Towards an HIV vaccine—selecting promising broadly neutralizing antibodies that can inhibit a range of viral strains
Neutralizing antibodies (Nabs) are immune proteins that recognize, bind to, and trigger the elimination of virus before
it can establish a chronic infection. How to elicit a potent Nab response capable of protecting against different HIV
subtypes and against different modes of infection is critical to the development of an AIDS vaccine. Two studies
published on July 9th in PLOS Pathogensprovide results on Nabs that could help guide vaccine design. One shows what type of Nab “repertoire” can be generated
following superinfection, and the second one examines the efficacy of Nabs in blocking direct cell-to-cell transmission
of HIV.
Julie Overbaugh, from the Fred Hutchinson Cancer Research Center in Seattle, USA, and colleagues characterized the
antibodies generated in 21 women who were superinfected, that is, infected sequentially at least twice with HIV by
different sexual partners. Their study—the first to examine Nab specificities in a cohort of superinfected individuals,
suggests that exposure to diverse HIV subtypes following superinfection may drive a broad and potent Nab response that
might be mediated at least in part by polyclonal antibodies targeting multiple different epitopes, or antigenic targets
found on the virus.
“As eliciting a highly diverse immune response may be favorable to providing protection against incredibly diverse HIV-1
variants in global circulation”, the researchers conclude that their study “supports further investigations of the
molecular and functional characteristics of the virus-antibody interplay in superinfected individuals, as superinfection
may provide insight to the development of a diverse Nab response with multiple epitope specificities.”
Besides infection with free virus, HIV can be transmitted also by direct cell-to-cell contact. And even though the
latter is thought to provide a more difficult challenge for neutralizing antibodies, most of the studies so far have
examined the antibodies in the context of free virus infections. To be able to address this gap, Alexandra Trkola, from
the University of Zurich, Switzerland, and colleagues first developed an assay that can specifically test the ability
and potency of Nabs to prevent direct cell transmission of HIV. Proving this point is tricky because free virus
infection occurs normally together with cell-to-cell transmission. By establishing an assay system where free virus
infection is restricted and infection can only occur through cell-cell transmission, the researchers could then test
whether a large selection of Nabs could prevent cell-to-cell transmission of different HIV strains.
They found that while Nabs showed an overall decreased activity during cell-cell transmission, losses varied
substantially depending on the antibody and the virus strain examined. A few Nabs retained activity during cell-cell
transmission for individual viruses; surprisingly, this was generally not associated with a high potency against free
virus infection. Neutralization of free virus, but not cell-cell transmission, was linked with the activity of specific
Nabs to inhibit prior to the binding of the virus to the CD4 receptor on T cells, highlighting the functional
differences of the two processes.
Using mathematical analysis, the researchers showed that cell-cell transmission was substantially more prone to give
rise to virus mutants that can escape immune control than free virus transmission and conclude that “this highlights the
importance of controlling virus replication via the cell-cell transmission pathway even if the contribution of this
transmission mode should prove to occur to a lesser extent than free virus spread in infected individuals.” They go on
to say that “since no single broadly neutralizing antibody combines the entire range of mechanistic features anticipated
to support in vivo efficacy, our study adds further evidence that combinations of such antibodies need to be considered for human
application.”
ENDS