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A mechanistic understanding of allosteric immune escape pathways in the HIV-1 envelope glycoprotein.

ABSTRACT: The HIV-1 envelope (Env) spike, which consists of a compact, heterodimeric trimer of the glycoproteins gp120 and gp41, is the target of neutralizing antibodies. However, the high mutation rate of HIV-1 and plasticity of Env facilitates viral evasion from neutralizing antibodies through various mechanisms. Mutations that are distant from the antibody binding site can lead to escape, probably by changing the conformation or dynamics of Env; however, these changes are difficult to identify and define mechanistically. Here we describe a network analysis-based approach to identify potential allosteric immune evasion mechanisms using three known HIV-1 Env gp120 protein structures from two different clades, B and C. First, correlation and principal component analyses of molecular dynamics (MD) simulations identified a high degree of long-distance coupled motions that exist between functionally distant regions within the intrinsic dynamics of the gp120 core, supporting the presence of long-distance communication in the protein. Then, by integrating MD simulations with network theory, we identified the optimal and suboptimal communication pathways and modules within the gp120 core. The results unveil both strain-dependent and -independent characteristics of the communication pathways in gp120. We show that within the context of three structurally homologous gp120 cores, the optimal pathway for communication is sequence sensitive, i.e. a suboptimal pathway in one strain becomes the optimal pathway in another strain. Yet the identification of conserved elements within these communication pathways, termed inter-modular hotspots, could present a new opportunity for immunogen design, as this could be an additional mechanism that HIV-1 uses to shield vulnerable antibody targets in Env that induce neutralizing antibody breadth.

SUBMITTER: Sethi A

PROVIDER: S-EPMC3656115 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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A mechanistic understanding of allosteric immune escape pathways in the HIV-1 envelope glycoprotein.

Sethi Anurag A Tian Jianhui J Derdeyn Cynthia A CA Korber Bette B Gnanakaran S S

PLoS computational biology 20130516 5

The HIV-1 envelope (Env) spike, which consists of a compact, heterodimeric trimer of the glycoproteins gp120 and gp41, is the target of neutralizing antibodies. However, the high mutation rate of HIV-1 and plasticity of Env facilitates viral evasion from neutralizing antibodies through various mechanisms. Mutations that are distant from the antibody binding site can lead to escape, probably by changing the conformation or dynamics of Env; however, these changes are difficult to identify and defi ...[more]

PMID: 23696718

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Project description:Interferon-induced transmembrane protein 3 (IFITM3) is a cellular factor that reduces HIV-1 infectivity by an incompletely understood mechanism. We show here that viruses differing only in the envelope glycoprotein (Env) expressed on their surface have different sensitivities to IFITM3. Measurements of the sensitivity of viruses to neutralizing antibodies showed that IFITM3 increased the sensitivity of IFITM3-sensitive viruses to PG16, which targets the V1V2 loop, suggesting that IFITM3 promotes exposure of the PG16 epitope of IFITM3-sensitive viruses. Exchanges of V1V2 loops between the Env proteins of sensitive and resistant viruses revealed that V1V2 and V3 act together to modulate viral sensitivity to IFITM3. Co-immunoprecipitation experiments showed that IFITM3 interacted with both the precursor (gp160) and cleaved (gp120) forms of Env from IFITM3-sensitive viruses, but only with the precursor (gp160) form of Env from IFITM3-resistant viruses. This finding suggests that the interaction between the Env of resistant viruses and IFITM3 was inhibited once Env had been processed in the Golgi apparatus. This hypothesis was supported by immunofluorescence experiments, which showed a strong colocalization of IFITM3 with the Env of sensitive viruses, but only weak colocalization with the Env of resistant viruses on the plasma membrane of virus-producing cells. Together, these results indicate that IFITM3 interacts with Env, inducing conformational changes that may decrease viral infectivity. This antiviral action is, nevertheless, modulated by the nature of the Env, in particular its V1V2 and V3 loops, which after maturation may be able to escape this interaction.IMPORTANCE Interferon-induced transmembrane protein 3 (IFITM3) is a cellular factor that reduces HIV-1 infectivity by an incompletely understood mechanism. This study aimed to elucidate the role of the HIV-1 envelope glycoprotein (Env) in determining viral susceptibility to IFITM3. We found that viruses differing only in Env expressed on their surface had different sensitivities to IFITM3. By comparing the Env proteins of viruses that were highly sensitive or resistant to IFITM3, we obtained new insight in the mechanisms by which HIV-1 escapes this protein. We showed that IFITM3 interacts with the Env protein of sensitive viruses in virion-producing cells, inducing conformational changes that may decrease viral infectivity. However, this antiviral action is modulated by the nature of Env, particularly the V1V2 and V3 loops, which may be able to escape this interaction after processing in the Golgi.

Project description:The rational design of HIV-1 immunogens to trigger the development of broadly neutralizing antibodies (bNAbs) requires understanding the viral evolutionary pathways influencing this process. An acute HIV-1-infected individual exhibiting >50% plasma neutralization breadth developed neutralizing antibody specificities against the CD4-binding site (CD4bs) and V1V2 regions of Env gp120. Comparison of pseudoviruses derived from early and late autologous env sequences demonstrated the development of >2 log resistance to VRC13 but not to other CD4bs-specific bNAbs. Mapping studies indicated that the V3 and CD4-binding loops of Env gp120 contributed significantly to developing resistance to the autologous neutralizing response and that the CD4-binding loop (CD4BL) specifically was responsible for the developing resistance to VRC13. Tracking viral evolution during the development of this cross-neutralizing CD4bs response identified amino acid substitutions arising at only 4 of 11 known VRC13 contact sites (K282, T283, K421, and V471). However, each of these mutations was external to the V3 and CD4BL regions conferring resistance to VRC13 and was transient in nature. Rather, complete resistance to VRC13 was achieved through the cooperative expression of a cluster of single amino acid changes within and immediately adjacent to the CD4BL, including a T359I substitution, exchange of a potential N-linked glycosylation (PNLG) site to residue S362 from N363, and a P369L substitution. Collectively, our data characterize complex HIV-1 env evolution in an individual developing resistance to a VRC13-like neutralizing antibody response and identify novel VRC13-associated escape mutations that may be important to inducing VRC13-like bNAbs for lineage-based immunogens.IMPORTANCEThe pursuit of eliciting broadly neutralizing antibodies (bNAbs) through vaccination and their use as therapeutics remains a significant focus in the effort to eradicate HIV-1. Key to our understanding of this approach is a more extensive understanding of bNAb contact sites and susceptible escape mutations in HIV-1 envelope (env). We identified a broad neutralizer exhibiting VRC13-like responses, a non-germline restricted class of CD4-binding site antibody distinct from the well-studied VRC01-class. Through longitudinal envelope sequencing and Env-pseudotyped neutralization assays, we characterized a complex escape pathway requiring the cooperative evolution of four amino acid changes to confer complete resistance to VRC13. This suggests that VRC13-class bNAbs may be refractory to rapid escape and attractive for therapeutic applications. Furthermore, the identification of longitudinal viral changes concomitant with the development of neutralization breadth may help identify the viral intermediates needed for the maturation of VRC13-like responses and the design of lineage-based immunogens.

Dataset Information

A mechanistic understanding of allosteric immune escape pathways in the HIV-1 envelope glycoprotein.

Publications

A mechanistic understanding of allosteric immune escape pathways in the HIV-1 envelope glycoprotein.

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