Influence of the broadly neutralizing antibody VRC01 on HIV breakthrough virus populations in antibody-mediated prevention trials

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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.
Funding Information
  • National Institute of Allergy and Infectious Diseases (UM1 AI068614)
  • National Institute of Allergy and Infectious Diseases (UM1 AI068635)
  • National Institute of Allergy and Infectious Diseases (UM1 AI068618)
  • National Institute of Allergy and Infectious Diseases (UM1 AI068619)
  • National Institute of Allergy and Infectious Diseases (UM1 AI068613)
  • National Institute of Allergy and Infectious Diseases (UM1 AI068617)
  • National Institute of Allergy and Infectious Diseases (R01 AI152115)
  • National Institute of Allergy and Infectious Diseases (K25 AI155224, R01 AI186721-01)
  • National Institute of Allergy and Infectious Diseases (R01 AI157854)
  • Bill and Melinda Gates Foundation (1032144, INV-016189)
  • Vetenskapsrådet (2018-02381)

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