Influence of the broadly neutralizing antibody VRC01 on HIV breakthrough virus populations in antibody-mediated prevention trials
Abstract
Abstract In the antibody mediated prevention (AMP) trials, the broadly neutralizing antibody (bNAb) VRC01 demonstrated protective efficacy against susceptible HIV strains. To understand how VRC01 shaped breakthrough infections, deep sequencing was performed on 172 participants (>100,000 gag-Δpol and rev-env-Δnef sequences), at diagnosis and over time, in the placebo and treatment arms of the African (HVTN703/HPTN081; NCT02568215) and Americas/Europe (HVTN704/HPTN085; NCT02716675) cohorts. A high frequency of multilineage infections was detected (38%), including co-infection with both VRC01 sensitive and resistant viruses. This high frequency is largely accounted for by low-abundance lineages. Although VRC01 does not significantly affect the genetic transmission bottleneck compared to placebo, higher VRC01 doses trend towards greater VRC01 neutralization differences among co-infecting lineages. Two-thirds of multilineage infections showed evidence of recombination at the diagnostic timepoint. In the treatment group there is evidence of recombinant viruses preferentially inheriting resistance-associated mutations. This study provides critical insights into viral genetic and antigenic diversity that needs to be targeted to achieve protection, and highlights the role of recombination in facilitating escape.
Article Details
Authors (49)
Carolyn Williamson
Chivonne Moodley
Craig A. Magaret
Elena E. Giorgi
Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Center
Morgane Rolland
U.S. Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research
Dylan H. Westfall
Infectious Disease Division, Fred Hutchinson Cancer Center
Anna Yssel
Wenjie Deng
Raabya Rossenkhan
Nonhlanhla N. Mkhize
Lennie Chen
Hong Zhao
Tanmoy Bhattacharya
Alec Pankow
Ben Murrell
Talita York
Asanda Gwashu-Nyangiwe
Nonkululeko Ndabambi
Ruwayhida Thebus
Paula Cohen
Bronwen Lambson
Haajira Kaldine
Sinethemba Bhebhe
Michal Juraska
Hongjun Bai
U.S. Military HIV Research Program, Center for Infectious Disease Research, Walter Reed Army Institute of Research
Allan C. deCamp
Maurine D. Miner
James Ludwig
Cindy Molitor
Nicolas Beaume
David Matten
Yunda Huang
Lily Zhang
Daniel B. Reeves
Bryan Mayer
Shelly T. Karuna
John A. Hural
Lynn Morris
David Montefiori
Roger E. Bumgarner
Penny L. Moore
Paul T. Edlefsen
Srilatha Edupuganti
Emory Vaccine Center, Emory University School of Medicine
Nyaradzo Mgodi
M. Juliana McElrath
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center
Myron S. Cohen
Lawrence Corey
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center
Peter B. Gilbert
James I. Mullins