부산대학교 도서관

Transmitted/founder (T/F) HIV-1 envelope proteins (Envs) from infected individuals that developed neutralization breadth are likely to possess inherent features desirable for vaccine immunogen design. To explore this premise, we conducted an immunization study in rhesus macaques (RM) using T/F Env sequences from two human subjects, one of which developed potent and broad neutralizing antibodies (Z1800M) while the other developed little to no neutralizing antibody responses (R66M) during HIV-1 infection. Using a DNA/MVA/protein immunization protocol, 10 RM were immunized with each T/F Env. Within each T/F Env group, the protein boosts were administered as either monomeric gp120 or stabilized trimeric gp140 protein. All vaccination regimens elicited high titers of antigen-specific IgG, and two animals that received monomeric Z1800M Env gp120 developed autologous neutralizing activity. Using early Env escape variants isolated from subject Z1800M as guides, the serum neutralizing activity of the two immunized RM was found to be dependent on the gp120 V5 region. Interestingly, the exact same residues of V5 were also targeted by a neutralizing monoclonal antibody (nmAb) isolated from the subject Z1800M early in infection. Glycan profiling and computational modeling of the Z1800M Env gp120 immunogen provided further evidence that the V5 loop is exposed in this T/F Env and was a dominant feature that drove neutralizing antibody targeting during infection and immunization. An expanded B cell clonotype was isolated from one of the neutralization-positive RM and nmAbs corresponding to this group demonstrated V5-dependent neutralization similar to both the RM serum and the human Z1800M nmAb. The results demonstrate that neutralizing antibody responses elicited by the Z1800M T/F Env in RM converged with those in the HIV-1 infected human subject, illustrating the potential of using immunogens based on this or other T/F Envs with well-defined immunogenicity as a starting point to drive breadth. Author summary: A subset of HIV-1 infected individuals generates antibodies that neutralize many different viral strains. However, this process requires years of infection and has proved difficult to achieve through vaccination. The envelope proteins of the infecting HIV-1 virus likely contain features that drive neutralization breadth within an individual. To explore this, we immunized rhesus macaques using envelope proteins from two HIV-1 infected human subjects that developed either high or low neutralizing antibody levels during infection. Several animals developed neutralizing antibodies when immunized with the envelope protein derived from the high neutralizing individual. Using viral escape variants that emerged in this infected individual over time, we mapped the targets of vaccine-elicited neutralizing antibodies to a distinct loop region of the envelope protein, which was also targeted by neutralizing monoclonal antibodies isolated from both the infected individual and the immunized rhesus macaques. Modeling of the envelope protein used in the vaccine demonstrated why this loop is vulnerable to antibody attack in infection and vaccination. By recapitulating the early HIV-1 human neutralizing antibody responses in a nonhuman primate immunization model, we demonstrate remarkable similarities as well as the potential of using this approach as a starting point to drive neutralizing antibody breadth, one of the ultimate goals of vaccine design. [ABSTRACT FROM AUTHOR]