The Human Immunodeficiency Virus (HIV) infection remains a major global health concern, with an estimated 37.7 million people living with the virus worldwide and new contaminations above a million cases yearly. Efficient anti-retroviral therapies are available, allowing a sustained relief for infected individuals. Combined with novel uses, these therapeutics allowed for better prevention and helped curb the epidemic in high-income countries. However, a vaccine is still highly awaited, notably in lower-income regions and precarious settings. The existence of broadly Neutralizing Antibodies (bNAbs) has been demonstrated and their protective role unequivocally assessed in both animal models and in human setting. A B-cell-based vaccine able to elicit such bNAbs could be foreseen as an answer to this pandemic.
We have performed a longitudinal study of the immune repertoire of an HIV-primo-infected elite-neutralizer to isolate novel bNAbs and decipher the genesis of large-breadth neutralization. The present study leverages the access to historic cohort samples with the combined use of scRNA-seq and bulk-NGS to enable high-throughput exploration of the immune repertoire and recovery of bNAbs. Isolated antibodies have been characterized for their neutralization abilities against large pseudoviruses panels.
The results presented in this work unveil novel neutralizing lineages targeting the Env glycoproteic trimer of the HIV, some of which aiming at the high-mannose patch supersite of vulnerability with consequent breadth and potency. Isolated bNAbs recapitulate the serum activity of the donor, and achieve neutralization against 62.4 % of a large predictive panel of pseudoviruses. Best neutralization is achieved with a potency of 4.2 ng.mL-1. Among recovered neutralizing lineages, mode of recognition of the Env trimer differed : some lineages are sensitive to the presence of a glycan in position N332, whereas some do not depend on glycan usage. Best neutralizing lineage show continuous evolution spanning over 6.5 years of maturation.
​ Overall, this study presents a description of the neutralization in one untreated primo-infected donor and its evolution. Together, these findings can help fuel a reverse vaccinal approach to a successful HIV immunization design.
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