In recent years, new technologies have facilitated the discovery of an expanding number of antibodies capable of neutralizing a broad array of primary HIV isolates from different clades. As covered previously on the blog, these broadly neutralizing antibodies (bNAbs) have been fished from the plasma of individuals with chronic HIV infection and, in most cases, do not seem to be present at titers sufficient to control viral load or retard disease progression; however, there are reasons to hope that if similar antibodies could be induced by vaccination, they could rebuff the relatively small amount of HIV that enters the body during a typical exposure.
A common feature of the bNAbs is that the B cells that produce them have gone through many more rounds of somatic hypermutation than is typically seen in other infections. Somatic hypermutation is the process by which the B-cell's antibody-producing genetic code is progressively revised, potentially leading to an increase in the affinity of the antibody for its target. The genetic code that the B-cell starts out with is known as the germline sequence (or unmutated common ancestor or UCA), and it is typically altered by around 5-15% to produce antibodies against common infections, whereas the range is 19-46% for the bNAbs against HIV. This requirement for extensive mutation appears to be connected to the unusual shapes the bNAbs must form to access the hard-to-reach conserved areas of the HIV envelope (Env) protein, which are cloaked by highly variable decoy targets.
In a paper published yesterday in the journal Nature, researchers report tracking the development of a bNAb response in an HIV-positive person, in parallel with documenting the evolution of the infecting virus. The study shows that the Env protein of the virus at the time of acute infection was able to activate B cells with a germline sequence that then underwent progressive somatic hypermation, leading to the appearance of antibodies with increasing breadth of activity against a panel of HIV isolates during weeks 41-92 of follow-up. Driving the B-cell somatic hypermutation process was stimulation of the cells by the ever-mutating Env protein of the infecting virus, which evolved and became more diverse over time (as is typical in untreated HIV infection). The researchers were able to demonstrate that the diversification of the Env protein preceded the appearance of bNAb response.
This brief description greatly simplifies a complicated study, but the implication for HIV vaccines is that it may be possible to try and mimic the process observed in this individual using sequential immunization with vaccines containing similar Env proteins of increasing diversity. The hope would be to initially activate the right B cell, and then push it along a somatic hyermutation pathway that would lead to the eventual generation of bNAbs.
Whether this is actually feasible, however, remains to be seen. Because there is a degree of randomness involved, it may be that the relatively rare individuals who develop bNAbs represent instances of B-cells essentially hitting the somatic hypermutation jackpot as a result of repeated stimulation. But, given the implications for HIV vaccines if bNAbs could be successfully induced with some reliability, it will be essential to fully pursue the idea. In addition to the Nature paper, several other recently published studies report data relevant to this pursuit (links also appended below).
Nature (2013) doi:10.1038/nature12053
Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus
Nature (2013) doi:10.1038/nature12091
HIV: Roadmaps to a vaccine
Science. 2013 Mar 29. [Epub ahead of print]
Rational HIV Immunogen Design to Target Specific Germline B Cell Receptors.
J Exp Med. 2013 Mar 27. [Epub ahead of print]
Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies.
Proc Natl Acad Sci U S A. 2013 Mar 22. [Epub ahead of print]
Structural basis for HIV-1 gp120 recognition by a germ-line version of a broadly neutralizing antibody. (free full text)
Cell. 2013 Mar 28;153(1):126-38. doi: 10.1016/j.cell.2013.03.018.
Somatic Mutations of the Immunoglobulin Framework Are Generally Required for Broad and Potent HIV-1 Neutralization.
Richard Jefferys is the coordinator of the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog at the Treatment Action Group (TAG). The original blog post may be viewed here.