Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: Implications for evasion of immune responses and design of vaccine immunogens

Protein Interactions Group, CCRNP, NCI-Frederick, NIH, Frederick, MD 21702, USA.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 09/2009; 390(3):404-9. DOI: 10.1016/j.bbrc.2009.09.029
Source: PubMed


Several human monoclonal antibodies (hmAbs) including b12, 2G12, and 2F5 exhibit relatively potent and broad HIV-1-neutralizing activity. However, their elicitation in vivo by vaccine immunogens based on the HIV-1 envelope glycoprotein (Env) has not been successful. We have hypothesized that HIV-1 has evolved a strategy to reduce or eliminate the immunogenicity of the highly conserved epitopes of such antibodies by using "holes" (absence or very weak binding to these epitopes of germline antibodies that is not sufficient to initiate and/or maintain an efficient immune response) in the human germline B cell receptor (BCR) repertoire. To begin to test this hypothesis we have designed germline-like antibodies corresponding most closely to b12, 2G12, and 2F5 as well as to X5, m44, and m46 which are cross-reactive but with relatively modest neutralizing activity as natively occurring antibodies due to size and/or other effects. The germline-like X5, m44, and m46 bound with relatively high affinity to all tested Envs. In contrast, germline-like b12, 2G12, and 2F5 lacked measurable binding to Envs in an ELISA assay although the corresponding mature antibodies did. These results provide initial evidence that Env structures containing conserved vulnerable epitopes may not initiate humoral responses by binding to germline antibodies. Even if such responses are initiated by very weak binding undetectable in our assay it is likely that they will be outcompeted by responses to structures containing the epitopes of X5, m44, m46, and other antibodies that bind germline BCRs with much higher affinity/avidity. This hypothesis, if further supported by data, could contribute to our understanding of how HIV-1 evades immune responses and offer new concepts for design of effective vaccine immunogens.

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Available from: Ponraj Prabakaran,
    • "Moreover, when the immunoglobulin sequences of bNAbs are experimentally reverted to their germline precursors, as they are found on naive B cells, binding to HIV-1 Env is often significantly diminished or even completely abrogated (Bonsignori et al., 2011; Haynes et al., 2012b; McGuire et al., 2014; Scheid et al., 2011; Wu et al., 2011; Xiao et al., 2009). This suggests difficulties in inducing bNAbs in HIV-1-infected patients and also by vaccination, because many rounds of affinity maturation are required which means that immunizations should be repeated many times as well. "
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    ABSTRACT: Antibodies with modest neutralizing activity and narrow breadth are commonly elicited in HIV-1. Here, we evaluated the complementary and synergistic activities of a set of monoclonal antibodies (MAb) isolated from a single patient, directed to V3, CD4 binding site (CD4bs), and CD4 induced (CD4i) epitopes. Despite low somatic hypermutation percentages in the variable regions, these MAbs covered viral strains from subtypes B, C, A and CRF01_AE and transmitted/founder viruses in terms of binding, neutralizing and antibody-dependent cell-mediated cytotoxicity (ADCC) activities. In addition, a combination of the anti-V3 and CD4bs MAbs showed a synergistic effect over the neutralization of HIV-1JR-FL. A humoral response from a single patient covered a wide range of viruses by complementary and synergistic activities of antibodies with different specificities. Inducing a set of narrow neutralizing antibodies, easier to induce than the broadly neutralizing antibodies, could be a strategy for developing an effective vaccine against HIV-1. Copyright © 2014 Elsevier Inc. All rights reserved.
    Virology 12/2014; 475C:187-203. DOI:10.1016/j.virol.2014.11.011 · 3.32 Impact Factor
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    • "Our earlier observation of the extensive maturation of HIV-1 bnAbs in contrast to those against some viruses causing acute infections led to the antibody germline/maturation hypothesis (9–11, 13, 14). According to this hypothesis, it is critical to identify immunogens that would bind to germline and/or intermediate antibodies of bnAbs, as well as the exploration of antibodyomes could be useful for identifying such immunogens (14). "
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    ABSTRACT: We have previously observed that all known potent broadly neutralizing antibodies (bnAbs) against HIV-1 are highly divergent from their putative germline predecessors in contrast to bnAbs against viruses causing acute infections such as henipaviruses and SARS CoV, which are much less divergent from their germline counterparts. Consequently, we have hypothesized that germline antibodies may not bind to the HIV-1 envelope glycoprotein (Env) because they are so different compared to the highly somatically mutated HIV-1-specific bnAbs. We have further hypothesized that the immunogenicity of highly conserved epitopes on the HIV-1 envelope glycoproteins (Envs) may be reduced or eliminated by their very weak or absent interactions with germline antibodies and immune responses leading to the elicitation of bnAbs may not be initiated and/or sustained. Even if such responses are initiated, the maturation pathways are so extraordinarily complex that prolonged periods of time may be required for elicitation of bnAbs with defined unique sequences. We provided the initial evidence supporting this antibody germline/maturation hypothesis, which prompted a number of studies to design vaccine immunogens that could bind putative germline predecessors of known bnAbs and to explore complex B cell lineages. However, guiding the immune system through the exceptionally complex antibody maturation pathways to elicit known bnAbs remains a major challenge. Here, we discuss studies exploring the antibody germline/maturation hypothesis as related to elicitation of bnAbs against HIV-1 and present our recent data demonstrating the existence of germline-like precursors of VRC01 antibodies in a human cord blood IgM library.
    Frontiers in Immunology 08/2014; 5:398. DOI:10.3389/fimmu.2014.00398
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    • "These unusual Ab characteristics will unfortunately be extremely difficult to generate by vaccination. Several of these HIV-1 bNAbs have been reverted experimentally to their unmutated ancestral state, and were found to bind weakly or undetectably to native HIV-1 Env (77, 78), which means that Ab responses induced by vaccination will have to occur following intricate pathways of B-cell maturation. "
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    ABSTRACT: HIV antibody (Ab) functions capable of preventing mucosal cell-free or cell-to-cell HIV transmission are critical for the development of effective prophylactic and therapeutic vaccines. In addition to CD4(+) T cells, other potential HIV-target cell types including antigen-presenting cells (APCs) (dendritic cells, macrophages) residing at mucosal sites are infected. Moreover, the interactions between APCs and HIV lead to HIV cell-to-cell transmission. Recently discovered broadly neutralizing antibodies (NAbs) are able to neutralize a broad spectrum of HIV strains, inhibit cell-to-cell transfer, and efficiently protect from infection in the experimentally challenged macaque model. However, the 31% protection observed in the RV144 vaccine trial in the absence of detectable NAbs in blood samples pointed to the possible role of additional Ab inhibitory functions. Increasing evidence suggests that IgG Fcγ receptor (FcγR)-mediated inhibition of Abs present at the mucosal site may play a role in protection against HIV mucosal transmission. Moreover, mucosal IgA Abs may be determinant in protection against HIV sexual transmission. Therefore, defining Ab inhibitory functions that could lead to protection is critical for further HIV vaccine design. Here, we review different inhibitory properties of HIV-specific Abs and discuss their potential role in protection against HIV sexual transmission.
    Frontiers in Immunology 06/2014; 5:289. DOI:10.3389/fimmu.2014.00289
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