Article

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: 4.65). 03/2006; 80(3):1414-26. DOI: 10.1128/JVI.80.3.1414-1426.2006
Source: PubMed

ABSTRACT 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.

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    • "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). "
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    PLoS ONE 03/2013; 8(3):e59803. DOI:10.1371/journal.pone.0059803 · 3.23 Impact Factor
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    • "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). "
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