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174 The Broadly Cross-Reactive Primary Virus Neutralizing Antibody (Nab) Response Induced by R2 Envelope Mimics the Neutralizing Cross-Reactivity of Strain R2 and Reference Serum HNS2
M. Dong,* J. Lee, F. Grieder, P. F. Zhang, P. Valenti, and G. Quinnan
Uniformed Services Univ. of the Hlth. Sci., Bethesda, MD, USA
Background: The envelope clone R2 was obtained from the donor of the reference human serum, HNS2, which displays broadly cross-reactive, HIV-1 primary virus neutralizing activity. The cross-reactivity is greater among clades A, B, C, and F than among clades D and E. The R2 envelope is neutralized cross-reactively by sera from people infected with clade A, B, and C strains of HIV, and to a lesser extent by sera from people infected with clade D and E strains. Because the serum and envelope cross-reactivity profiles are similar, the envelope may display epitopes responsible for induction of the cross-reactive Nab found in HNS2.
Methods: The R2 env gene has been expressed using a Venezuelan equine encephalitis virus replicon system (VEE). Protein expression and immunogenicity in mice and rabbits have been characterized.
Results: Relative in vitro expression levels of gp160, gp140, and gp160DCT (cytoplasmic tail deleted) were approximately 1:10:2. The gp160 was membrane associated, gp140 was >50% secreted, and gp140 DCT was released from cells anchored in membrane-bound vesicles. Relative ELISA and neutralizing antibody responses of C3H mice to VEE-R2env immunization were approximately 1:1:10, for gp160, gp140, and gp140-TM, respectively, with the gp140-TM response also occurring earlier. The rate and magnitude of the Nab response was also substantially influenced by the sequences of the VEE envelope protein used for packaging replicon particles. The Nab induced were cross-reactive among clade B and C, but not clade E strains of HIV-1. The titers of Nab induced in mice against various HIV-1 strains correlated significantly with titers against the same strains found in human sera.
Conclusions: In vivo expression of appropriately selected HIV env gene using this high-efficiency expression system can result in potent, HIV-1 primary virus neutralizing antibody responses.
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