title: Autologous neutralizing antibodies to the transmitted/founder viruses emerge late after simian immunodeficiency virus SIVmac251 infection of rhesus monkeys.
abstract: While the simian immunodeficiency virus (SIV)-infected rhesus monkey is an important animal model for human immunodeficiency virus type 1 (HIV-1) infection of humans, much remains to be learned about the evolution of the humoral immune response in this model. In HIV-1 infection, autologous neutralizing antibodies emerge 2 to 3 months after infection. However, the ontogeny of the SIV-specific neutralizing antibody response in mucosally infected animals has not been defined. We characterized the kinetics of the autologous neutralizing antibody response to the transmitted/founder SIVmac251 using a pseudovirion-based TZM-bl cell assay and monitored env sequence evolution using single-genome amplification in four rhesus animals that were infected via intrarectal inoculations. We show that the SIVmac251 founder viruses induced neutralizing antibodies at 5 to 8 months after infection. Despite their slow emergence and low titers, these neutralizing antibodies selected for escape mutants that harbored substitutions and deletions in variable region 1 (V1), V2, and V4 of Env. The neutralizing antibody response was initially focused on V4 at 5 to 8 months after infection and then targeted V1/V2 and V4 by 16 months. These findings reveal a striking delay in the development of neutralizing antibodies in SIVmac-infected animals, thus raising questions concerning the suitability of SIVmac251 as a challenge strain to screen AIDS vaccines that elicit neutralizing antibodies as a means to prevent virus acquisition. They also illustrate the capacity of the SIVmac quasispecies to modify antigenic determinants in response to very modest titers of neutralizing antibodies.
authors.affiliation: Division of Viral Pathogenesis, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Yeh
authors.forename: Ishita
authors.initials: I
authors.lastname: Rahman
authors.forename: Peter
authors.initials: P
authors.lastname: Hraber
authors.forename: Rory T
authors.initials: RT
authors.lastname: Coffey
authors.forename: Daiva
authors.initials: D
authors.lastname: Nevidomskyte
authors.forename: Ayush
authors.initials: A
authors.lastname: Giri
authors.forename: Mohammed
authors.initials: M
authors.lastname: Asmal
authors.forename: Svetlana
authors.initials: S
authors.lastname: Miljkovic
authors.forename: Marcus
authors.initials: M
authors.lastname: Daniels
authors.forename: James B
authors.initials: JB
authors.lastname: Whitney
authors.forename: Brandon F
authors.initials: BF
authors.lastname: Keele
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.forename: Bette T
authors.initials: BT
authors.lastname: Korber
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology*; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology*; D004195:Disease Models, Animal; D015658:HIV Infections / Q000097:blood / Q000145:classification / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D010802:Phylogeny; D016415:Sequence Alignment; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D014759:Viral Envelope Proteins