title: Germline-targeting immunogens.
abstract: In 2009, Dimitrov's group reported that the inferred germline (iGL) forms of several HIV-1 broadly neutralizing antibodies (bNAbs) did not display measurable binding to a recombinant gp140 Env protein (derived from the dual-tropic 89.6 virus), which was efficiently recognized by the mature (somatically mutated) antibodies. At that time, a small number of bNAbs were available, but in the following years, the implementation of high-throughput B-cell isolation and sequencing assays and of screening methodologies facilitated the isolation of greater numbers of bNAbs from infected subjects. Using these newest bNAbs, and a wide range of diverse recombinant Envs, we and others confirmed the observations made by Dimitrov's group. The results from these studies created a paradigm shift in our collective thinking as to why recombinant Envs are ineffective in eliciting bNAbs and has led to the "germline-targeting" immunization approach. Here we discuss this approach in detail: what has been done so far, the advantages and limitations of the current germline-targeting immunogens and of the animal models used to test them, and we conclude with a few thoughts about future directions in this area of research.
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.|Department of Global Health, University of Washington, Seattle, WA, USA.
authors.forename: Leonidas
authors.initials: L
authors.lastname: Stamatatos
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Pancera
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: McGuire
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology* / Q000821:virology; D015483:HIV Antibodies / Q000378:metabolism*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D057166:High-Throughput Screening Assays; D006801:Humans; D011485:Protein Binding; D014611:Vaccination; D014759:Viral Envelope Proteins / Q000276:immunology*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D014759:Viral Envelope Proteins; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1
keywords: 
  HIV
  ; B-cell receptors; Env; germline antibodies; immunogens