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Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach.

ABSTRACT: BK virus (BKV) associated nephropathy affects 1-10% of kidney transplant recipients, leading to graft failure in about 50% of cases. Immune responses against different BKV antigens have been shown to have a prognostic value for disease development. Data currently suggest that the structural antigens and regulatory antigens of BKV might each trigger a different mode of action of the immune response. To study the influence of different modes of action of the cellular immune response on BKV clearance dynamics, we have analysed the kinetics of BKV plasma load and anti-BKV T cell response (Elispot) in six patients with BKV associated nephropathy using ODE modelling. The results show that only a small number of hypotheses on the mode of action are compatible with the empirical data. The hypothesis with the highest empirical support is that structural antigens trigger blocking of virus production from infected cells, whereas regulatory antigens trigger an acceleration of death of infected cells. These differential modes of action could be important for our understanding of BKV resolution, as according to the hypothesis, only regulatory antigens would trigger a fast and continuous clearance of the viral load. Other hypotheses showed a lower degree of empirical support, but could potentially explain the clearing mechanisms of individual patients. Our results highlight the heterogeneity of the dynamics, including the delay between immune response against structural versus regulatory antigens, and its relevance for BKV clearance. Our modelling approach is the first that studies the process of BKV clearance by bringing together viral and immune kinetics and can provide a framework for personalised hypotheses generation on the interrelations between cellular immunity and viral dynamics.

SUBMITTER: Blazquez-Navarro A

PROVIDER: S-EPMC5944912 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The rapid outbreak of the COVID-19 also known as SARS-CoV2 has been declared pandemic with serious global concern. As there is no effective therapeutic against COVID-19, there is an urgent need for explicit treatment against it. The focused objective of the current study is to propose promising drug candidates against the newly identified potential therapeutic target (endonuclease, NSP15) of SARS-CoV2. NSP15 is an attractive druggable target due to its critical role in SARS-CoV2 replication and virulence in addition to interference with the host immune system. Here in the present study, we integrated the high throughput computational screening and dynamic simulation approach to identify the most promising candidate lead compound against NSP15.5-fluoro-2-oxo-1H-pyrazine-3-carboxamide (favipiravir), (3R,4R, 5R)-3,4-Bis(benzyloxy)-5-((benzyloxy) methyl) dihydrofuran-2(3H)-one) remedesivir, 1,3-thiazol-5-ylmethyl N-[(2S,3S, 5S)-3-hydroxy-5-[[(2 S)-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenylhexan-2-yl]carbamate (ritonavir), ethyl (3R,4R, 5S)-4-acetamido-5-amino-3-pentan-3-yloxycyclohexene-1-carboxylate (oseltamivir), and (2 S)-N-[(2S,4S, 5S)-5-[[2-(2,6-dimethylphenoxy)acetyl]amino]-4-hydroxy-1,6-diphenylhexan-2-yl]-3-methyl-2-(2-oxo-1,3-diazinan-1-yl)butanamide (lopinavir) were chosen as a training set to generate the pharmacophore model. A dataset of ~140,000 compounds library was screened against the designed pharmacophore model and 10 unique compounds were selected that passed successfully through geometry constraints, Lipinski Rule of 5, and ADME/Tox filters along with a strong binding affinity for NSP15 binding cavity. The best fit compound was selected for dynamic simulation to have detailed structural features critical for binding with the NSP15 protein. Given our detailed integrative computational analysis, a Small molecule (3,3-Dimethyl-N-[4-(1-piperidinylcarbonyl) phenyl] butanamide) with drug-like properties and high binding affinity with the NSP15 is proposed as a most promising potential drug against COVID-19. The current computational integrative approach may complement high-throughput screening and the shortlisted small molecule may contribute to selective targeting of NSP15 to stop the replication of SARS-CoV2.

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Differential T cell response against BK virus regulatory and structural antigens: A viral dynamics modelling approach.

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