Structural Descriptors of gp120 V3 Loop for the Prediction of HIV-1 Coreceptor Usage

Abstract

HIV-1 cell entry commonly uses, in addition to CD4, one of the chemokine receptors CCR5 or CXCR4 as coreceptor. Knowledge of coreceptor usage is critical for monitoring disease progression as well as for supporting therapy with the novel drug class of coreceptor antagonists. Predictive methods for inferring coreceptor usage based on the third hypervariable (V3) loop region of the viral gene coding for the envelope protein gp120 can provide us with these monitoring facilities while avoiding expensive phenotypic tests. All simple heuristics (such as the 11/25 rule) as well as statistical learning methods proposed to date predict coreceptor usage based on sequence features of the V3 loop exclusively. Here, we show, based on a recently resolved structure of gp120 with an untruncated V3 loop, that using structural information on the V3 loop in combination with sequence features of V3 variants improves prediction of coreceptor usage. In particular, we propose a distance-based descriptor of the spatial arrangement of physicochemical properties that increases discriminative performance. For a fixed specificity of 0.95, a sensitivity of 0.77 was achieved, improving further to 0.80 when combined with a sequence-based representation using amino acid indicators. This compares favorably with the sensitivities of 0.62 for the traditional 11/25 rule and 0.73 for a prediction based on sequence information as input to a support vector machine and constitutes a statistically significant improvement. A detailed analysis and interpretation of structural features important for classification shows the relevance of several specific hydrogen-bond donor sites and aliphatic side chains to coreceptor specificity towards CCR5 or CXCR4. Furthermore, an analysis of side chain orientation of the specificity-determining residues suggests a major role of one side of the V3 loop in the selection of the coreceptor. The proposed method constitutes the first approach to an improved prediction of coreceptor usage based on an original integration of structural bioinformatics methods with statistical learning.

Molecular and structural characterization of HIV-1 subtype B Brazilian isolates with GWGR tetramer at the tip of the V3-loop

“…It has been shown that intrahost evolution of the V3 loop structure is highly diverse and structurally flexible throughout the infection (Watabe et al, 2006). Therefore, structural modifications seem to be related to immune pressures and interactions with the cell coreceptor (Sander et al, 2007). Indeed, monoclonal antibodies directed against the D19 epitope within the V3 region neutralize only the X4 variants (Lusso et al, 2005).…”

“…Indeed, monoclonal antibodies directed against the D19 epitope within the V3 region neutralize only the X4 variants (Lusso et al, 2005). Consequently, inaccessibility of this antibody to R5 might indicate that there are significant V3 loop conformational differences between these two variants (Sander et al, 2007). In fact, it has been demonstrated that intricate electrostatic interactions occur among amino acid residues in order to preserve the proper tertiary structure of the V3 loop (Rosen et al, 2006).…”

Determinação do tropismo do HIV-1 pelos correceptores CCR5 e CXCR4 pelo uso de ferramentas de bioinformática.

“…Isso explica porque apenas alguns indivíduos desenvolvem cepas X4 (Mild et al, 2009 (Poon et al, 2007;Rosen et al, 2006;Sander et al, 2007). Ainda não está claro se o aparecimento de aminoácidos básicos nas posições 11 e 25 é suficiente ou mesmo necessário para a emergência de cepas X4, mas diferenças intrínsecas na alça V3 entre os subtipos podem levar a diferenças na emergência das cepas X4 e é provável que a troca do tropismo seja um processo gradual de acúmulo de mutações (Hughes e Nelson, 2009;Jensen et al, 2003).…”

“…Ainda não está claro se o aparecimento de aminoácidos básicos nas posições 11 e 25 é suficiente ou mesmo necessário para a emergência de cepas X4, mas diferenças intrínsecas na alça V3 entre os subtipos podem levar a diferenças na emergência das cepas X4 e é provável que a troca do tropismo seja um processo gradual de acúmulo de mutações (Hughes e Nelson, 2009;Jensen et al, 2003). (Braun e Wiesmann, 2007;Sander et al, 2007;Sierra et al, 2007).…”

“…De fato, os ensaios fenotípicos detectam cepas minoritárias de até 1%, enquanto o sequenciamento direto de amostras dos pacientes é capaz de detectar a presença de cepas minoritárias superior a 20% da população viral total. Informações sobre a estrutura tridimensional da alça V3, dados clínicos e laboratoriais dos pacientes, como contagem de linfócitos T também são capazes de aumentar substancialmente a qualidade da predição Sander et al, 2007).…”