Biology subjects

Pienaar, E.

Publications and source records attributed to Pienaar, E..

13 recordsLinked to original sources

bioRxiv2025

Partially-functional exhausted CD8+ T cells can contribute to short-term viral suppression: a computational prediction for children with perinatal HIV

We and others have reported evidence of T cell exhaustion in children with perinatal HIV with increased expression of inhibitory receptors PD-1, CD160, and TIM-3, but there is limited data on the virologic functional consequences of this immune exhaustion. We address this by using an immune database from Kenyan children with perinatal HIV and unexposed controls. We computationally integrate T cell profiles of differentiation, activation and exhaustion in an agent-based model (ABM) to predict how T cell exhaustion impacts viral control following HIV exposure in vitro. Our ABM includes macrophages, CD4 and CD8 T cells, cytokines, and HIV. Model mechanisms include viral dynamics, macrophage activation, T cell activation and proliferation, cytotoxic T cell killing, and cytokine/HIV diffusion and degradation. Participants are grouped by HIV plasma viremia and by age, less than 5 years or 5-18 years. Our findings indicate that cells from virally active participants, who have the highest levels of exhaustion, have lower predicted viral concentrations and infected cells compared to other participant groups during new infection. However, this coincides with higher cell death, suggesting that short-term viral control is associated with excessive inflammation, which could be detrimental long-term. Cells from virally suppressed participants older than 5 years can maintain lower viral concentrations while limiting cell death, reflecting a more sustainable short-term immune response. In virally suppressed children younger than 5 years, immune response patterns strongly resemble the age-matched healthy control group, suggesting early viral suppression may preserve antiviral immune responses. Our model predicts unique patterns of cell death for each participant group, with CD8 T cell death being dominant in virally active groups and CD4 T cell and macrophage death being dominant in healthy and virally suppressed groups. Finally, exhausted CD8 T cells are predicted to contribute significantly to CD8 T cell killing, proliferation, and activation in the virally active group, indicating partially functional CD8 T cells can still contribute to short-term viral control. Our analysis functionally integrates participant-specific immunophenotypic data to allow quantification of the extent, mechanisms, and impact of immune dysfunction in perinatal HIV and could inform pediatric HIV remission and cure strategies. Author SummaryCytotoxic CD8+ T cells are vital for our ability to kill infected cells. However, chronic stimulation of CD8+ T cells can result in T cell exhaustion, leading to cellular dysfunction and reduced ability to fight infections. Here we ask: What impact does CD8+ T cell exhaustion have on the ability to control HIV replication over the short term? We answer this using a computational model, anchored in experimental data from children with perinatal HIV. We use participant-specific data on dozens of immune markers that characterize the state of their immune system. We carefully map these markers to known immune cell functions and use our model to predict how immune cells with these participant-specific markers would respond to HIV infection. Our results suggest that earlier viral suppression can lead to better immune function in children with perinatal HIV. Our findings also suggest that exhausted CD8+ T cells could still contribute to fighting HIV infection, but only if there are enough of them to compensate for their reduced functionality. Our work uses computational models to put valuable participant-specific data into context, allowing us to predict short-term infection outcomes and better understand immune function in children with perinatal HIV.

systems biology↗

bioRxiv2025

Local traveling waves of cytosolic calcium elicited by defense signals or wounding are propagated by distinct mechanisms

Cytosolic Ca2+ signatures with specific spatiotemporal patterns play crucial roles in plant responses to biotic and abiotic stresses. Perception of microbe- or damage-associated molecular patterns (MAMPs or DAMPs) initiates signaling cascades that represent the first layer of plant defense against pathogens known as pattern-triggered immunity (PTI). During PTI, MAMP/DAMP-induced cytosolic Ca2+ fluxes serve as essential messengers in the initiation and transmission of defense signals at the cellular, whole organ, and systemic levels. However, the specific patterns of these Ca2+ signatures in response to different pathogen cues, and the mechanisms that encode them, remain largely unexplored. In this study, we quantitatively assessed Ca2+ signatures at the single-cell level as well as the local traveling Ca2+ waves induced by global treatment of Arabidopsis cotyledons with MAMPs or DAMPs. We demonstrated that MAMPs induced distinct local spatiotemporal Ca2+ responses in epidermal pavement cells, with Ca2+ traveling waves consistently initiated from a subset of cells and spreading in an approximately radial pattern. These local traveling waves propagated at a slow but constant speed of approximately 1 {micro}m/s and spread to a limited number of neighboring cells. In contrast, wound-induced traveling waves displayed a diffusion-like decay pattern that moved rapidly away from the wounded cell but with diminishing speed over time and distance. Mathematical modeling supported a calcium-induced calcium release mechanism that could recapitulate the constant wave speed induced by MAMPs. These findings contribute to a deeper understanding of plant defense-related Ca2+ signaling mechanisms as well as how defense responses are spatially restricted within tissues. One Sentence SummaryA slow, local traveling wave of calcium is initiated from a subset of epidermal cells during plant immune signaling.

cell biology↗

bioRxiv2024

Timing matters in Macrophage / CD4+ T cell interactions: An agent-based model comparing Mycobacterium tuberculosis host-pathogen interactions between latently infected and naïve individuals

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a significant health challenge. Clinical manifestations of TB exist across a spectrum with a majority of infected individuals remaining asymptomatic, commonly referred to as latent TB infection (LTBI). In vitro models have demonstrated that cells from individuals with LTBI can better control Mtb growth, and form granuloma-like structures more quickly, compared to cells from uninfected (Mtb-naive) individuals. These in vitro results agree with animal and clinical evidence that LTBI protects, to some degree, against reinfection. However, the mechanisms by which LTBI might offer protection against reinfection remain unclear, and quantifying the relative contributions of multiple control mechanisms is challenging using experimental methods alone. To complement in vitro models, we have developed an in silico agent-based model to help elucidate host responses that might contribute to protection against reinfection. Our simulations indicate that earlier contact between macrophages and CD4+ T cells leads to LTBI simulations having more activated CD4+ T cells and, in turn, more activated infected macrophages which all contribute to decreased bacterial load early on. Our simulations also demonstrate that granuloma-like structures support this early macrophage activation in LTBI simulations. We find that differences between LTBI and Mtb-naive simulations are driven by TNF and IFN{gamma}-associated mechanisms as well as macrophage phagocytosis and killing mechanisms. Together, our simulations show how important the timing of the first interactions between innate and adaptive immune cells is, how this impacts infection progression, and why cells from LTBI individuals might be faster to respond to reinfection. ImportanceTuberculosis (TB) remains a significant global health challenge, with millions of new infections and deaths annually. Despite extensive research, the mechanisms by which latent TB infection (LTBI) confers protection against reinfection remain unclear. In this study, we developed an in silico agent-based model to simulate early immune responses to Mycobacterium tuberculosis (Mtb) infection based on experimental in vitro infection of human donor cells. Our simulations reveal that early interactions between macrophages and CD4+ T cells, driven by TNF and IFN{gamma}, are critical for bacterial control and granuloma formation in LTBI. These findings offer new insights into the immune processes involved in TB, which could inform the development of targeted vaccines and host-directed therapies. By integrating experimental data with computational predictions, our research provides a robust framework for understanding TB immunity and guiding future interventions to mitigate the global TB burden.

immunology↗

bioRxiv2023

Agent-based model predicts that layered structure and 3D movement work synergistically to reduce bacterial load in 3D in vitro models of tuberculosis granuloma

Tuberculosis (TB) remains a global public health threat with increasing prevalence. Understanding the dynamics of host-pathogen interactions within TB granulomas will assist in identifying what leads to successful elimination of infection. In vitro TB models provide a controllable environment to study these granuloma dynamics. Previously we developed a biomimetic 3D spheroid granuloma model that controls bacteria better than a traditional monolayer culture counterpart. We used agent-based simulations to predict the mechanistic reason for this difference. Our calibrated simulations were able to predict heterogeneous bacterial dynamics that are consistent with experimental data. In one group of simulations, spheroids are found to have a higher macrophage activation than their traditional counterparts, leading to better bacterial control. This higher macrophage activation in the spheroids was not due to higher T cell activation, rather fewer activated T cells were able to activate more macrophages due to the proximity of these cells within the spheroid. In a second group of simulations, spheroids again have more macrophage activation but also more T cell activation, specifically CD8+ T cells. This higher level of CD8+ T cell activation is predicted to be due to the proximity of these cells to the cells that activate them. Multiple mechanisms of control were predicted. Virtual knockouts show one group has a CD4+ T cell dominant response, while the other has a mixed/CD8+ T cell dominant response. Lastly, we demonstrated that the initial structure and movement rules work synergistically to reduce bacterial load. These findings provide valuable insights into how the structural complexity of in vitro models impacts immune responses. Moreover, our study has implications for engineering more physiologically relevant in vitro models and advancing our understanding of TB pathogenesis and potential therapeutic interventions.

systems biology↗

bioRxiv2023

Impact of Ebola virus nucleoprotein on VP40 virus-like particle production: a computational approach

Ebola virus (EBOV) protein VP40 can assemble and bud in the form of virus-like particles (VLPs) when expressed in the absence of other EBOV proteins in mammalian cells. When nucleoprotein (NP) is co-expressed, VLPs will contain inclusion-body (IB) cores, and VLP production can be increased. However, the mechanism of how NP impacts VLP production remains unclear. Here, we use a computational approach to study NP-VP40 interactions. We find that NP may enhance VLP production through stabilizing VP40 filaments and accelerating the VLP budding step. Also, both the relative timing and amount of NP expression compared to VP40 are important for the effective production of IB-containing VLPs. We further find that there exists an optimum NP/VP40 expression ratio, and that earlier expression of NP compared to VP40 will produce IB-containing VLPs more efficiently. We conclude that disrupting the relative timing and amount of NP and VP40 expression could provide new avenues to treat EBOV infection. This work provides quantitative insights into how EBOV proteins interact and how those interactions could impact virion generation and drug efficacy.

systems biology↗

bioRxiv2023

Evaluation of Fendiline Treatment in VP40 System with Nucleation-Elongation Process: A Computational Model of Ebola Virus Matrix Protein Assembly

Ebola virus (EBOV) infection is threatening human health, especially in Central and West Africa. Limited clinical trials and the requirement of biosafety level-4 (BSL-4) laboratories hinders experimental work to advance our understanding of EBOV and evaluation of treatment. In this work, we use a computational model to study the assembly and budding process of EBOV and evaluate the effect of fendiline on these processes. Our results indicate that the assembly of VP40 filaments may follow the nucleation-elongation theory, as it is critical to maintain a pool of VP40 dimer for the maturation and production of virus-like particles (VLPs). We further find that the nucleation-elongation process can also be influenced by phosphatidylserine (PS), which can complicate the efficacy of fendiline, a drug that lowers cellular PS levels. We observe that fendiline may increase VLP production at earlier time points (24 h) and under low concentrations ([≤] 2 M). But this effect is transient and does not change the conclusion that fendiline generally decreases VLP production. We also conclude that fendiline can be more efficient at the stage of VLP budding relative to earlier phases. Combination therapy with a VLP budding step-targeted drug may further increase the treatment efficiency of fendiline. Finally, we also show that fendiline has higher efficacy when VP40 expression is high. While these are single-cell level results based on the VP40 system, it points out a potential way of fendiline application affecting EBOV assembly, which can be further tested in experimental studies with multiple EBOV proteins or live virus. ImportanceEBOV infection can cause deadly hemorrhagic fever, which has a mortality rate around 90% without treatment. The recent outbreaks in Uganda and Democratic Republic of the Congo illustrate its treat to human health. Though two antibody-based treatments are approved, mortality rates in the last outbreak is still higher than 30%. This can partly be due to the requirement of advanced medical facilities for current treatments. As a result, it is very important to develop and evaluate new therapies for EBOV infection, especially those can be easily applied in the developing world. The significance of our research is that we evaluate the potential treatment effect of fendiline on EBOV infection in the VP40 system with a computational approach, which both greatly saves time and lowers cost compared to traditional experimental studies, and provides innovative new tools to study viral protein dynamics.

systems biology↗

bioRxiv2023

In silico agent-based modeling approach to characterize multiple in vitro tuberculosis infection models

In vitro models of Mycobacterium tuberculosis (Mtb) infection are a valuable tool to examine host-pathogen interactions and screen drugs. With the development of more complex in vitro models, there is a need for tools to help analyze and integrate data from these models. We introduce an agent-based model (ABM) representation of the interactions between immune cells and bacteria in an in vitro setting. This in silico model was used to independently simulate both traditional and spheroid cell culture models by changing the movement rules and initial spatial layout of the cells. These two setups were calibrated to published experimental data in a paired manner, by using the same parameters in both simulations. Within the calibrated set, heterogeneous outputs are seen for outputs of interest including bacterial count and T cell infiltration into the macrophage core of the spheroid. The simulations are also able to predict many outputs with high time resolution, including spatial structure. The structure of a single spheroid can be followed across the time course of the simulation, allowing the relationship between cell localization and immune activation to be explored. Uncertainty analyses are performed for both model setups using latin hypercube sampling and partial rank correlation coefficients to allow for easier comparison, which can provide insight into ideal use cases for the independent setups. Future model iterations can be guided by the limitations of the current model, specifically which parts of the output space were harder to reach. This ABM can be used to represent more in vitro Mtb infection models due to its flexible structure, providing a powerful analysis tool that can be used in tandem with experiments. Author SummaryTuberculosis is an infectious disease that causes over 1.4 million deaths every year. During infection, immune cells surround the bacteria forming structures called granulomas in the lungs. New laboratory models generate spheroids that aim to recreate these structures to help understand infection and find new ways to treat tuberculosis. Computational modeling is used to compare these newer spheroid models to traditional models, which dont recreate the structure of the cell clusters. After calibration to data from laboratory experiments to ensure that the computational model can represent both systems, the structures were characterized over time. The traditional and spheroid model were also compared by looking at how model inputs impact outputs, allowing users to figure out when one model should be used over the other. This computational tool can be used to help integrate data from different laboratory models, generate hypothesis to be tested in laboratory models, and predict pathways to be targeted by drugs.

systems biology↗

bioRxiv2023

Mathematical modeling indicates that regulatory inhibition of CD8+ T cell cytotoxicity can limit efficacy of IL-15 immunotherapy in cases of high pre-treatment SIV viral load

Immunotherapeutic cytokines can activate immune cells against cancers and chronic infections. N-803 is an IL-15 superagonist that expands CD8+ T cells and increases their cytotoxicity. N-803 also temporarily reduced viral load in a limited subset of non-human primates infected with simian immunodeficiency virus (SIV), a model of HIV. However, viral suppression has not been observed in all SIV cohorts and may depend on pre-treatment viral load and the corresponding effects on CD8+ T cells. Starting from an existing mechanistic mathematical model of N-803 immunotherapy of SIV, we develop a model that includes activation of SIV-specific and non-SIV-specific CD8+ T cells by antigen, inflammation, and N-803. Also included is a regulatory counter-response that inhibits CD8+ T cell proliferation and function, representing the effects of immune checkpoint molecules and immunosuppressive cells. We simultaneously calibrate the model to two separate SIV cohorts. The first cohort had low viral loads prior to treatment ({approx}3-4 log viral RNA copy equivalents (CEQ)/mL), and N-803 treatment transiently suppressed viral load. The second had higher pre-treatment viral loads ({approx}5-7 log CEQ/mL) and saw no consistent virus suppression with N-803. The mathematical model can replicate the viral and CD8+ T cell dynamics of both cohorts based on different pre-treatment viral loads and different levels of regulatory inhibition of CD8+ T cells due to those viral loads (i.e. initial conditions of model). Our predictions are validated by additional data from these and other SIV cohorts. While both cohorts had high numbers of activated SIV-specific CD8+ T cells in simulations, viral suppression was precluded in the high viral load cohort due to elevated inhibition of cytotoxicity. Thus, we mathematically demonstrate how the pre-treatment viral load can influence immunotherapeutic efficacy, highlighting the in vivo conditions and combination therapies that could maximize efficacy and improve treatment outcomes. Author SummaryImmunotherapy bolsters and redirects the immune system to fight chronic infections and cancers. However, the effectiveness of some immunotherapies may depend on the level of pre-treatment inflammation and the corresponding presence of regulatory cells and immune checkpoint molecules that normally function to prevent immune overreaction. Here, we consider two previously published cohorts of macaques who were given the immunotherapeutic N-803 to treat Simian Immunodeficiency Virus, an analog of Human Immunodeficiency Virus (HIV). One cohort had low viral loads before treatment, and N-803 temporarily suppressed viral loads. The second cohort had high viral loads that did not consistently decrease with N-803 treatment. In this work, we demonstrate with a mathematical model how these two distinct outcomes can arise due only to the different viral loads and the corresponding immune activation and regulatory response. In the model, we find that the key limiting factor is the direct inhibition of the cytotoxic action of immune cells by immune checkpoint molecules. This model indicates that simultaneous blockade of immune checkpoint molecules may be necessary for effective application of N-803 for the treatment of HIV. This and similar models can inform the design of such combination therapies for cancer and chronic infection.

systems biology↗

bioRxiv2022

Chemokine Signaling Caused by Mycobacterium avium Biofilms in the Lung Airway Increases Bacterial Loads by Spatially Diverting Macrophages

Mycobacterium avium Complex (MAC) are ubiquitous environmental biofilm-forming microbes that can colonize and infect patient lungs. Incidence and prevalence of MAC infections are increasing globally, and reinfection is common. Thus, MAC infections present a significant public health challenge. MAC infections are notoriously difficult to treat and there is an urgent need for MAC-targeted therapeutics. To identify potential drug targets, we quantify the impact of MAC biofilms and repeated exposure on infection progression using a computational model of MAC infection in lung airways. MAC biofilms aid epithelial cell invasion, cause premature macrophage apoptosis, and limit antibiotic efficacy. We develop an agent-based model that incorporates the interactions between bacteria, biofilm and immune cells. We perform virtual knockouts to quantify the effects of the sources of biofilm (biofilm simultaneously deposited with bacteria vs. formed in the airway after initial bacterial deposition), and their effects on macrophages (inducing apoptosis and slowing phagocytosis). We also quantify the effects of repeated bacterial exposure to assess the impact of reinfection on infection progression. Our results show that chemokines released by biofilm-induced apoptosis bias macrophage chemotaxis towards pockets of infected and apoptosed macrophages. This bias results in fewer macrophages finding extracellular bacteria, allowing the extracellular planktonic bacteria to replicate freely. These spatial macrophage trends are further exacerbated with repeated deposition of bacteria. Our model indicates that interventions to either abrogate macrophages apoptotic responses to bacterial biofilms and/or reduce frequency of patient exposure to bacteria will lower bacterial load, and likely overall risk of infection.

systems biology↗

bioRxiv2021

The Role of Biofilms, Bacterial Phenotypes, and Innate Immune Response in Mycobacterium avium Colonization to Infection

Mycobacterium avium complex (MAC), is known for colonizing and infecting humans following inhalation of the bacteria. MAC pulmonary disease is notoriously difficult to treat and prone to recurrence. Both the incidence and prevalence MAC pulmonary disease have been increasing globally. MAC is well known to form biofilms in the environment, and in vitro, these biofilms have been shown to aid MAC in epithelial cell invasion, protect MAC from phagocytosis, and cause premature apoptosis in macrophages. In vivo, the system of interactions between MAC, biofilms and host macrophages is complex, difficult to replicate in vitro and in animal models, has not been fully characterized. Here we present a three-dimensional agent-based model of a lung airway to help understand how these interactions evolve in the first 14 days post-bacterial inhalation. We parameterized the model using published data and performed uncertainty analysis to characterize outcomes and parameters effects on those outcomes. Model results show diverse outcomes, including wide ranges of macrophage recruitment levels, and bacterial loads and phenotype distribution. Though most bacteria are phagocytosed by macrophages and remain intracellular, there are also many simulations in which extracellular bacteria continue to drive the colonization and infection. Initial parameters dictating host immune levels, bacterial loads introduced to the airway, and biofilm conditions have significant and lasting impacts on the course of these results. Additionally, though macrophage recruitment is key for suppressing bacterial loads, there is evidence of significant excess recruitment that fail to impact bacterial numbers. These results highlight a need and identify a path for further exploration into the inhalation events in MAC infection. Early infection dynamics could have lasting impacts on the development of nodular bronchiectatic or fibrocavitary disease as well as inform possible preventative and treatment intervention targeting biofilm-macrophage interactions.

systems biology↗

bioRxiv2021

Mechanisms of phosphatidylserine influence on viral production: a computational model of Ebola virus matrix protein assembly

Ebola virus (EBOV) infections continue to pose a global public health threat, with high mortality rates and sporadic outbreaks in Central and Western Africa. A quantitative understanding of the key processes driving EBOV assembly and budding could provide valuable insights to inform drug development. Here we used a computational model to evaluate EBOV matrix assembly. Our model focused on the assembly kinetics of VP40, the matrix protein in EBOV, and its interaction with phosphatidylserine (PS) in the host cell membrane. Human cells transfected with VP40-expressing plasmids are capable of producing virus-like particles (VLPs) that closely resemble EBOV virions. We used data from this in vitro VP40 system to calibrate our computational model. PS levels in the host cell membrane had been shown to affect VP40 dynamics as well as VLP production through recruiting VP40 dimers to plasma membrane inner leaflet. Our computational results indicated that PS may have direct influence on VP40 filament growth and affect multiple steps in the assembly and budding of VP40 VLPs. We also proposed that the assembly of VP40 filaments may follow the nucleation-elongation theory where initialization and oligomerization of VP40 are two separate and distinct steps in the assembly process. This work illustrated how computational and experimental approaches can be combined to allow for additional analysis and hypothesis generation. Our findings advanced understanding of the molecular process of EBOV assembly and budding processes and may help the development of new EBOV treatments targeting VP40 matrix assembly.

systems biology↗

bioRxiv2021

The Ebola virus matrix protein clusters phosphatidylserine, a critical step in viral budding

Phosphatidylserine (PS) has been shown to be a critical lipid factor in the assembly and spread of numerous lipid enveloped viruses. Here, we describe the ability of the Ebola virus (EBOV) matrix protein eVP40 to induce clustering of PS and promote viral budding in vitro, as well as the ability of an FDA approved drug, fendiline, to reduce PS clustering subsequently reducing virus budding and entry. To gain mechanistic insight into fendiline inhibition of EBOV replication, multiple in vitro assays were employed including imaging, viral budding and viral entry assays. Fendiline reduced the PS content in mammalian cells and PS in the plasma membrane, reducing the ability of VP40 to form new virus particles. Further, particles that do form from fendiline treated cells have altered particle morphology and decreased infectivity capacity. These complementary studies reveal the mechanism by which filovirus matrix proteins cluster PS to enhance viral assembly, budding, and spread from the host cell while also laying the groundwork for fundamental drug targeting strategies.

microbiology↗

bioRxiv2020

Mathematical modeling of N-803 treatment in SIV-infected non-human primates

Immunomodulatory drugs could contribute to a functional cure for Human Immunodeficiency Virus (HIV). Interleukin-15 (IL-15) promotes expansion and activation of CD8+ T cell and natural killer (NK) cell populations. In one study, an IL-15 superagonist, N-803, suppressed Simian Immunodeficiency Virus (SIV) in non-human primates (NHPs) who had received prior SIV vaccination. However, viral suppression attenuated with continued N-803 treatment, partially returning after long treatment interruption. While there is evidence of concurrent drug tolerance, immune regulation, and viral escape, the relative contributions of these mechanisms to the observed viral dynamics have not been quantified. Here, we utilize mathematical models of N-803 treatment in SIV-infected macaques to estimate contributions of these three key mechanisms to treatment outcomes: 1) drug tolerance, 2) immune regulation, and 3) viral escape. We calibrated our model to viral and lymphocyte responses from the above-mentioned NHP study. Our models track CD8+ T cell and NK cell populations with N-803-dependent proliferation and activation, as well as viral dynamics in response to these immune cell populations. We compared mathematical models with different combinations of the three key mechanisms based on Akaike Information Criterion and important qualitative features of the NHP data. Two minimal models were capable of reproducing the observed SIV response to N-803. In both models, immune regulation strongly reduced cytotoxic cell activation to enable viral rebound. Either long-term drug tolerance or viral escape (or some combination thereof) could account for changes to viral dynamics across long breaks in N-803 treatment. Theoretical explorations with the models showed that less-frequent N-803 dosing and concurrent immune regulation blockade (e.g. PD-L1 inhibition) may improve N-803 efficacy. However, N-803 may need to be combined with other immune therapies to countermand viral escape from the CD8+ T cell response. Our mechanistic model will inform such therapy design and guide future studies. Author summaryImmune therapy may be a critical component in the functional cure for Human Immunodeficiency Virus (HIV). N-803 is an immunotherapeutic drug that activates antigen-specific CD8+ T cells of the immune system. These CD8+ T cells eliminate HIV-infected cells in order to limit the spread of infection in the body. In one study, N-803 reduced plasma viremia in macaques that were infected with Simian Immunodeficiency Virus, an analog of HIV. Here, we used mathematical models to analyze the data from this study to better understand the effects of N-803 therapy on the immune system. Our models indicated that inhibitory signals may be reversing the stimulatory effect of N-803. Results also suggested the possibilities that tolerance to N-803 could build up within the CD8+ T cells themselves and that the treatment may be selecting for virus strains that are not targeted by CD8+ T cells. Our models predict that N-803 therapy may be made more effective if the time between doses is increased or if inhibitory signals are blocked by an additional drug. Also, N-803 may need to be combined with other immune therapies to target virus that would otherwise evade CD8+ T cells.

systems biology↗