title: Motif-optimized subtype A HIV envelope-based DNA vaccines rapidly elicit neutralizing antibodies when delivered sequentially.
abstract: HIV-1 infection results in the development of a diverging quasispecies unique to each infected individual. Envelope (Env)-specific neutralizing antibodies (NAbs) typically develop over months to years after infection and initially are limited to the infecting virus. In some subjects, antibody responses develop that neutralize heterologous isolates (HNAbs), a phenomenon termed broadening of the NAb response. Studies of co-crystalized antibodies and proteins have facilitated the identification of some targets of broadly neutralizing monoclonal antibodies (NmAbs) capable of neutralizing many or most heterologous viruses; however, the ontogeny of these antibodies in vivo remains elusive. We hypothesize that Env protein escape variants stimulate broad NAb development in vivo and could generate such NAbs when used as immunogens. Here we test this hypothesis in rabbits using HIV Env vaccines featuring: (1) use of individual quasispecies env variants derived from an HIV-1 subtype A-infected subject exhibiting high levels of NAbs within the first year of infection that increased and broadened with time; (2) motif optimization of envs to enhance in vivo expression of DNA formulated as vaccines; and (3) a combined DNA plus protein boosting regimen. Vaccines consisted of multiple env variants delivered sequentially and a simpler regimen that utilized only the least and most divergent clones. The simpler regimen was as effective as the more complex approach in generating modest HNAbs and was more efficient when modified, motif-optimized DNA was used in combination with trimeric gp140 protein. This is a rationally designed strategy that facilitates future vaccine design by addressing the difficult problem of generating HNAbs to HIV by empirically testing the immunogenicity of naturally occurring quasispecies env variants.
authors: Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97217, USA.
authors: Franco
authors: F
authors: Pissani
authors: Delphine C
authors: DC
authors: Malherbe
authors: Harlan
authors: H
authors: Robins
authors: Victor R
authors: VR
authors: DeFilippis
authors: Byung
authors: B
authors: Park
authors: George
authors: G
authors: Sellhorn
authors: Leonidas
authors: L
authors: Stamatatos
authors: Julie
authors: J
authors: Overbaugh
authors: Nancy L
authors: NL
authors: Haigwood
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing; D003198:Computer Simulation; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D007115:Immunization Schedule; D007117:Immunization, Secondary; D011817:Rabbits; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D019444:Vaccines, DNA; D054299:env Gene Products, Human Immunodeficiency Virus