS, hepatitis B virus (HBV).We propose a mathematical model involving the role of total immune response (innate, CTL, and humoral) and treatment for productively infected cells and free virus to understand the dynamics of virus–host interactions. A threshold condition for the extinction or persistence of infection, i.e. basic reproductive number, in the presence of immune response (RI ) is established. We study the global stability of virus-free equilibrium and interior equilibrium using LaSalle’s principle and Lyapunov’s direct method. The global stability of virus-free equilibrium ensures the clearance of virus from the body, which is independent of initial status of subpopulations. Central manifold theory is used to study the behavior of equilibrium points at RI = 1, i.e. when the basic reproductive number in the presence of immune response is one. A special case, when the immune response (IR) is not present, has also been discussed. Analysis of special case suggests that the basic reproductive number in the absence of immune response R0 is greater than that of in the presence of immune response RI , i.e. R0> RI . It indicates that infection may be eradicated if RI  < 1. Numerical simulations are performed to illustrate the analytical results using MatLab and Mathematica

Mathematical modeling of immunological reactions

3. Models of HIV infection and other infectious diseases 4. Models of T cell activation and proliferatio

Latency reversal and viral clearance to cure HIV-1

Research toward a cure for human immunodeficiency virus type 1 (HIV-1) infection has joined prevention and treatment efforts in the global public health agenda. A major approach to HIV eradication envisions antiretroviral suppression, paired with targeted therapies to enforce the expression of viral antigen from quiescent HIV-1 genomes, and immunotherapies to clear latent infection. These strategies are targeted to lead to viral eradication—a cure for AIDS. Paired testing of latency reversal and clearance strategies has begun, but additional obstacles to HIV eradication may emerge. Nevertheless, there is reason for optimism that advances in long-acting antiretroviral therapy and HIV prevention strategies will contribute to efforts in HIV cure research and that the implementation of these efforts will synergize to markedly blunt the effect of the HIV pandemic on society

Cleavage site compensatory substitutions partially restore fitness to simian immunodeficiency virus variants

The human immunodeficiency virus is presently one of the most significant global health issues to date, with a disease burden that encumbers developing and developed nations alike. Although current antiretroviral therapy can help patients maintain undetectable levels of the virus throughout their bodies, once the treatment is ceased, the virus will rebound and disease progression continues. Thus, modalities to; 1- stop HIV transmission and spread, or 2- eradicate the virus once it is acquired are both urgently needed. In this project, we seek to evaluate and understand the impact of a candidate vaccine therapy that targets the HIV protease cleavage sites (PCS) on viral fitness. Vaccination with this modality in a monkey model induces mutations at virus regions that are intolerant to change, presumably affecting the "fitness" of viral strains recovered from vaccines. Preliminary results of the study show that in the vaccine group (n=11), a disruption to one or more of the HIV protease cleavage sites results in improved maintenance of CD4+ T cells compared to unvaccinated controls (n=5). Furthermore, a correlation between the percentage of PCS mutations and reductions in viral load were seen. Our data indicate that the most common sites of mutation occur at two cleavage regions PCS2 and PCS12. We used site directed mutagenesis to introduce multiple PCS mutations into infectious clones of SIV. Our ongoing studies are evaluating the viral fitness of the SIV mutants in a cell lines and PBMC using competitive viral fitness assays. The data from these studies will help inform in the areas of vaccine and therapy development for HIV-1

TRANSGENE IL-21-ENGINEERED ANTIGEN-SPECIFIC EXOSOME TARGETED T CELL-BASED VACCINE POTENTLY CONVERTS CTL EXHAUSTION IN CHRONIC INFECTION

CD8+ cytotoxic T lymphocytes (CTLs), the potent effector T cells, capable of directly destroying virus-infected cells, correlate with acute viral control and long-term non-progression in virus-mediated infectious diseases, play an important role in controlling viral infections. However, CD8+ CTLs due to persistent viral stimulation showed functional exhaustion in virally induced chronic infections, which expressed inhibitory molecules such as inhibitory programmed death (PD)-1, programmed death ligand (PDL)-1, T-cell Ig and mucin protein-3 (TIM3) and lymphocyte-activation gene 3 (LAG-3), and were functionally exhausted such as defect in effector cytokine IFN- production, lack of cytolytic effect and reduction of recall responses upon the pathogen reencounter. Therefore, CTL exhaustion has become one of the major obstacles for the ineffectiveness of viral control in chronic infectious diseases such as human immunodeficiency virus (HIV)-1. We previously generated novel ovalbumin (OVA)-specific 41BBL-expressing OVA-TEXO and HIV-1 Gag-specific Gag-TEXO vaccines inducing therapeutic immunity in B6 mice and converting CTL exhaustion via its CD40L signaling activation of the PI3K-Akt-mTORC1 pathway in recombinant OVA-specific adenovirus AdVOVA-infected B6 (AdVOVA-B6) mice with chronic infection. In AdVOVA-B6 mice, OVA-specific CTLs expressing IL-7R, IL-21R and inhibitory PD-1, PDL-1 and LAG-3 were inflated and functionally exhausted. Cytokine IL-21, a member of the common -chain cytokine family, produced by CD4+ helper T cells, plays an important role in controlling chronic infections. IL-21 promotes CTL activation and survival by activation of the phosphatidylinositol-3 kinase (PI3K) and the mTORC1-regulated T-bet pathway. In this study, we constructed recombinant transgene IL-21-expressing AdVIL-21 by recombinant DNA technology, generated IL-21-expressing OVA-TEXO/IL-21 and Gag-TEXO/IL21 vaccines or the control OVA-TEXO/Null and Gag-TEXO/Null vaccines by infection of OVA-TEXO and Gag-TEXO cells with AdVIL-21 or the control AdVNull without transgene, and assessed their stimulatory immunogenicity in wild-type B6 or AdVOVA-B6 mice, respectively. We demonstrate that both OVA-TEXO/IL-21 and the control OVA-TEXO/Null vaccines are capable of converting CTL exhaustion in chronic infection. However, IL-21-expressing OVA-TEXO/IL-21 vaccine more efficiently rescues exhausted CTLs through increasing CTL proliferation and effector cytokine IFN-ɤ expression by 6-fold than the 3-fold in OVA-TEXO/Null-vaccinated AdVOVA-B6 mice, though these two vaccines stimulated comparable OVA-specific responses and immunity against OVA-expressing BL6-10OVA melanoma in B6 mice. In vivo OVA-TEXO/IL-21-stimulated CTLs more efficiently up-regulate phosphorylation of mTORC1-regulated EIF4E and expression of mTORC1-controlled T-bet molecules as well as Ki67 (a protein associated with cell-cycle progression) than the control OVA-TEXO/Null-stimulated CTLs, indicating that enhancement of converting CTL exhaustion in chronic infection by OVA-TEXO/IL-21 vaccination is mostly through the stronger activation of the PI3K-Akt-mTORC1 pathway derived from both its endogenous CD40L and transgenic IL-21 signaling. Importantly, Gag-TEXO/IL21 vaccine also induces stronger Gag-specific therapeutic immunity against established Gag-expressing BL6-10Gag melanoma lung metastases than Gag-TEXO/Null vaccine in chronic infection. Therefore, this study should have a strong impact on developing new therapeutic vaccines for chronic infectious diseases such as HIV-1 infection

A review of mathematical models of influenza A infections within a host or cell culture: lessons learned and challenges ahead

Most mathematical models used to study the dynamics of influenza A have thus far focused on the between-host population level, with the aim to inform public health decisions regarding issues such as drug and social distancing intervention strategies, antiviral stockpiling or vaccine distribution. Here, we investigate mathematical modeling of influenza infection spread at a different scale; namely that occurring within an individual host or a cell culture. We review the models that have been developed in the last decades and discuss their contributions to our understanding of the dynamics of influenza infections. We review kinetic parameters (e.g., viral clearance rate, lifespan of infected cells) and values obtained through fitting mathematical models, and contrast them with values obtained directly from experiments. We explore the symbiotic role of mathematical models and experimental assays in improving our quantitative understanding of influenza infection dynamics. We also discuss the challenges in developing better, more comprehensive models for the course of influenza infections within a host or cell culture. Finally, we explain the contributions of such modeling efforts to important public health issues, and suggest future modeling studies that can help to address additional questions relevant to public health

International AIDS Society global scientific strategy: towards an HIV cure 2016

Antiretroviral therapy is not curative. Given the challenges in providing life-long therapy to a global population of over 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy