Date Published: December 1, 2007
Publisher: Public Library of Science
Author(s): David Montefiori, Quentin Sattentau, Jorge Flores, José Esparza, John Mascola
Abstract: The authors discuss humoral immune responses to HIV and approaches to designing vaccines that induce viral neutralizing and other potentially protective antibodies.
Partial Text: The Global HIV Vaccine Enterprise convened a two-day workshop in May of 2007 to discuss humoral immune responses to HIV and approaches to design vaccines that induce viral neutralizing and other potentially protective antibody responses. The goals of this workshop were to identify key scientific issues, gaps, and opportunities that have emerged since the Enterprise Strategic Plan was first published in 2005 , and to make recommendations that Enterprise stakeholders can use to plan new activities.
Clinical studies have demonstrated that immunization with the gp120 surface unit of the HIV-1 envelope protein does not lead to the induction of potent or broadly reactive neutralizing antibodies. In order to develop better immunogens, it is likely that we will need a more detailed understanding of the atomic level structure of epitopes on the native envelope glycoprotein. Data on the X-ray crystal structure of liganded and unliganded partial gp120 molecules have provided valuable information about the atomic level interaction of gp120 and neutralizing antibodies [9–12]. The recent atomic level resolution of monoclonal antibody (MAb) b12 bound to the CD4 receptor binding site of the gp120 molecule provides new insights into how successful neutralizing antibodies access functionally conserved regions of the Env glycoprotein . Crystal structures of complete monomeric gp120 and gp120–gp41 trimer complexes in their native unliganded form need to be elucidated, as these are the natural targets for neutralizing antibodies. This information is needed for multiple genetic subtypes of the virus and for transmitted strains of the virus. Coupled with this effort should be a program to make necessary improvements in electron tomography technology to gain a higher resolution of native Env spikes as they exist on virus particles [14–16]. An improved understanding of the structural basis of antibody binding to the HIV-1 Env glycoprotein will likely form the foundation for a rational program of novel vaccine design. Ongoing efforts to stabilize gp120 into more immunogenic forms or to scaffold conserved neutralization epitopes into foreign proteins may lead to more promising antibody responses.
Recent findings have generated renewed interest in so-called “non-neutralizing” antibodies that are unable to directly inhibit free virus entry into target cells, but nonetheless exhibit antiviral activity mediated by the Fc region of the antibody molecule. These antibody effector mechanisms include complement binding and viral lysis, phagocytosis of antibody-coated virions, and antibody-dependent cellular cytotoxicity [35–38]. Recent studies have suggested examples of Fc-dependent antiviral effects of HIV-1-positive serum in cases where there was little or no detectable activity in conventional neutralization assays [39,40].
In order to adequately monitor neutralization breadth and potency and to compare and prioritize immunogens, assays are needed that are sensitive, quantitative, high throughput, and have correlative value. Substantial improvements have been made in the past several years in assay technology and in available reference reagents. Thus, cumbersome and expensive assays using peripheral blood mononuclear cells (PBMC) and uncloned viruses are being replaced with assays that utilize molecularly cloned Envpseudotyped viruses and genetically engineered target cells lines [2,42–45]. This new technology affords greater sensitivity, reproducibility, high throughput, and cost-effectiveness compared to PBMC assays, and as a result, it has been responsible for an explosion of new data. Steps are being taken by the Collaboration for AIDS Vaccine Discovery to transfer this new technology to multiple laboratories around the world and to implement a validated proficiency testing program to assure inter-laboratory equivalency in assay performance.
This workshop identified several critical gaps in the current understanding of B cell regulatory pathways that impede a more rational development of an effective antibody-based HIV-1 vaccine. For example, broadly neutralizing antibodies in patient serum bind epitopes that are present on monomeric gp120 , yet this is a poor immunogen for neutralizing antibody induction in vaccine recipients. Moreover, as mentioned above, viral epitopes for the known broadly neutralizing MAbs appear to be poorly immunogenic in infected individuals and as vaccine candidates. Insights into the immunoregulation of some of these latter epitopes (e.g., epitopes defined by MAbs 2F5 and 4E10) was provided by recent studies in which the MAbs were discovered to bind one or more self antigens [50,51], raising the possibility that these antibody specificities are subjected to negative regulation mechanisms, such as receptor editing or deletion. Thus, Env as an immunogen may bypass key steps in the B cell inductive pathway, or may actively induce negative production or downregulation of production of some broadly neutralizing antibodies [52–54].