title: Viral escape from HIV-1 neutralizing antibodies drives increased plasma neutralization breadth through sequential recognition of multiple epitopes and immunotypes.
abstract: Identifying the targets of broadly neutralizing antibodies to HIV-1 and understanding how these antibodies develop remain important goals in the quest to rationally develop an HIV-1 vaccine. We previously identified a participant in the CAPRISA Acute Infection Cohort (CAP257) whose plasma neutralized 84% of heterologous viruses. In this study we showed that breadth in CAP257 was largely due to the sequential, transient appearance of three distinct broadly neutralizing antibody specificities spanning the first 4.5 years of infection. The first specificity targeted an epitope in the V2 region of gp120 that was also recognized by strain-specific antibodies 7 weeks earlier. Specificity for the autologous virus was determined largely by a rare N167 antigenic variant of V2, with viral escape to the more common D167 immunotype coinciding with the development of the first wave of broadly neutralizing antibodies. Escape from these broadly neutralizing V2 antibodies through deletion of the glycan at N160 was associated with exposure of an epitope in the CD4 binding site that became the target for a second wave of broadly neutralizing antibodies. Neutralization by these CD4 binding site antibodies was almost entirely dependent on the glycan at position N276. Early viral escape mutations in the CD4 binding site drove an increase in wave two neutralization breadth, as this second wave of heterologous neutralization matured to recognize multiple immunotypes within this site. The third wave targeted a quaternary epitope that did not overlap any of the four known sites of vulnerability on the HIV-1 envelope and remains undefined. Altogether this study showed that the human immune system is capable of generating multiple broadly neutralizing antibodies in response to a constantly evolving viral population that exposes new targets as a consequence of escape from earlier neutralizing antibodies.
authors.affiliation: Centre for HIV and STIs, National Institute for Communicable Diseases (NICD), of the National Health Laboratory Service (NHLS), Johannesburg, South Africa ; Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Constantinos Kurt
authors.initials: CK
authors.lastname: Wibmer
authors.forename: Jinal N
authors.initials: JN
authors.lastname: Bhiman
authors.forename: Elin S
authors.initials: ES
authors.lastname: Gray
authors.forename: Nancy
authors.initials: N
authors.lastname: Tumba
authors.forename: Salim S
authors.initials: SS
authors.lastname: Abdool Karim
authors.forename: Carolyn
authors.initials: C
authors.lastname: Williamson
authors.forename: Lynn
authors.initials: L
authors.lastname: Morris
authors.forename: Penny L
authors.initials: PL
authors.lastname: Moore
mesh_terms: D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology*; D000918:Antibody Specificity; D015704:CD4 Antigens / Q000097:blood / Q000276:immunology; D015331:Cohort Studies; D000939:Epitopes / Q000097:blood / Q000276:immunology*; D005260:Female; D015483:HIV Antibodies / Q000097:blood / Q000276:immunology*; D015658:HIV Infections / Q000097:blood / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D057131:Immune Evasion
chemical_list: D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies