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Review
. 2010 Jul;10(7):527-35.
doi: 10.1038/nri2801.

Structure-function relationships of HIV-1 envelope sequence-variable regions refocus vaccine design

Susan Zolla-Pazner  1 , Timothy Cardozo
Affiliations
Review

Structure-function relationships of HIV-1 envelope sequence-variable regions refocus vaccine design

Susan Zolla-Pazner et al. Nat Rev Immunol. 2010 Jul.

Abstract

One of the main challenges of developing an HIV-1 vaccine lies in eliciting immune responses that can overcome the antigenic variability exhibited by HIV. Most HIV-1 vaccine development has focused on inducing immunity to conserved regions of the HIV-1 envelope. However, new studies of the sequence-variable regions of the HIV-1 gp120 envelope glycoprotein have shown that there are conserved immunological and structural features in these regions. Recombinant immunogens that include these features may provide the means to address the antigenic diversity of HIV-1 and induce protective antibodies that can prevent infection with HIV-1.

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Figures

Figure 1
Figure 1
A. Ribbon diagram of the crystallographic structure of the gp120 monomer bound to CD4. The locations on the structure are shown for the variable regions and bridging sheet (colored ribbons and color key). This gp120 monomer structure is adapted from Kwong et. al and represents the truncated, deglycosylated conserved core of gp120 without the variable loops. The colored regions indicate the locations of the variable regions. B. Ribbon diagram of the crystallographic structure of the V3 loop in situ on gp120 from the crystal structure solved by Huang et. al. indicating the base, stem and crown regions of the V3 loop. C. Zones of sequence variability mapped onto the β-hairpin conformation of the V3 crown (adapted from ). The crystallographic structure of the V3 crown is shown as a ribbon diagram, with commonly occurring side chains shown in stick depiction. A multi-colored illustrative cylinder is superimposed on the structure to highlight the four zones of the V3 crown: the arch (green), the hydrophilic face (red) and hydrophobic face (blue) of the circlet, and the band (brown). Only the hydrophilic face has high sequence variability, but the amino acids that constitute it are distributed widely in the linear protein sequence, which obscures its existence unless the 3D structural context is appreciated. Side chains bound by neutralizing monoclonal antibodies are annotated with colored lines and a color key: monoclonal antibody 268 neutralizes only a few HIV strains and engages various side chains including one in the variable hydrophilic face of V3; monoclonal antibodies 3074 and 2219 neutralize viruses from several HIV-1 subtypes and avoid engagement of the hydrophilic variable zone.
Figure 2
Figure 2
Conserved and variable residues in the V1, V2, and V3 loops of gp120. A. Sequence Logo depicting the amino acid conservation pattern across a multiple alignment of many V1 loops, each of which was selected because it has the most common V1 length depicted in Figure 3A. Data used to derive the Sequence Logo were derived from LANL, using one sequence per patient, and all HIV-1 subtypes were included. The height of the letter indicates the degree of conservation of the most common amino acid at that position. Amino acids are colored according to their chemical properties: polar amino acids (G,S,T,Y,C,Q,N) are green, basic amino acids (K,R,H) are blue, acidic amino acids (D,E) are red, and hydrophobic amino acids (A,V,L,I,P,W,F,M) are black. The few N- and C-terminal amino acids of the V1 loop show reasonable conservation, but most of the loop fades to small letters representative of no conservation except for a run of asparagines (N) and threonines (T) near the center suggesting a glycosylation region. B. Sequence Logo depicting the amino acid conservation pattern across a multiple alignment of many V2 loops, each of which was selected from LANL (one sequence per patient, all subtypes included) because it has the most common V2 length depicted in Figure 3B. The height of the letter indicates the degree of conservation of that particular most common amino acid at that position. Although the V2 loop has many more insertions and deletions than the V3 loop, it has a degree of amino acid conservation approaching that of the V3 loop when one controls for loop length as explained above. C. Amino acid positions and glycosylation sites that are implicated in the binding of V2-specific monoclonal antibody 697 and QNE-specific monoclonal antibodies PG9, PG16 and 2909 are mapped onto a schematic illustration of the V1/V2 loop structure. Map notations are colored according to the color key below the illustration. Brackets indicate more than one commonly occurring amino acid at a single position. The individual sites associated with each single Ab are distributed throughout the V1/V2 loop linearly, but must cluster in 3D space into one or a few overlapping epitopes. The amino acid numbering in this panel may not exactly match that in Figrues 2A and 2B due to the variation in V1 and V2 lengths. D. Sequence Logo in the same fashion as Figures 2A and 2B depicting the amino acid conservation pattern across a multiple alignment of all V3 loops from LANL (one sequence per patient, all subtypes included)
Figure 3
Figure 3
Histograms showing the length distributions of the V1 (A) and V2 (B) loops from recorded HIV-1 sequences in LANL. The histograms shows the number (y-axis) of recorded viruses exhibiting each V1 or V2 length (number of amino acids, (x-axis) from zero to the maximal recorded length, so, for example, the origin shows that no viruses are recorded to have entirely deleted V1 or V2 loops (length of loop = 0).
Figure 3
Figure 3
Histograms showing the length distributions of the V1 (A) and V2 (B) loops from recorded HIV-1 sequences in LANL. The histograms shows the number (y-axis) of recorded viruses exhibiting each V1 or V2 length (number of amino acids, (x-axis) from zero to the maximal recorded length, so, for example, the origin shows that no viruses are recorded to have entirely deleted V1 or V2 loops (length of loop = 0).
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