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. 2009 Apr;25(4):441-50.
doi: 10.1089/aid.2008.0188.

Worldwide distribution of HIV type 1 epitopes recognized by human anti-V3 monoclonal antibodies

Timothy Cardozo  1 , James Swetnam, Abraham Pinter, Chavdar Krachmarov, Arthur Nadas, David Almond, Susan Zolla-Pazner
Affiliations

Worldwide distribution of HIV type 1 epitopes recognized by human anti-V3 monoclonal antibodies

Timothy Cardozo et al. AIDS Res Hum Retroviruses. 2009 Apr.

Abstract

Epitopes, also known as antigenic determinants, are small clusters of specific atoms within macromolecules that are recognized by the immune system. Such epitopes can be targeted with vaccines designed to protect against specific pathogens. The third variable loop (V3 loop) of the HIV-1 pathogen's gp120 surface envelope glycoprotein can be a highly sensitive neutralization target. We derived sequence motifs for the V3 loop epitopes recognized by the human monoclonal antibodies (mAbs) 447-52D and 2219. Searching the HIV database for the occurrence of each epitope motif in worldwide viruses and correcting the results based on published WHO epidemiology reveal that the 447-52D epitope we defined occurs in 13% of viruses infecting patients worldwide: 79% of subtype B viruses, 1% of subtype C viruses, and 7% of subtype A/AG sequences. In contrast, the epitope we characterized for human anti-V3 mAb 2219 is present in 30% of worldwide isolates but is evenly distributed across the known HIV-1 subtypes: 48% of subtype B strains, 40% of subtype C, and 18% of subtype A/AG. Various assays confirmed that the epitopes corresponding to these motifs, when expressed in the SF162 Env backbone, were sensitively and specifically neutralized by the respective mAbs. The method described here is capable of accurately determining the worldwide occurrence and subtype distribution of any crystallographically resolved HIV-1 epitope recognized by a neutralizing antibody, which could be useful for multivalent vaccine design. More importantly, these calculations demonstrate that globally relevant, structurally conserved epitopes are present in the sequence variable V3 loop.

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Figures

FIG. 1.
FIG. 1.
Electrostatic surface of mAb 447-52D (red = negatively-charged surface, blue = positively-charged surface). The V3 crown peptide shown in ribbon depiction is colored from the N-terminus 307 position (blue) to the C-terminal 316 position (red) in a smooth gradient. R315 is shown in stick depiction in situ in the 447-52D electrostatic protein surface. The V3:mAb interaction surface is divided into three subdomains in terms of complementarity and how sequence variation would affect the interaction. Subdomain 1 is a side-by-side β-strand interaction between V3 and the mAb, and the area occupied by the V3 loop side chains (not shown, but pointing up and down perpendicular to the β-strand, see arrows) in this subdomain is loose and accommodating, so sequence variation in this subdomain is highly tolerated. Conversely, the surface enclosing the side chains of subdomains 2 and 3 demonstrates a tight shape and electrostatic complementarity, indicating poor tolerance for sequence substitution (which results in a side chain change) at these sites. However, the sequence in subdomain 2 (GPG) is nearly universal in HIV-1 isolates so the tight complementarity does not constrain the mAb to specific virus strains. The R315 of subdomain 3 is present in only a subset of viruses, and the shape and electrostatic complementarity of the pocket enclosing R315 are seen to be tight and unforgiving. Therefore the sequence-specific epitope motif of mAb 447-52D based on this structural analysis is R315.
FIG. 2.
FIG. 2.
(A) Histogram plot of the logarithm of the binding energies (x-axis) calculated for peptides modeled into the 447-52D antibody surface of subdomain 1. Filled circles: peptide structures corresponding to the LANL sequence variation in subdomain 1. Open circles: peptide structures corresponding to the phage display sequence variation and in vitro ELISA tested peptides proven experimentally to bind to mAb 447-52D. Both distributions primarily form a normal or Gaussian distribution about a similar mean binding energy value. (B) Plot of expected observations occurring along a standard normal distribution (solid line) centered on the observed mean from (A), as plotted by standard deviations (x-axis). A tail of scores on the left indicates the presence of a subpopulation in LANL that deviates from the normal/Gaussian distribution. This subpopulation is predicted to be LANL subdomain 1 sequences that cannot be predicted statistically to bind mAb 447-52D and represents approximately 7% of R315 LANL sequences. This sequence population is characterized by the presence of phenylalanine, glutamate, glycine, and proline amino acids in subdomain 1.
FIG. 3.
FIG. 3.
Phylogenetic tree demonstrating the relationship between the sequences in subdomain 1 of SBIND and SLANL. SBIND members consist of phage display sequences from a previously published study18 and mAb 447-52D binding sequences,7,17 and are denoted by a prefix of “BIND_phage” and “BIND_,” respectively. SLANL are denoted by the pattern “LANL_x_y,” where x is the rank of the sequence by occurrence (1–100) and y is the number of times the sequence occurs in the database. Brackets (solid = SBIND; dashed =SLANL) indicate the “width” of evolutionary distance for each of the two sets. The names within the earliest or root 10 branches of the tree are colored alternatively and repetitively in shades of gray to highlight the branch groupings. Similarly, various shades of gray indicate amino acid conservation in the alignment.
FIG. 4.
FIG. 4.
Worldwide HIV-1 clade distribution. This diagram depicts the estimated global distribution of HIV-1 genetic subtypes in the year 2000.25 Hatched shape overlays illustrate the theoretical coverage of the two mAbs (447-52D and 2219) calculated in this work. The areas do not correspond exactly to the numbers calculated and are for illustrative purposes only.
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