Transmission Dynamics of the Recently-Identified BYD Virus Causing Duck Egg-Drop Syndrome

Baiyangdian (BYD) virus is a recently-identified mosquito-borne flavivirus that causes severe disease in ducks, with extremely rapid transmission, up to 15% mortality within 10 days and 90% reduction in egg production on duck farms within 5 days of infection. Because of the zoonotic nature of flaviviruses, the characterization of BYD virus and its epidemiology are important public health concerns. Here, we develop a mathematical model for the transmission dynamics of this novel virus. We validate the model against BYD outbreak data collected from duck farms in Southeast China, as well as experimental data obtained from an animal facility. Based on our model, the basic reproductive number of BYD virus is high (R0 = 21) indicating that this virus is highly transmissible, consistent with the dramatic epidemiology observed in BYDV-affected duck farms. Our results indicate that younger ducks are more vulnerable to BYD disease and that ducks infected with BYD virus reduce egg production (to about 33% on average) for about 3 days post-infection; after 3 days infected ducks are no longer able to produce eggs. Using our model, we predict that control measures which reduce contact between mosquitoes and ducks such as mosquito nets are more effective than insecticides

Correlation Between Anti-gp41 Antibodies and Virus Infectivity Decay During Primary HIV-1 Infection

Recent experiments have suggested that the infectivity of simian immunodeficiency virus (SIV) and human immunodeficiency virus type-1 (HIV-1) in plasma decreases over time during primary infection. Because anti-gp41 antibodies are produced early during HIV-1 infection and form antibody-virion complexes, we studied if such early HIV-1 specific antibodies are correlated with the decay in HIV-1 infectivity. Using a viral dynamic model that allows viral infectivity to decay and frequent early viral load data obtained from 6 plasma donors we estimate that HIV-1 infectivity begins to decay after about 2 weeks of infection. The length of this delay is consistent with the time before antibody-virion complexes were detected in the plasma of these donors and is correlated (p = 0.023, r = 0.87) with the time for antibodies to be first detected in plasma. Importantly, we identify that the rate of infectivity decay is significantly correlated with the rate of increase in plasma anti-gp41 IgG concentration (p = 0.046, r = 0.82) and the increase in IgM+IgG anti-gp41 concentration (p = 8.37 × 10−4, r = 0.98). Furthermore, we found that the viral load decay after the peak did not have any significant correlation with the rate of anti-gp41 IgM or IgG increase. These results indicate that early anti-gp41 antibodies may cause viral infectivity decay, but may not contribute significantly to controlling post-peak viral load, likely due to insufficient quantity or affinity. Our findings may be helpful to devise strategies, including antibody-based vaccines, to control acute HIV-1 infection

Treatment-Mediated Alterations in HIV Fitness Preserve CD4+ T Cell Counts but Have Minimal Effects on Viral Load

For most HIV-infected patients, antiretroviral therapy controls viral replication. However, in some patients drug resistance can cause therapy to fail. Nonetheless, continued therapy with a failing regimen can preserve or even lead to increases in CD4+ T cell counts. To understand the biological basis of these observations, we used mathematical models to explain observations made in patients with drug-resistant HIV treated with enfuvirtide (ENF/T-20), an HIV-1 fusion inhibitor. Due to resistance emergence, ENF was removed from the drug regimen, drug-sensitive virus regrown, and ENF was re-administered. We used our model to study the dynamics of plasma-viral RNA and CD4+ T cell levels, and the competition between drug-sensitive and resistant viruses during therapy interruption and re-administration. Focusing on resistant viruses carrying the V38A mutation in gp41, we found ENF-resistant virus to be 17±3% less fit than ENF-sensitive virus in the absence of the drug, and that the loss of resistant virus during therapy interruption was primarily due to this fitness cost. Using viral dynamic parameters estimated from these patients, we show that although re-administration of ENF cannot suppress viral load, it can, in the presence of resistant virus, increase CD4+ T cell counts, which should yield clinical benefits. This study provides a framework to investigate HIV and T cell dynamics in patients who develop drug resistance to other antiretroviral agents and may help to develop more effective strategies for treatment

Preface: Thematic Issue in Mathematical Biology and Applied Evolutionary Equations

Preface: Thematic Issue in Mathematical Biology and Applied Evolutionary Equation

Modeling HIV-1 infection in the brain.

While highly active antiretroviral therapy (HAART) is successful in controlling the replication of Human Immunodeficiency Virus (HIV-1) in many patients, currently there is no cure for HIV-1, presumably due to the presence of reservoirs of the virus. One of the least studied viral reservoirs is the brain, which the virus enters by crossing the blood-brain barrier (BBB) via macrophages, which are considered as conduits between the blood and the brain. The presence of HIV-1 in the brain often leads to HIV associated neurocognitive disorders (HAND), such as encephalitis and early-onset dementia. In this study we develop a novel mathematical model that describes HIV-1 infection in the brain and in the plasma coupled via the BBB. The model predictions are consistent with data from macaques infected with a mixture of simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV). Using our model, we estimate the rate of virus transport across the BBB as well as viral replication inside the brain, and we compute the basic reproduction number. We also carry out thorough sensitivity analysis to define the robustness of the model predictions on virus dynamics inside the brain. Our model provides useful insight into virus replication within the brain and suggests that the brain can be an important reservoir causing long-term viral persistence

Modeling Within-Host Dynamics of SARS-CoV-2 Infection: A Case Study in Ferrets

The pre-clinical development of antiviral agents involves experimental trials in animals and ferrets as an animal model for the study of SARS-CoV-2. Here, we used mathematical models and experimental data to characterize the within-host infection dynamics of SARS-CoV-2 in ferrets. We also performed a global sensitivity analysis of model parameters impacting the characteristics of the viral infection. We provide estimates of the viral dynamic parameters in ferrets, such as the infection rate, the virus production rate, the infectious virus proportion, the infected cell death rate, the virus clearance rate, as well as other related characteristics, including the basic reproduction number, pre-peak infectious viral growth rate, post-peak infectious viral decay rate, pre-peak infectious viral doubling time, post-peak infectious virus half-life, and the target cell loss in the respiratory tract. These parameters and indices are not significantly different between animals infected with viral strains isolated from the environment and isolated from human hosts, indicating a potential for transmission from fomites. While the infection period in ferrets is relatively short, the similarity observed between our results and previous results in humans supports that ferrets can be an appropriate animal model for SARS-CoV-2 dynamics-related studies, and our estimates provide helpful information for such studies

Modeling the Effects of Morphine-Altered Virus Specific Antibody Responses on HIV/SIV Dynamics

Abstract Drugs of abuse, such as opiates, have been widely associated with enhancing HIV replication, accelerating disease progression and diminishing host-immune responses, thereby making it harder to effectively manage HIV infection. It is thus important to study the effects of drugs of abuse on HIV-infection and immune responses. Here, we develop mathematical models that incorporate the effects of morphine-altered antibody responses on HIV/SIV dynamics. Based on fitting the model to experimental data from simian immunodeficiency virus (SIV) infections in control and morphine-addicted macaques, we found that two of the most significant effects of virus specific antibodies are neutralizing viral particles and enhancing viral clearance. Using our model, we quantified how morphine alters virus-specific antibody responses, and how this alteration affects the key components of virus dynamics such as infection rate, virus clearance, viral load, CD4+ T cell count, and CD4+ T cell loss in SIV-infected macaques under conditioning with morphine. We found that in a subpopulation of SIV-infected morphine addicted macaques, the presence of drugs of abuse may cause significantly diminished antibody responses, resulting in more severe infection with increased SIV infectivity, a decreased viral clearance rate, increased viral load, and higher CD4+ T cell loss