Translating HIV Sequences into Quantitative Fitness Landscapes Predicts Viral Vulnerabilities for Rational Immunogen Design

Ferguson, Andrew L.; Mann, Jaclyn K.; Omarjee, Saleha; Ndung’u, Thumbi; Walker, Bruce D.; Chakraborty, Arup K.

doi:10.1016/j.immuni.2012.11.022

Cited by 238 publications

(399 citation statements)

References 48 publications

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“…In the same comparison using the inde- The results presented here are reinforced by other recent studies of protein evolutionary landscapes Mann et al 2014;Figliuzzi et al 2015;Hopf et al 2017) where varying measures of experimental fitness are compared with statistical energies derived from correlated Potts models constructed from MSAs. The range of statistical energies and the correlation with fitness are qualitatively similar to those presented by Ferguson et al (2013) and Mann et al (2014) where statistical energies of engineered HIV-1 Gag variants generated using a similar inference technique are compared with replicative fitness assays. The same can be said for correlations between Potts scores and relative folding free energies of beta lactamase TEM-1 presented by Figliuzzi et al (2015).…”

Section: Protease Mutations Protein Stability and Replicative Capacitysupporting

confidence: 64%

“…The correlations induce epistatic effects, a primary or accessory resistance mutation can be either stabilizing or destabilizing depending on the genetic background. Recently epistasis has become a focus for analysis in structural biology and genomics as researchers have begun to successfully link the coevolutionary information in collections of protein sequences with the structural and functional fitness of those proteins (Hinkley et al 2011;Ferguson et al 2013;Mann et al 2014;Figliuzzi et al 2015;Hopf et al 2017;Barton et al 2016b;Butler et al 2016). In the current study, we have used the correlated mutations encoded in a MSA of drug-experienced HIV-1 protease sequences to parametrize a Potts model of sequence statistical energies that can be used as an estimator of stability and relative replicative capacity of individual protease sequences containing drug resistance mutations.…”

Section: Discussionmentioning

confidence: 99%

“…This process is then repeated for each position by selecting the merger of characters which minimizes the RMSD in MI between all pairs of positions ij with the original alphabet size Q ¼ 21 and reduced alphabet size Q ¼ Q 0 , and is stopped once Q ¼ 2. Due to residue conservation at many loci in the HIV-1 protease genome, the average number of characters per position is 2, and several previous studies of HIV-1 have used a binary alphabet to extract meaningful information from sequences (Wu et al 2003;Ferguson et al 2013;Shekhar et al 2013;Flynn et al 2015). However, using a binary alphabet (wildtype, mutant) marginalizes potentially informative distinctions between amino acids at certain positions, especially PI-associated sites, that acquire multiple mutations from the wildtype.…”

Section: Alphabet Reductionmentioning

confidence: 99%

“…Given a multiple sequence alignment (MSA) of related protein sequences, a probabilistic model of the network of interacting protein residues can be inferred from the pair correlations encoded in the MSA. Recently, probabilistic models, called Potts models, have been used to assign scores to individual protein sequences which correlate with experimental measures of fitness (Haq et al 2012;Ferguson et al 2013;Mann et al 2014;Figliuzzi et al 2015;Hopf et al 2017). These advances build upon previous and ongoing work in which Potts models have been used to extract information from sequence data regarding tertiary and quaternary structure of protein families (Weigt et al 2009;Morcos et al 2011Morcos et al , 2014Marks et al 2012;Sulkowska et al 2012;Sutto et al 2015;Barton et al 2016a;Haldane et al 2016;Jacquin et al 2016) and sequencespecific quantitative predictions of viral protein stability and fitness (Haq et al 2012;Shekhar et al 2013;Barton et al 2016b;Butler et al 2016).…”

Section: Introductionmentioning

confidence: 99%

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Inference of epistatic effects leading to entrenchment and drug resistance in HIV-1 protease

Flynn

Haldane

Torbett

et al. 2016

Preprint

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Understanding the complex mutation patterns that give rise to drug resistant viral strains provides a foundation for developing more effective treatment strategies for HIV/AIDS. Multiple sequence alignments of drug-experienced HIV-1 protease sequences contain networks of many pair correlations which can be used to build a (Potts) Hamiltonian model of these mutation patterns. Using this Hamiltonian model, we translate HIV-1 protease sequence covariation data into quantitative predictions for the probability of observing specific mutation patterns which are in agreement with the observed sequence statistics. We find that the statistical energies of the Potts model are correlated with the fitness of individual proteins containing therapy-associated mutations as estimated by in vitro measurements of protein stability and viral infectivity. We show that the penalty for acquiring primary resistance mutations depends on the epistatic interactions with the sequence background. Primary mutations which lead to drug resistance can become highly advantageous (or entrenched) by the complex mutation patterns which arise in response to drug therapy despite being destabilizing in the wildtype background. Anticipating epistatic effects is important for the design of future protease inhibitor therapies.

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Section: Protease Mutations Protein Stability and Replicative Capacitysupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Alphabet Reductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inference of epistatic effects leading to entrenchment and drug resistance in HIV-1 protease

Flynn

Haldane

Torbett

et al. 2016

Preprint

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show abstract

“…A third area of interest for HIV‐1 T‐cell vaccine design is the idea of focusing responses on epitopes that are presumed to be beneficial because they are either highly conserved,49, 50, 51, 52 require compensatory mutations to escape,53 or are associated with better viral control in natural infections 54. While particular epitopes can be identified that are good candidates for such design strategies, vaccines based on the delivery of concatenated epitopes have not been immunogenic in humans 55, 56.…”

Section: T‐cell Vaccine Design Strategiesmentioning

confidence: 99%

Polyvalent vaccine approaches to combat HIV‐1 diversity

Korber

Hraber

Wagh

et al. 2017

Immunological Reviews

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SummaryA key unresolved challenge for developing an effective HIV‐1 vaccine is the discovery of strategies to elicit immune responses that are able to cross‐protect against a significant fraction of the diverse viruses that are circulating worldwide. Here, we summarize some of the immunological implications of HIV‐1 diversity, and outline the rationale behind several polyvalent vaccine design strategies that are currently under evaluation. Vaccine‐elicited T‐cell responses, which contribute to the control of HIV‐1 in natural infections, are currently being considered in both prevention and treatment settings. Approaches now in preclinical and human trials include full proteins in novel vectors, concatenated conserved protein regions, and polyvalent strategies that improve coverage of epitope diversity and enhance the cross‐reactivity of responses. While many barriers to vaccine induction of broadly neutralizing antibody (bNAb) responses remain, epitope diversification has emerged as both a challenge and an opportunity. Recent longitudinal studies have traced the emergence of bNAbs in HIV‐1 infection, inspiring novel approaches to recapitulate and accelerate the events that give rise to potent bNAb in vivo. In this review, we have selected two such lineage‐based design strategies to illustrate how such in‐depth analysis can offer conceptual improvements that may bring us closer to an effective vaccine.

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Humoral responses to HIVconsv induced by heterologous vaccine modalities in rhesus macaques

Borthwick

Rosario

Schiffner

et al. 2015

Immunity Inflam & Disease

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Vaccines delivering T cell immunogen HIVconsv vectored by plasmid DNA, non-replicating simian adenovirus and non-replicating modified vaccinia virus Ankara (MVA) are under clinical evaluation in phase I/IIa trials in UK, Europe, and Africa. While these vaccines aim to induce effector T cell responses specific for HIV-1, we here characterized the humoral responses induced by HIVconsv administration to macaques using six different vaccine modalities: plasmid DNA, human adenovirus serotype 5, simian adenovirus serotype 63, MVA, Semliki Forest virus replicons, and adjuvanted overlapping synthetic long peptides (SLP). We found that only the SLP formulation, but none of the genetic vaccine platforms induced antibodies recognizing linear HIVconsv epitopes, median 32/46 SLP.HIVconsv peptides. These antibodies bound to 15-mer and SLP peptides, recombinant gp120 and trimeric gp140 of HIV-1 Bal, YU2, JRFL, and UG037, but failed to react with HIV-1 Bal and IIIB virions and HIV-1 Bal- and IIIB-infected human cells, and consequently failed to induce neutralizing antibodies. The HIVconsv immunogen contains conserved regions derived from Gag, Pol, Vif, and Env proteins of HIV-1, and antibodies induced by the SLP.HIVconsv vaccination resulted in positive signals in routine HIV-1 tests. Thus, only HIVconsv delivered by SLP resulted in seroconversion, an observation that provides important guidance for recruiting volunteers into future clinical trials. Furthermore, our data confirms that vaccine delivery by SLP induces humoral as well as cellular immune responses and could be considered for inclusion in future vaccine regimens where this is required.

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Translating HIV Sequences into Quantitative Fitness Landscapes Predicts Viral Vulnerabilities for Rational Immunogen Design

Cited by 238 publications

References 48 publications

Inference of epistatic effects leading to entrenchment and drug resistance in HIV-1 protease

Inference of epistatic effects leading to entrenchment and drug resistance in HIV-1 protease

Polyvalent vaccine approaches to combat HIV‐1 diversity

Humoral responses to HIVconsv induced by heterologous vaccine modalities in rhesus macaques

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