Anti-V2 antibodies virus vulnerability revealed by envelope V1 deletion in HIV vaccine candidates

Abstract

Summary The efficacy of ALVAC-based HIV and SIV vaccines in humans and macaques correlates with antibodies to envelope variable region 2 (V2). We show here that vaccine-induced antibodies to SIV variable region 1 (V1) inhibit anti-V2 antibody-mediated cytotoxicity and reverse their ability to block V2 peptide interaction with the α 4 β 7 integrin. SIV vaccines engineered to delete V1 and favor an α helix, rather than a β sheet V2 conformation, induced V2-specific ADCC correlating with decreased risk of SIV acquisition. Removal of V1 from the HIV-1 clade A/E A244 envelope resulted in decreased binding to antibodies recognizing V2 in the β sheet conformation. Thus, deletion of V1 in HIV envelope immunogens may improve antibody responses to V2 virus vulnerability sites and increase the efficacy of HIV vaccine candidates.

A Remarkable Genetic Shift in a Transmitted/Founder Virus Broadens Antibody Responses Against HIV-1

“…The greater breadth and cross-reactive responses resulted from the Y173-∆V1 library was most likely due to reducing the immunodominance of V1 epitopes as well as generation of breadth favoring conformational variants generated by Y173 switch. Consistent with these data is the recent report that showed that the responses directed to V1 loop interferes with binding of protective V2directed antibodies to Env and promotes virus acquisition in SIV vaccinated macaques (53). On the other hand, the H173 combinatorial libraries induced antibodies similar to CH58 mAb as shown by the CH58 blocking data.…”

“…For this library, we used the Y173 template in which a 15-amino acid residue mutational hotspot in the V1 loop (SNITVERNITIANDTYD) was replaced with a flexible linker (AGGAS) optimized through in silico structural modeling such that it will have minimal impact on the V1V2 backbone conformation. This Y173.ΔV1 library is also supposed to eliminate certain immunodominant residues in the V1 loop and enhance V2-directed antibody responses (53). These four combinatorial libraries plus the two original H173 and Y173 V2 immunogens as controls, were all expressed as gp16 nanoscaffolds in GnTi cells, and the recombinant proteins were purified.…”

“…Three of these are in the background of H173, Y173, and Y173.∆DSV templates. The fourth library has a V1 loop deletion as this deletion has previously been shown to modulate the immunogenicity of the Env protein and the subsequent antibody responses (51)(52)(53). For this library, we used the Y173 template in which a 15-amino acid residue mutational hotspot in the V1 loop (SNITVERNITIANDTYD) was replaced with a flexible linker (AGGAS) optimized through in silico structural modeling such that it will have minimal impact on the V1V2 backbone conformation.…”

“…The rationale behind choosing naturally selected mutations is not only to represent diverse HIV strains but to also ensure the structural and functional integrity of the V1V2 domain, thereby presenting only the most relevant epitope diversity to the immune system.Three different combinatorial gp16-V1V2 nanoscaffold libraries were constructed in the background of H173, Y173, and Y173.∆DSV templates. Deletion of V1 or V2 loop has previously been shown to modulate immunogenicity of the Env protein and subsequent antibody responses(40)(41)(42). Hence, we constructed a fourth library using Y173 template in which a 15-amino acid residue mutational hotspot in the V1 loop (SNITVERNITIANDTYD) was replaced with a flexible linker (AGGAS), the length of which was optimized through insilico structural modeling to have a minimal effect on the V1V2 backbone conformation.…”

Differential V2-directed Antibody Responses in Non-human Primates Infected with SHIVs or Immunized with Diverse HIV Vaccines

“…These include quaternary epitopes targeted by such Abs as PG9 and PGT145 (reviewed in 68 ), as well as epitopes that are not dependent on the trimeric structure of Env, such as those targeted by V2i mAbs such as 2158 and 697, and by V2p mAbs such as CH58 and CAP228-19F 15,19,20,69 . Data support the hypothesis that Abs directed at the V1V2 domain of gp120 contributed to a reduced risk of HIV infection in humans 2, 3, 4, 5, 70 , and similarly have been implicated in the reduction and control of infection of NHPs with SIV 69,71,72,73,74,75,76,77 . Additional studies in macaques infected with various strains of SHIV also appear to support this hypothesis but are not de nitive 53,78,8 ).…”