Analysis of the dynamics of a delayed HIV pathogenesis model

AbstractIn this paper, considering full Logistic proliferation of CD4+ T cells, we study an HIV pathogenesis model with antiretroviral therapy and HIV replication time. We first analyze the existence and stability of the equilibrium, and then investigate the effect of the time delay on the stability of the infected steady state. Sufficient conditions are given to ensure that the infected steady state is asymptotically stable for all delay. Furthermore, we apply the Nyquist criterion to estimate the length of delay for which stability continues to hold, and investigate the existence of Hopf bifurcation by using a delay τ as a bifurcation parameter. Finally, numerical simulations are presented to illustrate the main results

Mathematical Model of HIV superinfection dynamics and R5 to X4 switch

During the HIV infection several quasispecies of the virus arise, which are able to use different coreceptors, in particular the CCR5 and CXCR4 coreceptors (R5 and X4 phenotypes, respectively). The switch in coreceptor usage has been correlated with a faster progression of the disease to the AIDS phase. As several pharmaceutical companies are starting large phase III trials for R5 and X4 drugs, models are needed to predict the co-evolutionary and competitive dynamics of virus strains. We present a model of HIV early infection which describes the dynamics of R5 quasispecies and a model of HIV late infection which describes the R5 to X4 switch. We report the following findings: after superinfection or coinfection, quasispecies dynamics has time scales of several months and becomes even slower at low number of CD4+ T cells. The curve of CD4+ T cells decreases, during AIDS late stage, and can be described taking into account the X4 related Tumor Necrosis Factor dynamics. Phylogenetic inference of chemokine receptors suggests that viral mutational pathway may generate R5 variants able to interact with chemokine receptors different from CXCR4. This may explain the massive signaling disruptions in the immune system observed during AIDS late stages and may have relevance for vaccination and therapy.Comment: 21 pages, 14 figure

Vaccine innovation, translational research and the management of knowledge accumulation

What does it take to translate research into socially beneficial technologies like vaccines? Current policy that focuses on expanding research or strengthening incentives overlooks how the supply and demand of innovation is mediated by problem-solving processes that generate knowledge which is often fragmented and only locally valid. This paper details some of the conditions that allow fragmented, local knowledge to accumulate through a series of structured steps from the artificial simplicity of the laboratory to the complexity of real world application. Poliomyelitis is used as an illustrative case to highlight the importance of experimental animal models and the extent of co-ordination that can be required if they are missing. Implications for the governance and management of current attempts to produce vaccines for HIV, TB and Malaria are discussed. Article Outlin

Zika virus preferentially replicates in the female reproductive tract after vaginal inoculation of rhesus macaques.

Zika virus (ZIKV) is a mosquito-transmitted virus that can cause severe defects in an infected fetus. ZIKV is also transmitted by sexual contact, although the relative importance of sexual transmission is unclear. To better understand the role of sexual transmission in ZIKV pathogenesis, a nonhuman primate (NHP) model of vaginal transmission was developed. ZIKV was readily transmitted to mature cycling female rhesus macaque (RM) by vaginal inoculation with 104-106 plaque-forming units (PFU). However, there was variability in susceptibility between the individual RM with 1->8 vaginal inoculations required to establish infection. After treatment with Depoprovera, a widely used contraceptive progestin, two RM that initially resisted 8 vaginal ZIKV inoculations became infected after one ZIKV inoculation. Thus, Depoprovera seemed to enhance susceptibility to vaginal ZIKV transmission. Unexpectedly, the kinetics of virus replication and dissemination after intravaginal ZIKV inoculation were markedly different from RM infected with ZIKV by subcutaneous (SQ) virus inoculation. Several groups have reported that after SQ ZIKV inoculation vRNA is rapidly detected in blood plasma with vRNA less common in urine and saliva and only rarely detected in female reproductive tract (FRT) secretions. In contrast, in vaginally inoculated RM, plasma vRNA is delayed for several days and ZIKV replication in, and vRNA shedding from, the FRT was found in all 6 animals. Further, after intravaginal transmission ZIKV RNA shedding from FRT secretions was detected before or simultaneously with plasma vRNA, and persisted for at least as long. Thus, ZIKV replication in the FRT was independent of, and often preceded virus replication in the tissues contributing to plasma vRNA. These results support the conclusion that ZIKV preferentially replicates in the FRT after vaginal transmission, but not after SQ transmission, and raise the possibility that there is enhanced fetal infection and pathology after vaginal ZIKV transmission compared to a mosquito transmitted ZIKV

Assessment of treatment response in tuberculosis

Antibiotic treatment of tuberculosis has a duration of several months. There is significant variability of the host immune response and the pharmacokinetic-pharmacodynamic properties of Mycobacterium tuberculosis sub-populations at the site of disease. A limitation of sputum-based measures of treatment response may be sub-optimal detection and monitoring of Mycobacterium tuberculosis sub-populations. Potential biomarkers and surrogate endpoints should be benchmarked against hard clinical outcomes (failure/relapse/death) and may need tailoring to specific patient populations. Here, we assess the evidence supporting currently utilized and future potential host and pathogen-based models and biomarkers for monitoring treatment response in active and latent tuberculosis. Biomarkers for monitoring treatment response in extrapulmonary, pediatric and drug resistant tuberculosis are research priorities

In Vivo validation of a bioinformatics based tool to identify reduced replication capacity in HIV-1.

Although antiretroviral drug resistance is common in treated HIV infected individuals, it is not a consistent indicator of HIV morbidity and mortality. To the contrary, HIV resistance-associated mutations may lead to changes in viral fitness that are beneficial to infected individuals. Using a bioinformatics-based model to assess the effects of numerous drug resistance mutations, we determined that the D30N mutation in HIV-1 protease had the largest decrease in replication capacity among known protease resistance mutations. To test this in silico result in an in vivo environment, we constructed several drug-resistant mutant HIV-1 strains and compared their relative fitness utilizing the SCID-hu mouse model. We found HIV-1 containing the D30N mutation had a significant defect in vivo, showing impaired replication kinetics and a decreased ability to deplete CD4+ thymocytes, compared to the wild-type or virus without the D30N mutation. In comparison, virus containing the M184V mutation in reverse transcriptase, which shows decreased replication capacity in vitro, did not have an effect on viral fitness in vivo. Thus, in this study we have verified an in silico bioinformatics result with a biological assessment to identify a unique mutation in HIV-1 that has a significant fitness defect in vivo

Global dynamics of cell mediated immunity in viral infection models with distributed delays

In this paper, we investigate global dynamics for a system of delay differential equations which describes a virus-immune interaction in \textit{vivo}. The model has two distributed time delays describing time needed for infection of cell and virus replication. Our model admits three possible equilibria, an uninfected equilibrium and infected equilibrium with or without immune response depending on the basic reproduction number for viral infection $R_{0}$ and for CTL response $R_{1}$ such that $R_{1}<R_{0}$. It is shown that there always exists one equilibrium which is globally asymptotically stable by employing the method of Lyapunov functional. More specifically, the uninfected equilibrium is globally asymptotically stable if $R_{0}\leq1$, an infected equilibrium without immune response is globally asymptotically stable if $R_{1}\leq1<R_{0}$ and an infected equilibrium with immune response is globally asymptotically stable if $R_{1}>1$. The immune activation has a positive role in the reduction of the infection cells and the increasing of the uninfected cells if $R_{1}>1$.Comment: 16 pages, accepted by Journal of Mathematical Analysis and Application

Envelope Determinants of Equine Lentiviral Vaccine Protection

Lentiviral envelope (Env) antigenic variation and associated immune evasion present major obstacles to vaccine development. The concept that Env is a critical determinant for vaccine efficacy is well accepted, however defined correlates of protection associated with Env variation have yet to be determined. We reported an attenuated equine infectious anemia virus (EIAV) vaccine study that directly examined the effect of lentiviral Env sequence variation on vaccine efficacy. The study identified a significant, inverse, linear correlation between vaccine efficacy and increasing divergence of the challenge virus Env gp90 protein compared to the vaccine virus gp90. The report demonstrated approximately 100% protection of immunized ponies from disease after challenge by virus with a homologous gp90 (EV0), and roughly 40% protection against challenge by virus (EV13) with a gp90 13% divergent from the vaccine strain. In the current study we examine whether the protection observed when challenging with the EV0 strain could be conferred to animals via chimeric challenge viruses between the EV0 and EV13 strains, allowing for mapping of protection to specific Env sequences. Viruses containing the EV13 proviral backbone and selected domains of the EV0 gp90 were constructed and in vitro and in vivo infectivity examined. Vaccine efficacy studies indicated that homology between the vaccine strain gp90 and the N-terminus of the challenge strain gp90 was capable of inducing immunity that resulted in significantly lower levels of post-challenge virus and significantly delayed the onset of disease. However, a homologous N-terminal region alone inserted in the EV13 backbone could not impart the 100% protection observed with the EV0 strain. Data presented here denote the complicated and potentially contradictory relationship between in vitro virulence and in vivo pathogenicity. The study highlights the importance of structural conformation for immunogens and emphasizes the need for antibody binding, not neutralizing, assays that correlate with vaccine protection. © 2013 Craigo et al