Preventing acquisition of HIV is the only path to an AIDS-free generation

Corey, Lawrence; Gray, Glenda

doi:10.1073/pnas.1703236114

Cited by 15 publications

(15 citation statements)

References 11 publications

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“…Interventions that prevent HIV acquisition embody a realistic route to reducing HIV-associated morbidity, mortality, and stigma around the world [1]. Current oral pre-exposure prophylaxis (PrEP) regimens use antiretroviral therapy (ART) to mediate excellent but shortlasting protection against HIV infection [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Mathematical modeling to reveal breakthrough mechanisms in the HIV Antibody Mediated Prevention (AMP) trials

et al. 2020

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The ongoing Antibody Mediated Prevention (AMP) trials will uncover whether passive infusion of the broadly neutralizing antibody (bNAb) VRC01 can protect against HIV acquisition. Previous statistical simulations indicate these trials may be partially protective. In that case, it will be crucial to identify the mechanism of breakthrough infections. To that end, we developed a mathematical modeling framework to simulate the AMP trials and infer the breakthrough mechanisms using measurable trial outcomes. This framework combines viral dynamics with antibody pharmacokinetics and pharmacodynamics, and will be generally applicable to forthcoming bNAb prevention trials. We fit our model to human viral load data (RV217). Then, we incorporated VRC01 neutralization using serum pharmacokinetics (HVTN 104) and in vitro pharmacodynamics (LANL CATNAP database). We systematically explored trial outcomes by reducing in vivo potency and varying the distribution of sensitivity to VRC01 in circulating strains. We found trial outcomes could be used in a clinical trial regression model (CTRM) to reveal whether partially protective trials were caused by large fractions of VRC01-resistant (IC50>50 μg/mL) circulating strains or rather a global reduction in VRC01 potency against all strains. The former mechanism suggests the need to enhance neutralizing antibody breadth; the latter suggests the need to enhance VRC01 delivery and/or in vivo binding. We will apply the clinical trial regression model to data from the completed trials to help optimize future approaches for passive delivery of anti-HIV neutralizing antibodies. PLOS Computational Biology | https://doi.org/10.1371/journal.pcbi.

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Section: Introductionmentioning

confidence: 99%

Mathematical modeling to reveal breakthrough mechanisms in the HIV Antibody Mediated Prevention (AMP) trials

et al. 2020

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“…Hence, the first functional proteins presumably originated from short polypeptides. However, since short polypeptide segments cannot function in the same way that globular proteins do, supramolecular self‐assemblies may have provided peptides with the operative volume and network of interactions that are necessary, particularly for enzymatic functions. The first self‐reproducing macromolecules are likely to have been ribonucleic acids (RNAs).…”

Section: Introductionmentioning

confidence: 99%

Functional Proteins from Short Peptides: Dayhoff's Hypothesis Turns 50

2016

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First and foremost: Margaret Dayhoff's 1966 hypothesis on the origin of proteins is now an accepted model for the emergence of large, globular, functional proteins from short, simple peptides. However, the fundamental question of how the first protein(s) emerged still stands. The tools and hypotheses pioneered by Dayhoff, and the over 65 million protein sequences and 12 000 structures known today, enable those who follow in her footsteps to address this question.

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“…This model revealed that, even with efficacy as low as 50%, a HIV vaccine would avert millions of new infections worldwide, irrespective of whether ambitious treatment goals are met. These results identify the synergies between vaccination and treatment-as-prevention, and provide evidence to support continued investment in vaccine development 9,32 .…”

Section: Box 1 | Modelling Infectious Disease Transmission For Evidenmentioning

confidence: 64%

“…Here, we highlight a series of models focused on one of the defining infectious agents of our era: HIV. The virus has challenged science, medicine and public health at every scale, from its deft immune evasion to its death toll of more than 35 million over the last four decades 9 . We describe how clinical needs, research questions and data availability have shaped the design of HIV models across these scales.…”

Section: Modelling Across Scalesmentioning

confidence: 99%