Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies

A future HIV vaccine is widely assumed to require broadly neutralizing antibodies, which are able to recognize and neutralize diverse viruses from across the world. No vaccine so far has managed to elicit these kinds of antibodies, but some HIV infected people are able to naturally develop broadly neutralizing antibodies. Understanding how and why these rare people are able to make these antibodies may therefore provide a roadmap for HIV vaccine design.

In a paper published this month in Nature, WITS/NICD researchers Dr Penny Moore, Jinal Bhiman (a PhD student at the NICD, pictured) and Professor Lynn Morris, along with a consortium of researchers in South Africa and the USA describe the developmental pathway of one such antibody.

Antibodies which target a conserved epitope in the V2 region of the HIV envelope develop fairly frequently during infection. These are characterized by long CDRH3 “arms”, which are required to penetrate through the glycan shield that protects the HIV envelope. Until now it was not clear how these long CDRH3s developed. In this study, the team isolated a family of V2-directed antibodies with long CDRH3s from an infected donor, CAP256. Using deep sequencing of the antibody genes over 3 years of infection, they showed that the unmutated common ancestor (UCA) of the antibody family emerged 30-38 weeks after infection. Interestingly, the UCA contained a fully formed long CDRH3, which arose entirely as a result of VDJ recombination, and in contrast to the idea that this might take many years to develop.

A second part of the study defined exactly how breadth developed in CAP256. The UCA was initially able only to neutralize the virus that superinfected CAP256 at 15 weeks post-infection. However in response to extensive viral diversification, there was rapid somatic hypermutation resulting in these antibodies becoming broadly reactive for HIV within 4 months.

This study shows that a future vaccine targeting this region will rely on immunogens that are able to engage the rare subgroup of naïve B cells expressing B cell receptors with pre-formed long CDRH3. However this work also suggests that sequential immunogens that mirror viral evolution may be needed to drive the development of breadth. Overall, the precise delineation of the developmental pathway for the CAP256 antibody lineage should provide a basis for attempts to elicit broad V1V2-directed HIV-1-neutralizing antibodies through vaccination.

Story by: Wits Health Science Research News