Multiple recent studies have provided proof-of-concept that a ?functional cure? of HIV-1 infection, i.e. long-term control of HIV without continued treatment, is achievable. The VISCONTI study identified 14 HIV+ patients, who received antiretroviral treatment (ART) during primary HIV-1 infection, and maintained post-treatment control of their virus below the limit of detection for a median of 89 months after stopping therapy. Persaud et al. described a HIV-1 infected infant who started ART within 30 hours after birth, discontinued therapy at 18 months of age, then remained undetectable, off-therapy, for 27 months before the virus rebounded. A recent study showed that SIV-infected macaques on ART given an antibody (Ab) against the integrin ?4?7 could maintain undetectable plasma viremia for over 9 months after all treatment was stopped. Finally, treatment with broadly neutralizing Abs (bnAbs) in some macaques infected with SIV also led to virological control for an extended period even after completion of Ab treatment. To realize the promise of these advances, we need a better understanding of the factors that lead to establishment of undetectable or controlled viral loads in the absence of treatment. Here we propose to develop a set of new models to help understand how functional cure was obtained in the studies mentioned above and to understand more generally under what conditions and interventions functional cure can be achieved. To this end, we will collaborate with leading experimental scientists, who will provide novel datasets that will allow us to fulfil the following specific aims.
Aim 1. Determine the mechanisms of action of HIV-1 specific bnAbs in vivo. We will develop new models of antibody action, incorporating multiple biological functions, to explain experiments of bnAbs infusions in HIV-infected humans and SIV-infected macaques. These models will help determine the main mechanisms of action of bnAbs.
Aim 2. Determine whether treatment with monoclonal antibodies can lead to a change in viral load set-point. We will develop models with multiple stable steady states of viral load (high and low levels) driven by the interplay between immune responses and the establishment of the latent reservoir. These models will be calibrated by experimental data in humans and in the macaque model of SIV and will provide a mechanistic picture of the effects of these antibodies.
Aim 3. Determine the within host dynamics of Zika virus infection and predict the effects of therapy. We will leverage the work in the previous aims to develop models for this emerging infection and study the effects of different therapies, including antibodies, in controlling Zika virus.

Public Health Relevance

Even with better and simpler treatments, HIV-1 is still a life-long infection for millions of people. New research into the role of broadly neutralizing antibodies and potential for a functional cure could change that. Here we will study multiple datasets and develop mechanistic models to understand different interventions aimed at lowering viral load and viral reservoirs throughout the body, which possibly can be sustained in the absence of therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028433-30
Application #
9979727
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Gezmu, Misrak
Project Start
1990-07-01
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
30
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Triad National Security, LLC
Department
Type
DUNS #
080961356
City
Los Alamos
State
NM
Country
United States
Zip Code
87545
Cao, Youfang; Lei, Xue; Ribeiro, Ruy M et al. (2018) Probabilistic control of HIV latency and transactivation by the Tat gene circuit. Proc Natl Acad Sci U S A 115:12453-12458
Goyal, Ashish; Romero-Severson, Ethan Obie (2018) Screening for hepatitis D and PEG-Interferon over Tenofovir enhance general hepatitis control efforts in Brazil. PLoS One 13:e0203831
Ishida, Yuji; Chung, Tje Lin; Imamura, Michio et al. (2018) Acute hepatitis B virus infection in humanized chimeric mice has multiphasic viral kinetics. Hepatology 68:473-484
Canini, Laetitia; Lemenuel-Diot, Annabelle; Brennan, Barbara J et al. (2018) A pharmacokinetic/viral kinetic model to evaluate treatment of chronic HCV infection with a non-nucleoside polymerase inhibitor. Antivir Ther 23:353-361
Best, Katharine; Perelson, Alan S (2018) Mathematical modeling of within-host Zika virus dynamics. Immunol Rev 285:81-96
Ke, Ruian; Li, Hui; Wang, Shuyi et al. (2018) Superinfection and cure of infected cells as mechanisms for hepatitis C virus adaptation and persistence. Proc Natl Acad Sci U S A 115:E7139-E7148
Ke, Ruian; Conway, Jessica M; Margolis, David M et al. (2018) Determinants of the efficacy of HIV latency-reversing agents and implications for drug and treatment design. JCI Insight 3:
Aunins, Thomas R; Marsh, Katherine A; Subramanya, Gitanjali et al. (2018) Intracellular Hepatitis C Virus Modeling Predicts Infection Dynamics and Viral Protein Mechanisms. J Virol 92:
Vaidya, Naveen K; Ribeiro, Ruy M; Liu, Pinghuang et al. (2018) Correlation Between Anti-gp41 Antibodies and Virus Infectivity Decay During Primary HIV-1 Infection. Front Microbiol 9:1326
Chang, Christina C; Naranbhai, Vivek; Stern, Jared et al. (2018) Variation in cell-associated unspliced HIV RNA on antiretroviral therapy is associated with the circadian regulator brain-and-muscle-ARNT-like-1. AIDS 32:2119-2128

Showing the most recent 10 out of 253 publications