title: Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys.
abstract: The RV144 vaccine trial in Thailand demonstrated that an HIV vaccine could prevent infection in humans and highlights the importance of understanding protective immunity against HIV. We used a nonhuman primate model to define immune and genetic mechanisms of protection against mucosal infection by the simian immunodeficiency virus (SIV). A plasmid DNA prime/recombinant adenovirus serotype 5 (rAd5) boost vaccine regimen was evaluated for its ability to protect monkeys from infection by SIVmac251 or SIVsmE660 isolates after repeat intrarectal challenges. Although this prime-boost vaccine regimen failed to protect against SIVmac251 infection, 50% of vaccinated monkeys were protected from infection with SIVsmE660. Among SIVsmE660-infected animals, there was about a one-log reduction in peak plasma virus RNA in monkeys expressing the major histocompatibility complex class I allele Mamu-A*01, implicating cytotoxic T lymphocytes in the control of SIV replication once infection is established. Among Mamu-A*01-negative monkeys challenged with SIVsmE660, no CD8(+) T cell response or innate immune response was associated with protection against virus acquisition. However, low levels of neutralizing antibodies and an envelope-specific CD4(+) T cell response were associated with vaccine protection in these monkeys. Moreover, monkeys that expressed two TRIM5 alleles that restrict SIV replication were more likely to be protected from infection than monkeys that expressed at least one permissive TRIM5 allele. This study begins to elucidate the mechanisms of vaccine protection against immunodeficiency viruses and highlights the need to analyze these immune and genetic correlates of protection in future trials of HIV vaccine strategies.
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
authors.forename: Srinivas S
authors.initials: SS
authors.lastname: Rao
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.forename: Michael S
authors.initials: MS
authors.lastname: Seaman
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.forename: So-Yon
authors.initials: SY
authors.lastname: Lim
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Yeh
authors.forename: Mohammed
authors.initials: M
authors.lastname: Asmal
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Gelman
authors.forename: Ling
authors.initials: L
authors.lastname: Shen
authors.forename: James B
authors.initials: JB
authors.lastname: Whitney
authors.forename: Cathal
authors.initials: C
authors.lastname: Seoighe
authors.forename: Miguel
authors.initials: M
authors.lastname: Lacerda
authors.forename: Sheila
authors.initials: S
authors.lastname: Keating
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Norris
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hudgens
authors.forename: Peter B
authors.initials: PB
authors.lastname: Gilbert
authors.forename: Adam P
authors.initials: AP
authors.lastname: Buzby
authors.forename: Linh V
authors.initials: LV
authors.lastname: Mach
authors.forename: Jinrong
authors.initials: J
authors.lastname: Zhang
authors.forename: Harikrishnan
authors.initials: H
authors.lastname: Balachandran
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Schmidt
authors.forename: John-Paul
authors.initials: JP
authors.lastname: Todd
authors.forename: Alan
authors.initials: A
authors.lastname: Dodson
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Nabel
mesh_terms: D000483:Alleles; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D000882:Haplorhini; D006801:Humans; D009092:Mucous Membrane / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000472:pathogenicity*
chemical_list: D002352:Carrier Proteins