title: R5 clade C SHIV strains with tier 1 or 2 neutralization sensitivity: tools to dissect env evolution and to develop AIDS vaccines in primate models.
abstract: BACKGROUND
  HIV-1 clade C (HIV-C) predominates worldwide, and anti-HIV-C vaccines are urgently needed. Neutralizing antibody (nAb) responses are considered important but have proved difficult to elicit. Although some current immunogens elicit antibodies that neutralize highly neutralization-sensitive (tier 1) HIV strains, most circulating HIVs exhibiting a less sensitive (tier 2) phenotype are not neutralized. Thus, both tier 1 and 2 viruses are needed for vaccine discovery in nonhuman primate models.
  
  
  RESULTS
  We constructed a tier 1 simian-human immunodeficiency virus, SHIV-1157ipEL, by inserting an "early," recently transmitted HIV-C env into the SHIV-1157ipd3N4 backbone [1] encoding a "late" form of the same env, which had evolved in a SHIV-infected rhesus monkey (RM) with AIDS. SHIV-1157ipEL was rapidly passaged to yield SHIV-1157ipEL-p, which remained exclusively R5-tropic and had a tier 1 phenotype, in contrast to "late" SHIV-1157ipd3N4 (tier 2). After 5 weekly low-dose intrarectal exposures, SHIV-1157ipEL-p systemically infected 16 out of 17 RM with high peak viral RNA loads and depleted gut CD4+ T cells. SHIV-1157ipEL-p and SHIV-1157ipd3N4 env genes diverge mostly in V1/V2. Molecular modeling revealed a possible mechanism for the increased neutralization resistance of SHIV-1157ipd3N4 Env: V2 loops hindering access to the CD4 binding site, shown experimentally with nAb b12. Similar mutations have been linked to decreased neutralization sensitivity in HIV-C strains isolated from humans over time, indicating parallel HIV-C Env evolution in humans and RM.
  
  
  CONCLUSIONS
  SHIV-1157ipEL-p, the first tier 1 R5 clade C SHIV, and SHIV-1157ipd3N4, its tier 2 counterpart, represent biologically relevant tools for anti-HIV-C vaccine development in primates.
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Nagadenahalli B
authors.initials: NB
authors.lastname: Siddappa
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Watkins
authors.forename: Klemens J
authors.initials: KJ
authors.lastname: Wassermann
authors.forename: Ruijiang
authors.initials: R
authors.lastname: Song
authors.forename: Wendy
authors.initials: W
authors.lastname: Wang
authors.forename: Victor G
authors.initials: VG
authors.lastname: Kramer
authors.forename: Samir
authors.initials: S
authors.lastname: Lakhashe
authors.forename: Michael
authors.initials: M
authors.lastname: Santosuosso
authors.forename: Mark C
authors.initials: MC
authors.lastname: Poznansky
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Novembre
authors.forename: François
authors.initials: F
authors.lastname: Villinger
authors.forename: James G
authors.initials: JG
authors.lastname: Else
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.forename: Robert A
authors.initials: RA
authors.lastname: Rasmussen
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Ruprecht
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D004195:Disease Models, Animal; D019143:Evolution, Molecular; D015752:Genes, env / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016133:Polymerase Chain Reaction
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing