Immunotypes of a Quaternary Site of HIV-1 Vulnerability and Their Recognition by Antibodies

Vaccine Research Center, NIAID, NIH, 40 Convent Drive, Bethesda, MD 20892, USA.
Journal of Virology (Impact Factor: 4.44). 02/2011; 85(9):4578-85. DOI: 10.1128/JVI.02585-10
Source: PubMed

ABSTRACT HIV-1 is neutralized by a class of antibodies that preferentially recognize a site formed on the assembled viral spike. Such quaternary structure-specific antibodies have diverse neutralization breadths, with antibodies PG16 and PG9 able to neutralize 70 to 80% of circulating HIV-1 isolates while antibody 2909 is specific for strain SF162. We show that alteration between a rare lysine and a common N-linked glycan at position 160 of HIV-1 gp120 is primarily responsible for toggling between 2909 and PG16/PG9 neutralization sensitivity. Quaternary structure-specific antibodies appear to target antigenic variants of the same epitope, with neutralization breadth determined by the prevalence of recognized variants among circulating isolates.

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Available from: Sanjay Phogat, Aug 06, 2014
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    • "To test the effect on the entry phenotype of this residue, we generated a panel of mutant N160K or K160N viruses and analyzed their free virus infection and cell-cell transmission capacity. In agreement with previous studies [69], the effect of N160K on free virus entry ranged from a 10 to 90% loss of entry capacity for the different isolates tested (Figure 7). Notably, in two of the three strains which naturally contain a lysine at position 160, SF162 and CAP88, the K160N mutation reconstituted a potential N-linked glycosylation site and led to a high increase in free virus infectivity, highlighting the importance of this residue for free virus infectivity. "
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    ABSTRACT: Background Variable loops 1 and 2 (V1V2) of the HIV-1 envelope glycoprotein gp120 perform two key functions: ensuring envelope trimer entry competence and shielding against neutralizing antibodies. While preserving entry functionality would suggest a high need for V1V2 sequence optimization and conservation, shielding efficacy is known to depend on a high flexibility of V1V2 giving rise to its substantial sequence variability. How entry competence of the trimer is maintained despite the continuous emergence of antibody escape mutations within V1V2 has not been resolved. Since HIV cell-cell transmission is considered a highly effective means of virus dissemination, we investigated whether cell-cell transmission may serve to enhance infectivity of V1V2 variants with debilitated free virus entry.ResultsIn a detailed comparison of wt and V1V2 mutant envelopes, V1V2 proved to be a key factor in ascertaining free virus infectivity, with V1V2 mutants displaying significantly reduced trimer integrity. Despite these defects, cell-cell transmission was able to partially rescue infectivity of V1V2 mutant viruses. We identified two regions, encompassing amino acids 156 to 160 (targeted by broadly neutralizing antibodies) and 175 to 180 (encompassing the ¿4ß7 binding site) which were particularly prone to free virus infectivity loss upon mutation but maintained infectivity in cell-cell transmission. Of note, V1V2 antibody shielding proved important during both free virus infection and cell-cell transmission.Conclusions Based on our data we propose a model for V1V2 evolution that centers on cell-cell transmission as a salvage pathway for virus replication. Escape from antibody neutralization may frequently result in V1V2 mutations that reduce free virus infectivity. Cell-cell transmission could provide these escape viruses with sufficiently high replication levels that enable selection of compensatory mutations, thereby restoring free virus infectivity while ensuring antibody escape. Thus, our study highlights the need to factor in cell-cell transmission when considering neutralization escape pathways of HIV-1.
    Retrovirology 09/2014; 11(1):75. DOI:10.1186/PREACCEPT-1148975491133162 · 4.19 Impact Factor
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    • "We also made amino acid substitutions at positions 169 and 181, as these two locations were associated with vaccine-induced immune responses during the RV144 trial [3]. In addition, the lysine found at position 160 in SF162 was replaced with the more commonly represented residue at this position, asparagine, in order to reconstitute the critical glycan that has been shown to determine reactivity of the V1V2V3 quaternary mAbs [21], [34], [35]. Amino acid changes were introduced that occur at these positions in nature. "
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    ABSTRACT: In the case-control study of the RV144 vaccine trial, the levels of antibodies to the V1V2 region of the gp120 envelope glycoprotein were found to correlate inversely with risk of HIV infection. This recent demonstration of the potential role of V1V2 as a vaccine target has catapulted this region into the focus of HIV-1 research. We previously described seven human monoclonal antibodies (mAbs) derived from HIV-infected individuals that are directed against conformational epitopes in the V1V2 domain. In this study, using lysates of SF162 pseudoviruses carrying V1V2 mutations, we mapped the epitopes of these seven mAbs. All tested mAbs demonstrated a similar binding pattern in which three mutations (F176A, Y177T, and D180L) abrogated binding of at least six of the seven mAbs to ≤15% of SF162 wildtype binding. Binding of six or all of the mAbs was reduced to ≤50% of wildtype by single substitutions at seven positions (168, 180, 181, 183, 184, 191, and 193), while one change, V181I, increased the binding of all mAbs. When mapped onto a model of V2, our results suggest that the epitope of the conformational V2 mAbs is located mostly in the disordered region of the available crystal structure of V1V2, overlapping and surrounding the α4β7 binding site on V2.
    PLoS ONE 07/2013; 8(7):e70859. DOI:10.1371/journal.pone.0070859 · 3.23 Impact Factor
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    • "We initially examined whether PG9/PG16-like neutralizing activities were present in AC053 plasma, by comparing the neutralizing activity of this plasma using viruses produced in the absence or presence of kifunensine. PG9/16-like antibodies do not recognize the SF162 gp120 because it lacks glycans at position 160, which are necessary for PG9/16-Env binding [36], [52]. This would therefore explain why the anti- TRO.11, CAAN, or Zm214M neutralizing activity of AC053 plasma could not be eliminated by SF162gp120-based antibody adsorptions [14]. "
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    ABSTRACT: Broadly neutralizing antibodies are considered an important part of a successful HIV vaccine. A better understanding of the factors underlying their development during infection and of the epitopes they target is needed to elicit similar antibody responses by vaccination. We and others reported that, on average, it takes 2 to 3 years for cross-reactive neutralizing antibodies to become detectable in the sera of HIV-1-infected subjects and that they target a limited number of epitopes on the HIV Envelope. Here we investigated the emergence and evolution of the earliest cross-reactive neutralizing antibody specificities in one HIV-1-infected individual, AC053. We defined two distinct epitopes on Env that are targeted by the broadly neutralizing antibody responses developed by AC053. The first specificity became evident at 3 years post infection and targeted the CD4-binding site of Env. Antibodies responsible for that specificity neutralized most, but not all, viruses susceptible to neutralization by the plasma antibodies of AC053. The second specificity became apparent approximately a year later. It was due to PG9-like antibodies, which were able to neutralize those viruses not susceptible to the anti-CD4-BS antibodies in AC053. These findings improve our understanding of the co-development of broadly neutralizing antibodies that target more than one epitope during natural HIV-1-infection in selected HIV+ subjects. They support the hypothesis that developing broadly neutralizing antibody responses targeting distinct epitopes by immunization could be feasible.
    PLoS ONE 11/2012; 7(11):e49610. DOI:10.1371/journal.pone.0049610 · 3.23 Impact Factor
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