Abstract
It is commonly assumed that neutralizing Mabs that bind to the HIV-1 Env glycoprotein are more specific reagents than anti-HIV-1 polyclonal antisera and that knowledge of the structure of these Mabs facilitates the rational design of effective HIV-1 vaccine immunogens. However, after more than ten years of unsuccessful experimentation using the structure-based reverse vaccinology approach, it is now evident that it is not possible to infer from the structure of neutralizing Mabs which HIV immunogens induced their formation nor which vaccine immunogens will elicit similar Abs in an immunized host. The use of Mabs for developing an HIV-1 vaccine was counterproductive because it overlooked the fact that the apparent specificity of a Mab very much depends on the selection procedure used to obtain it and also did not take into account that an antibody is never monospecific for a single epitope but is always polyspecific for many epitopes. When the rationale of the proponents of the unsuccessful rational design strategy is analyzed, it appears that investigators who claim they are designing a vaccine immunogen are only improving the binding reactivity of a single epitope-paratope pair and are not actually designing an immunogen able to generate protective antibodies. The task of a designer consists in imagining what type of immunogen is likely to elicit a protective immune response but in the absence of knowledge regarding which features of the immune system are responsible for producing a functional neutralizing activity in antibodies, it is not feasible to intentionally optimize a potential immunogen candidate in order to obtain the desired outcome. The only available option is actually to test possible solutions by trial-and-error experiments until the preset goal is perhaps attained. Rational design and empirical approaches in HIV vaccine research should thus not be opposed as alternative options since empirical testing is an integral part of a so-called design strategy.
Highlights
It has been suggested that our inability over the past 25 years to develop an effective HIV vaccine is partly due to the fact that investigators adhered to several unwarranted assumptions and paradigms that made them pursue unfruitful research strategies [1,2]. One such misleading assumption central to the structure-based reverse vaccinology approach [3] was the belief that when an HIV-1 envelope glycoprotein complex (Env) epitope is found to bind to a broadly neutralizing monoclonal antibody, this epitope should be able to induce similar neutralizing antibodies when used as an immunogen [4]
The present review will discuss another detrimental assumption that impeded progress in the HIV vaccine field, namely the belief that a Mab that binds to the HIV-1 Env protein is a more appropriate and specific reagent for studying HIV immunology and vaccine immunogenicity than a polyclonal anti-HIV antiserum
The structure-based rational design of an HIV-1 vaccine is based on the assumption that knowledge of the structure of vulnerable Env epitopes targeted by broadly neutralizing monoclonal antibody (bnMab) will lead to the discovery of effective HIV-1 vaccine immunogens [4,14,41,42]
Summary
It has been suggested that our inability over the past 25 years to develop an effective HIV vaccine is partly due to the fact that investigators adhered to several unwarranted assumptions and paradigms that made them pursue unfruitful research strategies [1,2]. The Env-directed antibody response is believed to reflect the continual stimulation by evolving antigenic variants of Env rather than the continued production of antibodies elicited by the Env protein of the originally infecting virus [36] When the extent of change in bnAb susceptibility of HIV-1 within individual progressors was studied during the course of infection, it was found that viral variants resistant to one or more bnAbs could develop in most individuals [37] This led to the suggestion that since viral resistance against bnAb- mediated neutralization generally developed when autologous serum neutralization had faded, these changes were unlikely to have been driven by escape from autologous humoral immunity [37]. Since the epitope structure determined by the crystallographic analysis of a bnMab- HIV Env complex corresponds to only one of the many epitopes that could be accommodated by that Mab, there is no reason why the epitope identified in the complex should indicate which immunogen induced the Mab, thereby making it an hypothetical vaccine candidate
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