Rational Modifications of HIV-1 Envelope Glycoproteins for Immunogen Design

An effective vaccine against the human immunodeficiency virus type 1 (HIV-1) will likely require the elicitation of broadly neutralizing antibodies as well as cellular responses. The HIV exterior envelope glycoprotein trimers, gp120, and the transmembrane glycoprotein, gp41, mediate entry and are the sole viral targets for neutralizing antibodies. However, as subunit immunogens the envelope glycoproteins do not efficiently elicit antibodies capable of neutralizing the extremely diverse array of viruses circulating in the human population. The preponderance of data suggest that inefficient generation of broadly neutralizing antibodies is due to naturally evolved mechanisms of immune evasion inherent in the unmodified HIV envelope glycoproteins. Because the established modes of anti-viral vaccine development, liveattenuation and virus inactivation have not yet been successful for HIV, we and others have focused on subunit vaccine design. In this review, we describe current approaches of rational modification of the envelope glycoproteins based upon structure, antigenicity, biochemistry and biophysics to alter the properties of the envelope glycoproteins such that, as subunit immunogens, they now better elicit broadly neutralizing antibodies. The application of structure-assisted, rational subunit vaccine design may be a general paradigm for future efforts to develop vaccines against emerging human pathogens.