Characterization of Antibody Responses Elicited by Human Immunodeficiency Virus Type 1 Primary Isolate Trimeric and Monomeric Envelope Glycoproteins in Selected Adjuvants

Vaccine Research Center, National Institutes of Health, 40 Convent Drive, Rm 4512, Bethesda, MD 20892, USA.
Journal of Virology (Impact Factor: 4.44). 03/2006; 80(3):1414-26. DOI: 10.1128/JVI.80.3.1414-1426.2006
Source: PubMed


We previously reported that soluble, stable YU2 gp140 trimeric human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein immunogens could elicit improved breadth of neutralization against HIV-1 isolates compared to monomeric YU2 gp120 proteins. In this guinea pig immunization study, we sought to extend these data and determine if adjuvant could quantitatively or qualitatively alter the neutralizing response elicited by trimeric or monomeric immunogens. Consistent with our earlier studies, the YU2 gp140 immunogens elicited higher-titer neutralizing antibodies against homologous and heterologous isolates than those elicited by monomeric YU2 gp120. Additionally, the GlaxoSmithKline family of adjuvants AS01B, AS02A, and AS03 induced higher levels of neutralizing antibodies compared to emulsification of the same immunogens in Ribi adjuvant. Further analysis of vaccine sera indicated that homologous virus neutralization was not mediated by antibodies to the V3 loop, although V3 loop-directed neutralization could be detected for some heterologous isolates. In most gp120-inoculated animals, the homologous YU2 neutralization activity was inhibited by a peptide derived from the YU2 V1 loop, whereas the neutralizing activity elicited by YU2 gp140 trimers was much less sensitive to V1 peptide inhibition. Consistent with a less V1-focused antibody response, sera from the gp140-immunized animals more efficiently neutralized heterologous HIV-1 isolates, as determined by two distinct neutralization formats. Thus, there appear to be qualitative differences in the neutralizing antibody response elicited by YU2 gp140 compared to YU2 monomeric gp120. Further mapping analysis of more conserved regions of gp120/gp41 may be required to determine the neutralizing specificity elicited by the trimeric immunogens.

Download full-text


Available from: Richard Wyatt
  • Source
    • "One explanation for this lack of progress may be that the native Env trimer's compact nature renders it an inherently poor immunogen (see Fig. 4 in Tong et al. (2013)). It therefore remains possible that higher native Env trimer doses and/or the use of powerful dose-sparing adjuvants can address problem (Li et al., 2006; VanCott et al., 1997). Another problem with particle-based vaccines is that they carry non-functional Env on their surfaces, principally uncleaved (UNC) gp160 and gp41 stumps that are relatively accessible to binding by non-neutralizing antibodies and may therefore interfere with the development of neutralizing responses to the native Env trimer (Agrawal et al., 2011; Crooks et al., 2007; Hicar et al., 2010; Joyner et al., 2011; Leaman et al., 2010; Moore et al., 2006; Nyambi et al., 1998; Tong et al., 2012, 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Virus-like particles (VLPs) offer a platform to test the hypothesis that, since antibody binding to native envelope glycoprotein (Env) trimers results in HIV-1 neutralization, that native Env trimers presented in membranes may be useful for inducing neutralizing antibodies (nAbs) in a vaccine setting. So far, VLPs have not fulfilled this potential. Here, using a “shotgun” approach, we evaluated a wide cross-section of variables in a series of VLP immunizations. We identified 3 tentative leads. First, that VLP doses may not have been sufficient for optimal nAb induction. Second, that dampening the antigenicity of non-functional Env (for example uncleaved gp160) using either protease digests or IgG masking may be useful. Third, that guinea pig sera preferentially target non-conserved epitopes and exhibit relatively high background activity, suggesting that rabbits may be preferable as small animal vaccine models. Recent immunogenicity studies in rabbits appear to bear out all 3 of these leads.
    Preview · Article · May 2014 · Virology
  • Source
    • "The R2 Env is from a donor with bcnAb and is highly unusual with respect to its capacity to infect cells in the absence of CD4 [47]. Its immunogenicity is also unusual in that other Env immunization regimens have not induced immunity against heterologous SHIV challenge, and administration of the YU2 strain Env in the same GSK adjuvant did not result in the extensive cross-reactivity observed in our study [49]. Thus, it appears that some Envs may be more immunogenic than others, and it is possible that the presence of a bcnAb response in an individual may reflect certain characteristics of the virus strain with which they are infected. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A major goal of efforts to develop a vaccine to prevent HIV-1 infection is induction of broadly cross-reactive neutralizing antibodies (bcnAb). In previous studies we have demonstrated induction of neutralizing antibodies that did cross-react among multiple primary and laboratory strains of HIV-1, but neutralized with limited potency. In the present study we tested the hypothesis that immunization with multiple HIV-1 envelope glycoproteins (Envs) would result in a more potent and cross-reactive neutralizing response. One Env, CM243(N610Q), was selected on the basis of studies of the effects of single and multiple mutations of the four gp41 glycosylation sites. The other two Envs included R2 (subtype B) and 14/00/4 (subtype F), both of which were obtained from donors with bcnAb. Rhesus monkeys were immunized using a prime boost regimen as in previous studies. Individual groups of monkeys were immunized with either one of the three Envs or all three. The single N610Q and N615Q mutations of CM243 Env did not disrupt protein secretion, processing into, or reactivity with mAbs, unlike other single or multiple deglycosylation mutations. In rabbit studies the N610Q mutation alone or in combination was associated with an enhanced neutralizing response against homologous and heterologous subtype E viruses. In the subsequent monkey study the response induced by the R2 Env regimen was equivalent to the trivalent regimen and superior to the other monovalent regimens against the virus panel used for testing. The 14/00/4 Env induced responses superior to CM243(N610Q). The results indicate that elimination of the glycosylation site near the gp41 loop results in enhanced immunogenicity, but that immunization of monkeys with these three distinct Envs was not more immunogenic than with one.
    Full-text · Article · Mar 2013 · PLoS ONE
  • Source
    • "As for viral particle-based vaccines, immunization with these constructs has resulted in the elicitation of predominantly nonneutralizing or strain-specific antibody responses (see above). Immunogens Based on the Epitopes Recognized by bnAbs A significant fraction of HIV-infected individuals develop broadly neutralizing responses over time (Binley et al., 2008; Doria-Rose et al., 2009; Gray et al., 2009, 2011; Li et al., 2006; Sather et al., 2009; Simek et al., 2009; Stamatatos et al., 2009), including some ''elite neutralizers,'' who display outstanding serum neutralization potency (Simek et al., 2009). Mapping of serum responses in broad neutralizers shows the targeting of a relatively small number of broadly neutralizing epitopes on Env, such as the CD4 binding site (CD4bs), glycan-dependent epitopes, quaternary structure dependent epitopes, and the membrane proximal external region (MPER) (Gray et al., 2009; Stamatatos et al., 2009; Walker et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite numerous attempts over many years to develop an HIV vaccine based on classical strategies, none has convincingly succeeded to date. A number of approaches are being pursued in the field, including building upon possible efficacy indicated by the recent RV144 clinical trial, which combined two HIV vaccines. Here, we argue for an approach based, in part, on understanding the HIV envelope spike and its interaction with broadly neutralizing antibodies (bnAbs) at the molecular level and using this understanding to design immunogens as possible vaccines. BnAbs can protect against virus challenge in animal models, and many such antibodies have been isolated recently. We further propose that studies focused on how best to provide T cell help to B cells that produce bnAbs are crucial for optimal immunization strategies. The synthesis of rational immunogen design and immunization strategies, together with iterative improvements, offers great promise for advancing toward an HIV vaccine.
    Full-text · Article · Oct 2012 · Cell host & microbe
Show more