A study published on September 12th by the journal Immunity ties together two emerging areas of HIV vaccine research. In recent years, scientists have discovered that a small proportion of chronically infected individuals develop antibody responses capable of broadly neutralizing a diverse array HIV isolates. These antibody responses typically take years to develop, and are not present at sufficient titers to offer noticeable benefit to the infected individuals they are isolated from, but there is reason to believe that if they could be induced by a vaccine they could protect uninfected people against HIV acquisition. A potential complement to this line of investigation has been the discovery of T follicular helper cells (Tfh), a specialized CD4 T cell subset that plays a critical role in providing help to B cells, thereby facilitating antibody production. Researchers have posited that Tfh may have an important role in the generation of broadly neutralizing antibodies against HIV, but direct evidence has been lacking.
In the Immunity paper, Michela Locci and colleagues report that there is a circulating population of Tfh that can be identified using a combination of surface markers, and that in a large cohort of HIV-positive individuals the frequency of these cells correlated with the development of broadly neutralizing antibodies against HIV. The data suggest that inducing this type of Tfh response should be a goal for vaccines aiming to create neutralizing antibodies against HIV (or potentially any other pathogen).
In a helpful example of kismet, the September 13th issue of the journal Science featured an article by Jon Cohen describing progress in discovering broadly neutralizing antibodies to HIV, along with a review on the same topic and a podcast interview with the senior author of the review, Michel Nussenzweig.
Immunity, 12 September 2013 doi:10.1016/j.immuni.2013.08.031
Michela Locci1, 2, Colin Havenar-Daughton1, 2, Elise Landais4, Jennifer Wu1, Mark A. Kroenke1, Cecilia L. Arlehamn1, Laura F. Su6, Rafael Cubas7, Mark M. Davis6, Alessandro Sette1, Elias K. Haddad7, International AIDS Vaccine Initiative Protocol C Principal Investigators8, 9, Pascal Poignard4, 5 and Shane Crotty1, 2, 3
1 Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA
2 Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92037, USA
3 Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, La Jolla, CA 92037, USA
4 International AIDS Vaccine Initiative, Neutralizing Antibody Center, La Jolla, CA 92037, USA
5 Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
6 Department of Microbiology and Immunology and the Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94304, USA
7 Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida 34987, USA
8 International AIDS Vaccine Initiative, New York, NY 10038, USA
The vast majority of currently licensed human vaccines work on the basis of long-term protective antibody responses. It is now conceivable that an antibody-dependent HIV vaccine might be possible, given the discovery of HIV broadly neutralizing antibodies (bnAbs) in some HIV-infected individuals. However, these antibodies are difficult to develop and have characteristics indicative of a high degree of affinity maturation in germinal centers (GCs). CD4+ T follicular helper (Tfh) cells are specialized for B cell help and necessary for GCs. Therefore, the development of HIV bnAbs might depend on Tfh cells. Here, we identified in normal individuals a subpopulation of circulating memory PD-1+CXCR5+CD4+ T cells that are resting memory cells most related to bona fide GC Tfh cells by gene expression profile, cytokine profile, and functional properties. Importantly, the frequency of these cells correlated with the development of bnAbs against HIV in a large cohort of HIV+ individuals.