Abstract
Although the sequence variable loops of the human immunodeficiency virus' (HIV-1) surface envelope glycoprotein (gp120) can exhibit good immunogenicity, characterizing conserved (invariant) cross-strain neutralization epitopes within these loops has proven difficult. We recently developed a method to derive sensitive and specific signature motifs for the three-dimensional (3D) shapes of the HIV-1 neutralization epitopes in the third variable (V3) loop of gp120 that are recognized by human monoclonal antibodies (mAbs). We used the signature motif method to estimate the conservation of these epitopes across circulating worldwide HIV-1 strains. The epitope targeted by the anti-V3 loop neutralizing mAb 3074 is present in 87% of circulating strains, distributed nearly evenly among all subtypes. The results for other anti-V3 Abs are: 3791, present in 63% of primarily non-B subtypes; 2219, present in 56% of strains across all subtypes; 2557, present in 52% across all subtypes; 447-52D, present in 11% of primarily subtype B strains; 537-10D, present in 9% of primarily subtype B strains; and 268-D, present in 5% of primarily subtype B strains. The estimates correlate with in vitro tests of these mAbs against diverse viral panels. The mAb 3074 thus targets an epitope that is nearly completely conserved among circulating HIV-1 strains, demonstrating the presence of an invariant structure hidden in the dynamic and sequence-variable V3 loop in gp120. Since some variable loop regions are naturally immunogenic, designing immunogens to mimic their conserved epitopes may be a promising vaccine discovery approach. Our results suggest one way to quantify and compare the magnitude of the conservation.
Highlights
The gp120 surface envelope glycoprotein of HIV-1 (HIV) is the primary target for antibodies that neutralize HIV infection in vitro [1], and passive transfer of HIV gp120-specific antibodies confers protection from HIV and chimeric simian-human immune deficiency virus (SHIV) challenge in several animal models [2,3,4,5,6,7,8]
Extraordinary antigenic diversity is a hallmark of the HIV Group M strains that are causing the acquired immune deficiency syndrome (AIDS) pandemic, and this diversity is especially prominent in the sequence variable regions, including the V3 loop [15]
V3 loop amino acid positions making contact with the monoclonal antibodies (mAbs) only through their backbone atoms were deemed tolerant positions and not included in the sequence motif, whereas a contact between the V3 peptide and the mAb characterized by partial burial of the V3 side chain into the molecular surface of the mAb was deemed an intolerant position that corresponds to a defined amino acid letter in the sequence motif
Summary
The gp120 surface envelope glycoprotein of HIV-1 (HIV) is the primary target for antibodies that neutralize HIV infection in vitro [1], and passive transfer of HIV gp120-specific antibodies confers protection from HIV and chimeric simian-human immune deficiency virus (SHIV) challenge in several animal models [2,3,4,5,6,7,8]. One of the most productive approaches to interrogating the antigenic diversity of HIV viruses for conserved shapes that may be immunologically targeted is to isolate monoclonal antibodies from HIV-infected human subjects and study their specificities, their ability to neutralize in vitro infection by diverse HIV viruses. The breadth, potency and activities of the hundreds of variableloop-specific monoclonal antibodies (mAbs) isolated from HIVpositive subjects varies widely, as expected given the antigenic diversity in these regions [16,17]. Many such mAbs are nonneutralizing, as expected. The variable loops, and the V3 loop in particular, have been considered improbable targets for vaccine-induced protective antibodies [26], despite the observed immunogenicity advantages and despite extensive evidence that there is a great deal of immunologic cross-reactivity among V3 loops from diverse strains and clades [27,28,29]
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