The immunodominant epitopes expressed by the HIV-1 envelope protein gp120 are

The immunodominant epitopes expressed by the HIV-1 envelope protein gp120 are hypermutable, defeating attempts to develop an effective HIV vaccine. a stimulatory signal, and the binding of a spatially distinct epitope at the traditional combining site of the BCRs may furnish a second stimulatory signal. Flexible synthetic peptides can detect pre-existing CD4BDcore-specific neutralizing antibodies. However, induced-fit conformational transitions of the peptides dictated by the antibody combining site structure may induce the synthesis of non-neutralizing antibodies. Successful vaccine targeting of the CD4BD will require a sufficiently rigid immunogen that mimics the native epitope conformation and bypasses B cell checkpoints restricting synthesis of the neutralizing antibodies. expression vector (Rerks-Ngarm et al., 2009). This was the first trial showing a statistically significant reduction in the risk of contracting HIV infection, but the risk reduction was marginal, and the results are not clinically meaningful in slowing the pandemic. An envelope vaccine derived from a single HIV strain may be conceived to provide some protection against infection by strains that express sufficiently similar mutable epitopes, but it is practically Rabbit Polyclonal to GPR150. impossible to design a single vaccine immunogen capable of inducing antibodies that are broadly reactive with the mutable antigenic epitopes expressed by genetically divergent HIV strains. To develop a broadly protective vaccine, it is necessary to target an HIV determinant that is structurally constant across the range of Group M HIV-1 strains responsible for infection world-wide. Moreover, it is important that the target determinant fulfills an essential role in infectionotherwise antibodies to the determinant may not neutralize the virus. Many recent vaccine development efforts have been focused at the envelope determinants essential for interaction with host receptors. Such viral determinants are likely to be structurally conserved to maintain the ability to the virus to infect cells. Overview of the CD4BD The envelope glycoprotein complex (Env) on the HIV surface mediates entry into host cells and represents a prime target for neutralizing antibodies (Pantophlet and Burton, 2006). Env consists of homotrimeric complexes of non-covalently associated gp120-gp41 heterodimers derived by proteolytic processing of the precursor gp160 protein. The surface required for CD4 receptor binding is composed of gp120 residues with no involvement from gp41. Initial HIV binding to host cell CD4 NVP-BAG956 receptors is an obligatory step for infection by all HIV-1 subtypes. This provides a selective pressure for structural conservation of the gp120 determinant that binds CD4 (the CD4 binding determinant, CD4BD), and the CD4BD has remained mostly conserved while the sequence of other gp120 regions has increasingly diverged as various Group M HIV-1 strains have evolved over the course of the pandemic in the last 3 decades. The approximate spatial localization of the NVP-BAG956 CD4BD has been deduced from crystallography of gp120 that was experimentally rigidified by excision of certain flexible segments (Kwong et al., 1998) together with site-directed mutagenesis followed by analysis of CD4 binding and monitoring of infectivity (Olshevsky et al., 1990). The complete CD4BD is a discontinuous determinant composed of residues distributed over six structural segments of gp120 (Figure ?(Figure1):1): (1) the V1/V2 stem (2C3 segments), (2) loop regulatory check-points in B cell differentiation influencing neutralizing antibody … CD4BDcore The CD4BDcore is structurally distinct from the CD4BDOD. Except in the early years of HIV vaccine research, dominant research groups in the field have held that the CD4BDOD is the best target epitope for vaccination, and little attention was paid to the CD4BDcore as an alternative worthy of detailed structural discussion. However, the pdb files of various crystal structures of rigidified monomer gp120 contain important structural details that are consistent with NVP-BAG956 the suitability of the CD4BDcore as a vaccine target (model of innate germline antibody repertoire containing a wide range of antibodies with varying CD4BDcore-reactivity and HIV neutralizing potency. A small antibody subset … Figure 5 Hypothetical mechanism for induction of.