Title: Mechanistic basis of post-treatment control of SIV after anti-α4β7 antibody therapy

Abstract

Treating macaques with an anti-α4β7 antibody under the umbrella of combination antiretroviral therapy (cART) during early SIV infection can lead to viral remission, with viral loads maintained at < 50 SIV RNA copies/ml after removal of all treatment in a subset of animals. Depletion of CD8+ lymphocytes in controllers resulted in transient recrudescence of viremia, suggesting that the combination of cART and anti-α4β7 antibody treatment led to a state where ongoing immune responses kept the virus undetectable in the absence of treatment. A previous mathematical model of HIV infection and cART incorporates immune effector cell responses and exhibits the property of two different viral load set-points. While the lower set-point could correspond to the attainment of long-term viral remission, attaining the higher set-point may be the result of viral rebound. Here we expand that model to include possible mechanisms of action of an anti-α4β7 antibody operating in these treated animals. We show that the model can fit the longitudinal viral load data from both IgG control and anti-α4β7 antibody treated macaques, suggesting explanations for the viral control associated with cART and an anti-α4β7 antibody treatment. This effective perturbation to the virus-host interaction can also explain observations in other nonhuman primatemore » experiments in which cART and immunotherapy have led to post-treatment control or resetting of the viral load set-point. Interestingly, because the viral kinetics in the various treated animals differed—some animals exhibited large fluctuations in viral load after cART cessation—the model suggests that anti-α4β7 treatment could act by different primary mechanisms in different animals and still lead to post-treatment viral control. This outcome is nonetheless in accordance with a model with two stable viral load set-points, in which therapy can perturb the system from one set-point to a lower one through different biological mechanisms.« less

Authors:

Wells, Chad R.  ^[1];

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• Search DOE PAGES for ORCID "0000-0003-1370-8350"

Cao, Youfang  ^[2];

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• Search DOE PAGES for ORCID "0000-0002-5880-0006"

Durham, David P.  ^[1];

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Byrareddy, Siddappa N.  ^[3];

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• Search DOE PAGES for ORCID "0000-0002-6889-4640"

Ansari, Aftab A. ^[4]; Ruddle, Nancy H. ^[1]; Townsend, Jeffrey P.  ^[5];

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• Search DOE PAGES for ORCID "0000-0002-9890-3907"

Galvani, Alison P.  ^[6];

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• Search DOE PAGES for ORCID "0000-0002-2059-6716"

Perelson, Alan S.  ^[7]

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• Search DOE PAGES for ORCID "0000-0002-2455-0002"

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+ Show Author Affiliations

1. Yale School of Public Health, New Haven, CT (United States)
2. Merck & Co., Inc., Kenilworth, NJ (United States); Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
3. Univ. of Nebraska Medical Center, Omaha, NE (United States)
4. Amory Univ. School of Medicine, Atlanta, GA (United States)
5. Yale Univ., New Haven, CT (United States)
6. Yale School of Public Health, New Haven, CT (United States); Yale Univ., New Haven, CT (United States)
7. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

Publication Date:

Wed Jun 09 00:00:00 EDT 2021

Research Org.:

Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

Sponsoring Org.:

National Institutes of Health (NIH); USDOE

OSTI Identifier:

1828708

Report Number(s):

LA-UR-20-20333
Journal ID: ISSN 1553-7358

Grant/Contract Number:  

89233218CNA000001; R01-OD011095; R01-AI028433; P01-AI131365; R01-AI29745

Resource Type:

Accepted Manuscript

Journal Name:

PLoS Computational Biology (Online)

Additional Journal Information:

Journal Name: PLoS Computational Biology (Online); Journal Volume: 17; Journal Issue: 6; Journal ID: ISSN 1553-7358

Publisher:

Public Library of Science

Country of Publication:

United States

Language:

English

Subject:

60 APPLIED LIFE SCIENCES; HIV; Post treatment control; viral kinetic model; Effector cell response; Latent reservoir