Rajat Desikan, Rubesh Raja, Narendra M. Dixit
Abstract
Antiretroviral therapy (ART) for HIV-1 infection is life-long. Stopping therapy typically leads to the reignition of infection and progressive disease. In a major breakthrough, recent studies have shown that early initiation of ART can lead to sustained post-treatment control of viremia, raising hopes of long-term HIV-1 remission. ART, however, elicits post-treatment control in a small fraction of individuals treated. Strikingly, passive immunization with broadly neutralizing antibodies (bNAbs) of HIV-1 early in infection was found recently to elicit long-term control in a majority of SHIV-infected macaques, suggesting that HIV-1 remission may be more widely achievable. The mechanisms underlying the control elicited by bNAb therapy, however, remain unclear. Untreated infection typically leads to progressive disease. We hypothesized that viremic control represents an alternative but rarely realized outcome of the infection and that early bNAb therapy triggers a dynamical switch to this outcome. To test this hypothesis, we constructed a model of viral dynamics with bNAb therapy and applied it to analyse clinical data. The model fit quantitatively the complex longitudinal viral load data from macaques that achieved lasting control. The model predicted, consistently with our hypothesis, that the underlying system exhibited bistability, indicating two potential outcomes of infection. The first had high viremia, weak cytotoxic effector responses, and high effector exhaustion, marking progressive disease. The second had low viremia, strong effector responses, and low effector exhaustion, indicating lasting viremic control. Further, model predictions suggest that early bNAb therapy elicited lasting control via pleiotropic effects. bNAb therapy lowers viremia, which would also limit immune exhaustion. Simultaneously, it can improve effector stimulation via cross-presentation. Consequently, viremia may resurge post-therapy, but would encounter a primed effector population and eventually get controlled. ART suppresses viremia but does not enhance effector stimulation, explaining its limited ability to elicit post-treatment control relative to bNAb therapy.
Introduction
Current antiretroviral therapies (ART) for HIV-1 infection control viremia in infected individuals but are unable to eradicate the virus [1]. A reservoir of latently infected cells, which is established soon after infection [2], escapes drugs and the host immune response [3], is long-lived [4, 5], and can reignite infection following the cessation of therapy [6], presents the key obstacle to sterilizing cure. Efforts are now aimed at eliciting a “functional cure” of the infection, where the virus can be controlled without life-long treatment even though eradication is not possible [7]. That functional cure can be achieved has been demonstrated by the VISCONTI trial, where a subset of patients, following early initiation of ART, maintained undetectable viremia long after the cessation of treatment [8]. A limitation, however, is that the subset that achieves post-treatment control with ART is small, 5-15% of the patients treated [9]. In a major advance, Nishimura et al. [10] found recently that early, short-term passive immunization with a combination of two HIV-1 broadly neutralizing antibodies (bNAbs) elicited lasting control of viremia in 10 of 13, or nearly 77%, of SHIV-infected macaques treated. This high success rate raises the prospect of achieving functional cure in all HIV-1 infected individuals using short-term bNAb therapy. Efforts have been initiated to develop immunotherapies that may further improve response rates in primate models [11–14] and to translate them to humans [15–17].
Methods
We first present the model (Fig 1) that best fit the in vivo macaque data (Figs 2–4). We next describe its solution procedure, data fitting and parameter estimation. At the end, we outline the rational strategy that we employed to arrive at the model by gradually adding complexity to the basic model of viral dyanmics and assessing the resulting model at each stage.
Discussion
The recent success of passive immunization with bNAbs in eliciting functional cure of HIV-1 infection can potentially revolutionize HIV-1 care [10–17]. In this study, using mathematical modelling and analysis of in vivo data, we present a dynamical systems view of the infection that offers an explanation of how early exposure to bNAbs induces lasting viremic control and does so better than ART.
Citation: Desikan R, Raja R, Dixit NM (2020) Early exposure to broadly neutralizing antibodies may trigger a dynamical switch from progressive disease to lasting control of SHIV infection. PLoS Comput Biol 16(8): e1008064. https://doi.org/10.1371/journal.pcbi.1008064
Editor: Andrew J. Yates, Columbia University Medical Center, UNITED STATES
Received: January 22, 2020; Accepted: June 17, 2020; Published: August 20, 2020
Copyright: © 2020 Desikan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: This work was supported by the DBT/Wellcome Trust India Alliance Senior Fellowship IA/S/14/1/501307 (NMD) (https://www.indiaalliance.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
