title: Standardized assessment of NAb responses elicited in rhesus monkeys immunized with single- or multi-clade HIV-1 envelope immunogens.
abstract: The genetic diversity of HIV-1 envelope glycoproteins (Env) remains a major obstacle to the development of an antibody-based AIDS vaccine. The present studies examine the breadth and magnitude of neutralizing antibody (NAb) responses in rhesus monkeys after immunization with DNA prime-recombinant adenovirus (rAd) boost vaccines encoding either single or multiple genetically distant Env immunogens, and subsequently challenged with a pathogenic simian-human immunodeficiency virus (SHIV-89.6P). Using a standardized multi-tier panel of reference Env pseudoviruses for NAb assessment, we show that monkeys immunized with a mixture of Env immunogens (clades A, B, and C) exhibited a greater breadth of NAb activity against neutralization-sensitive Tier 1 viruses following both vaccination and challenge compared to monkeys immunized with a single Env immunogen (clade B or C). However, all groups of Env-vaccinated monkeys demonstrated only limited neutralizing activity against Tier 2 pseudoviruses, which are more characteristic of the neutralization sensitivity of circulating HIV-1. Notably, the development of a post-challenge NAb response against SHIV-89.6P was similar in monkeys receiving either clade B, clade C, or clade A+B+C Env immunogens, suggesting cross-clade priming of NAb responses. In addition, vaccines encoding Env immunogens heterologous to SHIV-89.6P primed for a rapid anamnestic NAb response following infection compared to vaccines lacking an Env component. These results show that DNA/rAd immunization with multiple diverse Env immunogens is a viable approach for enhancing the breadth of NAb responses against HIV-1, and suggest that Env immunogens can prime for anamnestic NAb responses against a heterologous challenge virus.
authors.affiliation: Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, 330 Brookline Ave/RE-204, Boston, MA 02215, USA. mseaman@bidmc.harvard.edu
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Leblanc
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Grandpre
authors.forename: Melissa T
authors.initials: MT
authors.lastname: Bartman
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage* / Q000276:immunology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015686:Gene Products, env / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D015483:HIV Antibodies / Q000097:blood*; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D006801:Humans; D007114:Immunization; D007117:Immunization, Secondary; D008253:Macaca mulatta; D009500:Neutralization Tests / Q000592:standards*; D011995:Recombination, Genetic; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000145:classification / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*
chemical_list: D016915:AIDS Vaccines; D015686:Gene Products, env; D015483:HIV Antibodies