Distinct, IgG1-driven antibody response landscapes demarcate individuals with broadly HIV-1 neutralizing activity. Journal of Experimental Medicine
Kadelka et al. aimed to define immune regulatory principles that underlie the link between the identified factors and broadly neutralizing antibodies (bnAb) evolution.
Building on the systematic survey of bnAb activity in 4,484 chronically HIV-1–infected individuals (“Swiss 4.5K Screen”), the authors established comprehensive antibody signatures based on IgG1, IgG2, and IgG3 activity to 13 HIV-1 antigens in the Swiss 4.5K Screen cohort. They showed that the same four parameters that were significantly linked with neutralization breadth, namely viral load, infection length, viral diversity, and ethnicity, also strongly influenced HIV-1– binding antibody responses. However, the effects proved selective, shaping binding antibody responses in an antigen and IgG subclass–dependent manner. IgG response landscapes in bnAb inducers indicated a differentially regulated, IgG1-driven HIV-1 antigen response, and IgG1 binding of the BG505 SOS IP trimer proved the best predictor of HIV-1 neutralization breadth in plasma.
In conclusion, the IgG1-driven landscape of HIV specific responses in potent neutralizers identified in this study unveils the need of creating a specific immune regulatory environment for the development of neutralization breadth. Deciphering the basis of these regulatory shifts will be important to determine the triggers of this bnAb-favoring environment in forthcoming HIV pathogenicity studies and vaccine trials and to explore how this environment can be induced and maintained in healthy individuals to make bnAb-based vaccines possible.