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Perelson, Alan S. (ORCID:0000000224550002)

Publications and source records attributed to Perelson, Alan S. (ORCID:0000000224550002).

9 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Understanding early HIV-1 rebound dynamics following antiretroviral therapy interruption: The importance of effector cell expansion

Most people living with HIV-1 experience rapid viral rebound once antiretroviral therapy is interrupted; however, a small fraction remain in viral remission for an extended duration. Understanding the factors that determine whether viral rebound is likely after treatment interruption can enable the development of optimal treatment regimens and therapeutic interventions to potentially achieve a functional cure for HIV-1. We built upon the theoretical framework proposed by Conway and Perelson to construct dynamic models of virus-immune interactions to study factors that influence viral rebound dynamics. We evaluated these models using viral load data from 24 individuals following antiretroviral therapy interruption. The best-performing model accurately captures the heterogeneity of viral dynamics and highlights the importance of the effector cell expansion rate. Our results show that post-treatment controllers and non-controllers can be distinguished based on the effector cell expansion rate in our models. Furthermore, these results demonstrate the potential of using dynamic models incorporating an effector cell response to understand early viral rebound dynamics post-antiretroviral therapy interruption.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Modeling the emergence of viral resistance for SARS-CoV-2 during treatment with an anti-spike monoclonal antibody

To mitigate the loss of lives during the COVID-19 pandemic, emergency use authorization was given to several anti-SARS-CoV-2 monoclonal antibody (mAb) therapies for the treatment of mild-to-moderate COVID-19 in patients with a high risk of progressing to severe disease. Monoclonal antibodies used to treat SARS-CoV-2 target the spike protein of the virus and block its ability to enter and infect target cells. Monoclonal antibody therapy can thus accelerate the decline in viral load and lower hospitalization rates among high-risk patients with variants susceptible to mAb therapy. However, viral resistance has been observed, in some cases leading to a transient viral rebound that can be as large as 3–4 orders of magnitude. As mAbs represent a proven treatment choice for SARS-CoV-2 and other viral infections, evaluation of treatment-emergent mAb resistance can help uncover underlying pathobiology of SARS-CoV-2 infection and may also help in the development of the next generation of mAb therapies. Although resistance can be expected, the large rebounds observed are much more difficult to explain. We hypothesize replenishment of target cells is necessary to generate the high transient viral rebound. Thus, we formulated two models with different mechanisms for target cell replenishment (homeostatic proliferation and return from an innate immune response antiviral state) and fit them to data from persons with SARS-CoV-2 treated with a mAb. We showed that both models can explain the emergence of resistant virus associated with high transient viral rebounds. We found that variations in the target cell supply rate and adaptive immunity parameters have a strong impact on the magnitude or observability of the viral rebound associated with the emergence of resistant virus. Both variations in target cell supply rate and adaptive immunity parameters may explain why only some individuals develop observable transient resistant viral rebound. Our study highlights the conditions that can lead to resistance and subsequent viral rebound in mAb treatments during acute infection.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

How robust are estimates of key parameters in standard viral dynamic models?

Mathematical models of viral infection have been developed, fitted to data, and provide insight into disease pathogenesis for multiple agents that cause chronic infection, including HIV, hepatitis C, and B virus. However, for agents that cause acute infections or during the acute stage of agents that cause chronic infections, viral load data are often collected after symptoms develop, usually around or after the peak viral load. Consequently, we frequently lack data in the initial phase of viral growth, i.e., when pre-symptomatic transmission events occur. Missing data may make estimating the time of infection, the infectious period, and parameters in viral dynamic models, such as the cell infection rate, difficult. However, having extra information, such as the average time to peak viral load, may improve the robustness of the estimation. Here, we evaluated the robustness of estimates of key model parameters when viral load data prior to the viral load peak is missing, when we know the values of some parameters and/or the time from infection to peak viral load. Although estimates of the time of infection are sensitive to the quality and amount of available data, particularly pre-peak, other parameters important in understanding disease pathogenesis, such as the loss rate of infected cells, are less sensitive. Viral infectivity and the viral production rate are key parameters affecting the robustness of data fits. Fixing their values to literature values can help estimate the remaining model parameters when pre-peak data is missing or limited. We find a lack of data in the pre-peak growth phase underestimates the time to peak viral load by several days, leading to a shorter predicted growth phase. On the other hand, knowing the time of infection (e.g., from epidemiological data) and fixing it results in good estimates of dynamical parameters even in the absence of early data. While we provide ways to approximate model parameters in the absence of early viral load data, our results also suggest that these data, when available, are needed to estimate model parameters more precisely.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Mathematical modeling of plus-strand RNA virus replication to identify broad-spectrum antiviral treatment strategies

Plus-strand RNA viruses are the largest group of viruses. Many are human pathogens that inflict a socio-economic burden. Interestingly, plus-strand RNA viruses share remarkable similarities in their replication. A hallmark of plus-strand RNA viruses is the remodeling of intracellular membranes to establish replication organelles (so-called “replication factories”), which provide a protected environment for the replicase complex, consisting of the viral genome and proteins necessary for viral RNA synthesis. In the current study, we investigate pan-viral similarities and virus-specific differences in the life cycle of this highly relevant group of viruses. We first measured the kinetics of viral RNA, viral protein, and infectious virus particle production of hepatitis C virus (HCV), dengue virus (DENV), and coxsackievirus B3 (CVB3) in the immuno-compromised Huh7 cell line and thus without perturbations by an intrinsic immune response. Based on these measurements, we developed a detailed mathematical model of the replication of HCV, DENV, and CVB3 and showed that only small virus-specific changes in the model were necessary to describe the in vitro dynamics of the different viruses. Our model correctly predicted virus-specific mechanisms such as host cell translation shut off and different kinetics of replication organelles. Further, our model suggests that the ability to suppress or shut down host cell mRNA translation may be a key factor for in vitro replication efficiency, which may determine acute self-limited or chronic infection. We further analyzed potential broad-spectrum antiviral treatment options in silico and found that targeting viral RNA translation, such as polyprotein cleavage and viral RNA synthesis, may be the most promising drug targets for all plus-strand RNA viruses. Moreover, we found that targeting only the formation of replicase complexes did not stop the in vitro viral replication early in infection, while inhibiting intracellular trafficking processes may even lead to amplified viral growth.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Antiviral and clinical activity of bamlanivimab in a randomized trial of non-hospitalized adults with COVID-19

Abstract Anti-SARS-CoV-2 monoclonal antibodies are mainstay COVID-19 therapeutics. Safety, antiviral, and clinical efficacy of bamlanivimab were evaluated in the randomized controlled trial ACTIV-2/A5401. Non-hospitalized adults were randomized 1:1 within 10 days of COVID-19 symptoms to bamlanivimab or blinded-placebo in two dose-cohorts (7000 mg, n = 94; 700 mg, n = 223). No differences in bamlanivimab vs placebo were observed in the primary outcomes: proportion with undetectable nasopharyngeal SARS-CoV-2 RNA at days 3, 7, 14, 21, and 28 (risk ratio = 0.82–1.05 for 7000 mg [ p (overall) = 0.88] and 0.81–1.21 for 700 mg [ p (overall) = 0.49]), time to symptom improvement (median 21 vs 18.5 days [ p = 0.97], 7000 mg; 24 vs 20.5 days [ p = 0.08], 700 mg), or grade 3+ adverse events. However, bamlanivimab was associated with lower day 3 nasopharyngeal viral levels and faster reductions in inflammatory markers and viral decay by modeling. This study provides evidence of faster reductions in nasopharyngeal SARS-CoV-2 RNA levels but not shorter symptom durations in non-hospitalized adults with early variants of SARS-CoV-2. Trial Registration: ClinicalTrials.gov Identifier: NCT04518410.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

A participant-derived xenograft model of HIV enables long-term evaluation of autologous immunotherapies

HIV-specific CD8+ T cells partially control viral replication and delay disease progression, but they rarely provide lasting protection, largely due to immune escape. Here, we show that engrafting mice with memory CD4+ T cells from HIV+ donors uniquely allows for the in vivo evaluation of autologous T cell responses while avoiding graft-versus-host disease and the need for human fetal tissues that limit other models. Treating HIV-infected mice with clinically relevant HIV-specific T cell products resulted in substantial reductions in viremia. In vivo activity was significantly enhanced when T cells were engineered with surface-conjugated nanogels carrying an IL-15 superagonist, but it was ultimately limited by the pervasive selection of a diverse array of escape mutations, recapitulating patterns seen in humans. By applying mathematical modeling, we show that the kinetics of the CD8+ T cell response have a profound impact on the emergence and persistence of escape mutations. This “participant-derived xenograft” model of HIV provides a powerful tool for studying HIV-specific immunological responses and facilitating the development of effective cell-based therapies.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

CD8 Lymphocyte Depletion Enhances the Latency Reversal Activity of the SMAC Mimetic AZD5582 in ART-Suppressed Simian Immunodeficiency Virus-Infected Rhesus Macaques

ABSTRACT Inducing latency reversal to reveal infected cells to the host immune system represents a potential strategy to cure human immunodeficiency virus (HIV) infection. In separate studies, we have shown previously that CD8 + T cells may contribute to the maintenance of viral latency and have identified a novel SMAC (second mitochondrial activator of caspases) mimetic/IAP (inhibitor of apoptosis protein) inhibitor (AZD5582) capable of reversing HIV/simian immunodeficiency virus (SIV) latency in vivo by activating the noncanonical (nc) NF-κB pathway. Here, we use AZD5582 in combination with antibody (Ab)-mediated depletion of CD8α + cells to further evaluate the role of CD8 + T cells in the maintenance of viral latency. Six rhesus macaques (RMs) were infected with SIV mac239 and treated with antiretroviral therapy (ART) starting at week 8 postinfection. After 84 to 85 weeks of ART, all animals received a single dose of the anti-CD8α depleting Ab MT807R1 (50 mg/kg of body weight, administered subcutaneously [s.c.]), followed by five weekly doses of AZD5582 (0.1 mg/kg, administered intravenously [i.v.]). Following combined treatment with CD8α depletion and AZD5582, 100% of RMs experienced on-ART viremia levels above 60 copies per ml of plasma. In comparator groups of SIV-infected, ART-suppressed RMs treated with AZD5582 only or CD8α depletion only, on-ART viremia was experienced by 56% and 57% of the animals, respectively. Furthermore, the increased frequency of viremic episodes during the treatment period was greater in the group treated with CD8α depletion plus AZD5582 than in the other groups. Mathematical modeling of virus reactivation suggested that in addition to viral dynamics during acute infection, CD8α depletion influenced the response to AZD5582. This work suggests that the latency reversal induced by activation of the ncNF-κB signaling pathway with AZD5582 can be enhanced by CD8α + cell depletion. IMPORTANCE A favored approach to curing HIV infection aims at inducing viral expression using latency-reversing agents (LRAs) to allow the elimination of infected cells. Here, we tested a combination of two recently identified LRAs, the SMAC mimetic/IAP inhibitor AZD5582, which activates the noncanonical NF-κB pathway, and the antibody (Ab) MT807R1, which depletes CD8α + cells, in SIV-infected rhesus macaques (RMs) on ART. Latency reversal, as defined by increased on-ART viremia, was observed in all six SIV-infected, ART-treated RMs that received this combined treatment. Furthermore, comparison of viral reactivation between these animals and groups of SIV-infected, ART-treated RMs treated with AZD5582 only or CD8α + cell depletion only showed more frequent increases in viremic episodes when the two treatments were combined. This study provides additional evidence that CD8 + T cells may contribute to the maintenance of HIV/SIV latency on ART and potentially inhibit latency reversal during HIV cure approaches.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Suppression of hepatitis B virus through therapeutic activation of RIG-I and IRF3 signaling in hepatocytes

Hepatitis B virus (HBV) mediates persistent infection, chronic hepatitis, and liver disease. HBV covalently closed circular (ccc)DNA is central to viral persistence such that its elimination is considered the cornerstone for HBV cure. Inefficient detection by pathogen recognition receptors (PRRs) in the infected hepatocyte facilitates HBV persistence via avoidance of innate immune activation and interferon regulatory factor (IRF)3 induction of antiviral gene expression. We evaluated a small molecule compound, F7, and 5'-triphosphate-poly-U/UC pathogen-associated-molecular-pattern (PAMP) RNA agonists of RIG-I, a PRR that signals innate immunity, for ability to suppress cccDNA. F7 and poly-U/UC PAMP treatment of HBV-infected cells induced RIG-I signaling of IRF3 activation to induce antiviral genes for suppression of cccDNA formation and accelerated decay of established cccDNA, and were additive to the actions of entecavir. Our study shows that activation of the RIG-I pathway and IRF3 to induce innate immune actions offers therapeutic benefit toward elimination of cccDNA.

60 APPLIED LIFE SCIENCES↗