PROJECT

Development of therapeutic broadly neutralizing monoclonal antibodies against circulating HIV-1 clade C in children and adults

October 2023 - September 2027

Objectives:

i. Preparation of virus panel that represents circulating HIV-1 C across adult and paediatric population from across geographic regions in India.
ii. Preparation and characterization of HIV-1 Indian clade C soluble and stable trimeric antigenic baits from HIV-1 clade C infected children and adults from different regions of India that will be useful for characterizing and optimizing novel bNAbs.
iii. Detailed characterization of novel anti-HIV-1 broadly neutralizing monoclonal antibodies (bNAbs) isolated from HIV-1 clade C infected adult and pediatric elite neutralizers.
iv. Comparison and prioritization of novel bNAbs and existing optimized bNAbs to develop a specific cocktail of bNAbs effective against circulating Clade C.

Study Overview:

Given the genetic distinctness of Indian clade C, we hypothesized that the existing global bNAbs may not be sufficient for enhanced neutralizing coverage of currently circulating HIV-1 subtypes and recombinants. Further, evidence from limited sets of data indicate that genetic features of the viral env differentially influence viral adaptation in children compared to adults and that paediatric viruses are relatively resistant to bNAbs. Hence the study aimed to identify additional novel bNAbs for neutralizing circulating HIV-1 Indian subtype C viruses.

Study Approach:

(i) Preparation of replication competent primary HIV-1 isolates and infectious molecular clones representing currently circulating Indian clade C viruses from ART-naïve HIV-1 infected adults and paediatric individuals.
(ii) Preparation of monomeric and trimeric soluble HIV-1 clade C env proteins through cloning experiments and characterization of their biophysical and biochemical properties, antigenic properties and conformational state.
(iii) Development of anti-HIV-1 monoclonal antibodies from HIV-1 clade C infected elite neutralizers.
(iv) Comparison of novel bNAbs identified for their breadth and potency with other existing bNAbs.

Expected Public Health Impact:

A neutralization panel of pseudoviruses representing major circulating strains across geographical regions of India will be generated to test the isolated bNAbs in neutralization assay. Development of 5-8 HIV-1 clade C envelope trimers from the circulating viruses, suitable to be used as antigenic baits for bNAb isolation. Discovery, characterization and preclinical evaluation of at least 3 novel bNAbs, that can provide value addition to the bNAb cocktail suitable for neutralization of circulating viruses in India, ready to be tech-transferred to industry for clinical development.