Characterizing the Relationship Between Neutralization Sensitivity and env Gene Diversity During ART Suppression

Frontiers in Immunology, Vol. 12 (2021)

Mots clés
Auteurs
  • Andrew Wilson
  • Lynch Lab, Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
  • Leyn Shakhtour
  • Lynch Lab, Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
  • Adam Ward
  • Jones Lab, Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, United States
  • Adam Ward
  • PhD Program in Epidemiology, The George Washington University Milken Institute School of Public Health, Washington, DC, United States
  • Yanqin Ren
  • Jones Lab, Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, United States
  • Melina Recarey
  • Lynch Lab, Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
  • Eva Stevenson
  • Jones Lab, Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, United States
  • Maria Korom
  • Lynch Lab, Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
  • Colin Kovacs
  • Department of Internal Medicine, Maple Leaf Medical Clinic, Toronto, ON, Canada
  • Erika Benko
  • Department of Internal Medicine, Maple Leaf Medical Clinic, Toronto, ON, Canada
  • R. Brad Jones
  • Jones Lab, Department of Medicine, Division of Infectious Diseases, Weill Cornell Medicine, New York, NY, United States
  • Rebecca M. Lynch
  • Lynch Lab, Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States

Résumé

Although antiretroviral therapy (ART) successfully suppresses HIV-1 replication, ART-treated individuals must maintain therapy to avoid rebound from an integrated viral reservoir. Strategies to limit or clear this reservoir are urgently needed. Individuals infected for longer periods prior to ART appear to harbor more genetically diverse virus, but the roles of duration of infection and viral diversity in the humoral immune response remain to be studied. We aim to clarify a role, if any, for autologous and heterologous antibodies in multi-pronged approaches to clearing infection. To that end, we have characterized the breadths and potencies of antibody responses in individuals with varying durations of infection and HIV-1 envelope (env) gene diversity as well as the sensitivity of their inducible virus reservoir to broadly neutralizing antibodies (bNAbs). Plasma was collected from 8 well-characterized HIV-1+ males on ART with varied durations of active infection. HIV envs from reservoir-derived outgrowth viruses were amplified and single genome sequenced in order to measure genetic diversity in each participant. IgG from plasma was analyzed for binding titers against gp41 and gp120 proteins, and for neutralizing titers against a global HIV-1 reference panel as well as autologous outgrowth viruses. The sensitivity to bNAbs of these same autologous viruses was measured. Overall, we observed that greater env diversity was associated with higher neutralizing titers against the global panel and also increased resistance to certain bNAbs. Despite the presence of robust anti-HIV-1 antibody titers, we did not observe potent neutralization against autologous viruses. In fact, 3 of 8 participants harbored viruses that were completely resistant to the highest tested concentration of autologous IgG. That this lack of neutralization was observed regardless of ART duration or viral diversity suggests that the inducible reservoir harbors ‘escaped’ viruses (that co-evolved with autologous antibody responses), rather than proviruses archived from earlier in infection. Finally, we observed that viruses resistant to autologous neutralization remained sensitive to bNAbs, especially CD4bs and MPER bNAbs. Overall, our data suggest that the inducible reservoir is relatively resistant to autologous antibodies and that individuals with limited virus variation in the env gene, such as those who start ART early in infection, are more likely to be sensitive to bNAb treatment.

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