@article{lavigne_russell_sherry_ke_2021, title={Autocrine and paracrine interferon signalling as 'ring vaccination' and 'contact tracing' strategies to suppress virus infection in a host}, volume={288}, ISSN={["1471-2954"]}, DOI={10.1098/rspb.2020.3002}, abstractNote={The innate immune response, particularly the interferon response, represents a first line of defence against viral infections. The interferon molecules produced from infected cells act through autocrine and paracrine signalling to turn host cells into an antiviral state. Although the molecular mechanisms of IFN signalling have been well characterized, how the interferon response collectively contribute to the regulation of host cells to stop or suppress viral infection during early infection remain unclear. Here, we use mathematical models to delineate the roles of the autocrine and the paracrine signalling, and show that their impacts on viral spread are dependent on how infection proceeds. In particular, we found that when infection is well-mixed, the paracrine signalling is not as effective; by contrast, when infection spreads in a spatial manner, a likely scenario during initial infection in tissue, the paracrine signalling can impede the spread of infection by decreasing the number of susceptible cells close to the site of infection. Furthermore, we argue that the interferon response can be seen as a parallel to population-level epidemic prevention strategies such as ‘contact tracing’ or ‘ring vaccination’. Thus, our results here may have implications for the outbreak control at the population scale more broadly.}, number={1945}, journal={PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES}, author={Lavigne, G. Michael and Russell, Hayley and Sherry, Barbara and Ke, Ruian}, year={2021}, month={Feb} }
 @article{huang_dai_ke_2019, title={Principles of Effective and Robust Innate Immune Response to Viral Infections: A Multiplex Network Analysis}, volume={10}, ISSN={["1664-3224"]}, DOI={10.3389/fimmu.2019.01736}, abstractNote={The human innate immune response, particularly the type-I interferon (IFN) response, is highly robust and effective first line of defense against virus invasion. IFN molecules are produced and secreted from infected cells upon virus infection and recognition. They then act as signaling/communication molecules to activate an antiviral response in neighboring cells so that those cells become refractory to infection. Previous experimental studies have identified the detailed molecular mechanisms for the IFN signaling and response. However, the principles underlying how host cells use IFN to communicate with each other to collectively and robustly halt an infection is not understood. Here we take a multiplex network modeling approach to provide a theoretical framework to identify key factors that determine the effectiveness of the IFN response against virus infection of a host. In this approach, we consider the virus spread among host cells and the interferon signaling to protect host cells as a competition process on a two-layer multiplex network. We focused on two types of network topology, i.e., the Erdős-Rényi (ER) network and the Geometric Random (GR) network, which represent the scenarios when infection of cells is mostly well mixed (e.g., in the blood) and when infection is spatially segregated (e.g., in tissues), respectively. We show that in general, the IFN response works effectively to stop viral infection when virus infection spreads spatially (a most likely scenario for initial virus infection of a host at the peripheral tissue). Importantly, we show that the effectiveness of the IFN response is robust against large variations in the distance of IFN diffusion as long as IFNs diffuse faster than viruses and they can effectively induce antiviral responses in susceptible host cells. This suggests that the effectiveness of the IFN response is insensitive to the specific arrangement of host cells in peripheral tissues. Thus, our work provides a quantitative explanation of why the IFN response can serve an effective and robust response in different tissue types to a wide range of viral infections of a host.}, journal={FRONTIERS IN IMMUNOLOGY}, author={Huang, Yufan and Dai, Huaiyu and Ke, Ruian}, year={2019}, month={Jul} }
 @article{koelle_farrell_brooke_ke_2019, title={Within-host infectious disease models accommodating cellular coinfection, with an application to influenza}, volume={5}, ISSN={["2057-1577"]}, DOI={10.1093/ve/vez018}, abstractNote={Abstract}, number={2}, journal={VIRUS EVOLUTION}, author={Koelle, Katia and Farrell, Alex P. and Brooke, Christopher B. and Ke, Ruian}, year={2019}, month={Jul} }
 @article{ke_conway_margolis_perelson_2018, title={Determinants of the efficacy of HIV latency-reversing agents and implications for drug and treatment design}, volume={3}, ISSN={["2379-3708"]}, DOI={10.1172/jci.insight.123052}, abstractNote={HIV eradication studies have focused on developing latency-reversing agents (LRAs). However, it is not understood how the rate of latent reservoir reduction is affected by different steps in the process of latency reversal. Furthermore, as current LRAs are host-directed, LRA treatment is likely to be intermittent to avoid host toxicities. Few careful studies of the serial effects of pulsatile LRA treatment have yet been done. This lack of clarity makes it difficult to evaluate the efficacy of candidate LRAs or predict long-term treatment outcomes. We constructed a mathematical model that describes the dynamics of latently infected cells under LRA treatment. Model analysis showed that, in addition to increasing the immune recognition and clearance of infected cells, the duration of HIV antigen expression (i.e., the period of vulnerability) plays an important role in determining the efficacy of LRAs, especially if effective clearance is achieved. Patients may benefit from pulsatile LRA exposures compared with continuous LRA exposures if the period of vulnerability is long and the clearance rate is high, both in the presence and absence of an LRA. Overall, the model framework serves as a useful tool to evaluate the efficacy and the rational design of LRAs and combination strategies.}, number={20}, journal={JCI INSIGHT}, author={Ke, Ruian and Conway, Jessica M. and Margolis, David M. and Perelson, Alan S.}, year={2018}, month={Oct} }
 @inproceedings{huang_dai_zhang_ke_2018, title={Network analysis of virus-innate immune interaction within a host}, DOI={10.1109/ciss.2018.8362278}, abstractNote={Viruses invade a host through infecting and spreading among host cells. Initial virus replication and transmission are counteracted by the host innate immune response, in particular the interferon response. Although the virus-innate immune interaction has been studied in laboratory for a long time, a theoretical understanding of how the interferon response impacts on viral spread is lacking. In this work, we model this interaction as a competition process between the virus spreading and the interferon response on a two-layer multiplex network with virus and interferon spread on the two layers separately. We specifically explore how the overlap between the two layers impacts on the threshold and the final size of virus spread. A mean-field method and a general homogeneous multiplex network are adopted to approximate and analyze the behavior of system. We find that interferon response can effectively stop the spread of the virus or reduce the final size of viral infection when the two networks largely overlap each other. This is true especially when the interferon response is strong. The results provide insights about how the innate immune response counteracts viral invasion and spread. It may also have implications for designing strategies for risk mitigation in computer or social networks.}, booktitle={2018 52nd Annual Conference on Information Sciences and Systems (CISS)}, author={Huang, Y. F. and Dai, M. and Zhang, Z. H. and Ke, R. A.}, year={2018} }
 @article{chang_naranbhai_stern_roche_dantanarayana_ke_tennakoon_solomon_hoh_hartogensis_et al._2018, title={Variation in cell-associated unspliced HIV RNA on antiretroviral therapy is associated with the circadian regulator brain-and-muscle-ARNT-like-1}, volume={32}, ISSN={["1473-5571"]}, DOI={10.1097/QAD.0000000000001937}, abstractNote={Objective(s): To determine whether variation in cell-associated unspliced (CA-US) HIV RNA in HIV-infected individuals on antiretroviral therapy (ART) has a circadian basis. Methods: Prospective observational study of HIV-infected individuals on ART. Blood was collected on three occasions and CA-US HIV RNA and mRNA of the circadian-locomotor-output-cycles-kaput (CLOCK)-associated genes quantified by real time PCR. CLOCK-associated proteins were over-expressed in a cell line stably transfected with an HIV long-terminal repeat (LTR) luciferase reporter. Results: Using a mixed effects model, there was a significant increase in log-CA-US RNA at the third visit compared with the first visit (effect size of 0.619 with standard error (SE) of 0.098, P < 0.001) and an independent effect of time of blood draw (effect size 0.051 (SE 0.025), P = 0.040). The CLOCK-associated gene, brain-and-muscle-ARNT-like-1 (BMAL-1) had a significant relationship with log CA-US HIV RNA (effect size 8.508 (SE 3.777), P = 0.028) and also with time (P = 0.045). Over expression of BMAL-1 and CLOCK in a cell line stably transfected with an HIV-LTR luciferase reporter resulted in an increase in luciferase expression and this was reduced following mutation of the second E-box in the HIV-LTR. Conclusion: The basal level of HIV transcription on ART can vary significantly and is modulated by the circadian regulator BMAL-1, amongst other factors.}, number={15}, journal={AIDS}, author={Chang, Christina C. and Naranbhai, Vivek and Stern, Jared and Roche, Michael and Dantanarayana, Ashanti and Ke, Ruian and Tennakoon, Surekha and Solomon, Ajantha and Hoh, Rebecca and Hartogensis, Wendy and et al.}, year={2018}, month={Sep}, pages={2119–2128} }
 @article{benzine_brandt_lovell_yamane_neddermann_de francesco_lemon_perelson_ke_mcgivern_2017, title={NS5A inhibitors unmask differences in functional replicase complex half-life between different hepatitis C virus strains}, volume={13}, ISSN={["1553-7374"]}, DOI={10.1371/journal.ppat.1006343}, abstractNote={Hepatitis C virus (HCV) RNA is synthesized by the replicase complex (RC), a macromolecular assembly composed of viral non-structural proteins and cellular co-factors. Inhibitors of the HCV NS5A protein block formation of new RCs but do not affect RNA synthesis by pre-formed RCs. Without new RC formation, existing RCs turn over and are eventually lost from the cell. We aimed to use NS5A inhibitors to estimate the half-life of the functional RC of HCV. We compared different cell culture-infectious strains of HCV that may be grouped based on their sensitivity to lipid peroxidation: robustly replicating, lipid peroxidation resistant (LPOR) viruses (e.g. JFH-1 or H77D) and more slowly replicating, lipid peroxidation sensitive (LPOS) viruses (e.g. H77S.3 and N.2). In luciferase assays, LPOS HCV strains declined under NS5A inhibitor therapy with much slower kinetics compared to LPOR HCV strains. This difference in rate of decline was not observed for inhibitors of the NS5B RNA-dependent RNA polymerase suggesting that the difference was not simply a consequence of differences in RNA stability. In further analyses, we compared two isoclonal HCV variants: the LPOS H77S.3 and the LPOR H77D that differ only by 12 amino acids. Differences in rate of decline between H77S.3 and H77D following NS5A inhibitor addition were not due to amino acid sequences in NS5A but rather due to a combination of amino acid differences in the non-structural proteins that make up the HCV RC. Mathematical modeling of intracellular HCV RNA dynamics suggested that differences in RC stability (half-lives of 3.5 and 9.9 hours, for H77D and H77S.3, respectively) are responsible for the different kinetics of antiviral suppression between LPOS and LPOR viruses. In nascent RNA capture assays, the rate of RNA synthesis decline following NS5A inhibitor addition was significantly faster for H77D compared to H77S.3 indicating different half-lives of functional RCs.}, number={6}, journal={PLOS PATHOGENS}, author={Benzine, Tiffany and Brandt, Ryan and Lovell, William C. and Yamane, Daisuke and Neddermann, Petra and De Francesco, Raffaele and Lemon, Stanley M. and Perelson, Alan S. and Ke, Ruian and McGivern, David R.}, year={2017}, month={Jun} }
 @article{ke_cong_li_garcia-lerma_perelson_2017, title={On the Death Rate of Abortively Infected Cells: Estimation from Simian-Human Immunodeficiency Virus Infection}, volume={91}, ISSN={["1098-5514"]}, DOI={10.1128/jvi.00352-17}, abstractNote={ABSTRACT}, number={18}, journal={JOURNAL OF VIROLOGY}, author={Ke, Ruian and Cong, Mian-er and Li, David and Garcia-Lerma, J. Gerardo and Perelson, Alan S.}, year={2017}, month={Sep} }
 @article{shan_deng_gao_xing_capoferri_durand_rabi_laird_kim_hosmane_et al._2017, title={Transcriptional Reprogramming during Effector-to-Memory Transition Renders CD4(+) T Cells Permissive for Latent HIV-1 Infection}, volume={47}, ISSN={["1097-4180"]}, DOI={10.1016/j.immuni.2017.09.014}, abstractNote={<h2>Summary</h2> The latent reservoir for HIV-1 in resting memory CD4<sup>+</sup> T cells is the major barrier to curing HIV-1 infection. Studies of HIV-1 latency have focused on regulation of viral gene expression in cells in which latent infection is established. However, it remains unclear how infection initially becomes latent. Here we described a unique set of properties of CD4<sup>+</sup> T cells undergoing effector-to-memory transition including temporary upregulation of CCR5 expression and rapid downregulation of cellular gene transcription. These cells allowed completion of steps in the HIV-1 life cycle through integration but suppressed HIV-1 gene transcription, thus allowing the establishment of latency. CD4<sup>+</sup> T cells in this stage were substantially more permissive for HIV-1 latent infection than other CD4<sup>+</sup> T cells. Establishment of latent HIV-1 infection in CD4<sup>+</sup> T could be inhibited by viral-specific CD8<sup>+</sup> T cells, a result with implications for elimination of latent HIV-1 infection by T cell-based vaccines.}, number={4}, journal={IMMUNITY}, author={Shan, Liang and Deng, Kai and Gao, Hongbo and Xing, Sifei and Capoferri, Adam A. and Durand, Christine M. and Rabi, S. Alireza and Laird, Gregory M. and Kim, Michelle and Hosmane, Nina N. and et al.}, year={2017}, month={Oct}, pages={766-+} }
 @article{ke_lewin_elliott_perelson_2015, title={Modeling the Effects of Vorinostat In Vivo Reveals both Transient and Delayed HIV Transcriptional Activation and Minimal Killing of Latently Infected Cells}, volume={11}, ISSN={["1553-7374"]}, DOI={10.1371/journal.ppat.1005237}, abstractNote={Recent efforts to cure human immunodeficiency virus type-1 (HIV-1) infection have focused on developing latency reversing agents as a first step to eradicate the latent reservoir. The histone deacetylase inhibitor, vorinostat, has been shown to activate HIV RNA transcription in CD4+ T-cells and alter host cell gene transcription in HIV-infected individuals on antiretroviral therapy. In order to understand how latently infected cells respond dynamically to vorinostat treatment and determine the impact of vorinostat on reservoir size in vivo, we have constructed viral dynamic models of latency that incorporate vorinostat treatment. We fitted these models to data collected from a recent clinical trial in which vorinostat was administered daily for 14 days to HIV-infected individuals on suppressive ART. The results show that HIV transcription is increased transiently during the first few hours or days of treatment and that there is a delay before a sustained increase of HIV transcription, whose duration varies among study participants and may depend on the long term impact of vorinostat on host gene expression. Parameter estimation suggests that in latently infected cells, HIV transcription induced by vorinostat occurs at lower levels than in productively infected cells. Furthermore, the estimated loss rate of transcriptionally induced cells remains close to baseline in most study participants, suggesting vorinostat treatment does not induce latently infected cell killing and thus reduce the latent reservoir in vivo.}, number={10}, journal={PLOS PATHOGENS}, author={Ke, Ruian and Lewin, Sharon R. and Elliott, Julian H. and Perelson, Alan S.}, year={2015}, month={Oct} }