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• W2079069987 abstract "Deliberate redirection of T cell responses to human immunodeficiency virus-1 might enhance immunity and thus aid viral containment. Dahirel et al., 2011Dahirel V. Shekhar K. Pereyra F. Miura T. Artyomov M. Talsania S. Allen T.M. Altfeld M. Carrington M. Irvine D.J. et al.Proc. Natl. Acad. Sci. USA. 2011; (in press. Published online June 20, 2011)https://doi.org/10.1073/pnas.1105315108Crossref PubMed Scopus (141) Google Scholar identify candidate antigens to achieve this with a theory derived from physics. Deliberate redirection of T cell responses to human immunodeficiency virus-1 might enhance immunity and thus aid viral containment. Dahirel et al., 2011Dahirel V. Shekhar K. Pereyra F. Miura T. Artyomov M. Talsania S. Allen T.M. Altfeld M. Carrington M. Irvine D.J. et al.Proc. Natl. Acad. Sci. USA. 2011; (in press. Published online June 20, 2011)https://doi.org/10.1073/pnas.1105315108Crossref PubMed Scopus (141) Google Scholar identify candidate antigens to achieve this with a theory derived from physics. The elephant in the conference room for those working with human immunodeficiency virus (HIV) vaccines is that despite 30 years of intense scientific effort and extremely generous global funding, we have no tenable vaccine. This research effort and the money spent have told us much about the virus and the immunity it evokes, but there has been no translation to a preventative vaccine. So far three large trials have failed to demonstrate protection against HIV-1 infection. We still do not know what form of immunity a vaccine must engender to prevent infection. The STEP trial has severely tempered enthusiasm for T cell vaccines (Buchbinder et al., 2008Buchbinder S.P. Mehrotra D.V. Duerr A. Fitzgerald D.W. Mogg R. Li D. Gilbert P.B. Lama J.R. Marmor M. Del Rio C. et al.Step Study Protocol TeamLancet. 2008; 372: 1881-1893Abstract Full Text Full Text PDF PubMed Scopus (1302) Google Scholar), but despite the negative result, the boosting or enhancement of anti-HIV cytotoxic T cells (CTLs) remains a stoical ambition of many groups. The enduring inspiration for this aim is the fact that HIV-1-specific CTLs do seem responsible for containment of the infection. Uncommonly, some individuals suppress HIV replication so well that virus is not detectable in their plasma. This phenomenon has been attributed, in part, to HIV-1-specific CTLs. Many of these patients have particular human leucocyte antigen (HLA) class I molecules that confer benefit in ways we barely understand. If CTL responses could be artificially boosted or redirected to the “right” antigens, then could protective immunity be induced or chronically infected patients be converted into “elite controllers”? Natural and artificially induced CTLs select retroviral mutants that evade immune recognition (Phillips et al., 1991Phillips R.E. Rowland-Jones S. Nixon D.F. Gotch F.M. Edwards J.P. Ogunlesi A.O. Elvin J.G. Rothbard J.A. Bangham C.R. Rizza C.R. et al.Nature. 1991; 354: 453-459Crossref PubMed Scopus (858) Google Scholar); the impact on clinical progression that immune escape confers is not clear. In an apparent paradox, immune escape might even slow progression, depending on the precise mutations that confer this effect (Frater et al., 2007Frater A.J. Brown H. Oxenius A. Günthard H.F. Hirschel B. Robinson N. Leslie A.J. Payne R. Crawford H. Prendergast A. et al.J. Virol. 2007; 81: 6742-6751Crossref PubMed Scopus (89) Google Scholar). Methods that quantify viral replicative capacity, or “fitness,” ex vivo have shown that immune escape mutations in certain HIV epitopes are associated with fitness costs whereas others exact no price. Three findings in patients strongly support the notion that some immune escape mutants impair virus replication: (1) the reversion of mutations upon transmission to new hosts who do not carry the same HLA class I alleles (Leslie et al., 2004Leslie A.J. Pfafferott K.J. Chetty P. Draenert R. Addo M.M. Feeney M. Tang Y. Holmes E.C. Allen T. Prado J.G. et al.Nat. Med. 2004; 10: 282-289Crossref PubMed Scopus (675) Google Scholar), (2) preliminary observations that immune escape may revert in end-stage AIDS as the immune system weakens (Huang et al., 2011Huang K.-H.G. Goedhals D. Carlson J.M. Brockman M.A. Mishra S. Brumme Z.L. Hickling S. Tang C.S. Miura T. Seebregts C. et al.Bloemfontein-Oxford Collaborative GroupPLoS ONE. 2011; 6: e19018Crossref PubMed Scopus (49) Google Scholar), and (3) the identification of compensatory viral mutations that partially or fully reinstate viral fitness (Crawford et al., 2007Crawford H. Prado J.G. Leslie A. Hué S. Honeyborne I. Reddy S. van der Stok M. Mncube Z. Brander C. Rousseau C. et al.J. Virol. 2007; 81: 8346-8351Crossref PubMed Scopus (178) Google Scholar). There is a dynamic between the triad of CTL pressure, viral adaptation, and viral fitness. The outcome of this battle will influence, perhaps markedly, clinical progression (Figure 1). In the 108th edition of the Proceedings of the National Academy of Science, Dahirel et al., 2011Dahirel V. Shekhar K. Pereyra F. Miura T. Artyomov M. Talsania S. Allen T.M. Altfeld M. Carrington M. Irvine D.J. et al.Proc. Natl. Acad. Sci. USA. 2011; (in press. Published online June 20, 2011)https://doi.org/10.1073/pnas.1105315108Crossref PubMed Scopus (141) Google Scholar report the application of random matrix theory (RMT) to a study of HIV viral evolution. RMT is a mathematical technique that filters out the noise present in large groups of varying data to find otherwise hidden correlations. The authors use RMT to search the HIV-1 genome for sites of variation that evolve together, in the same way financial stocks within either the building or pharmaceutical sectors might covary independently from other sectors. By grouping mutations in HIV-1 into these “sectors,” they identify conserved regions of the genome that would be candidates for vaccine antigens. This analysis is predicated on the idea that HIV adaptation to CTL pressure is ultimately limited by fitness costs. The resulting vaccine-induced immunity would select for mutants that carry high fitness costs and where compensatory mutations are not tolerated because of structural constraints. In the first instance the authors analyze 1,600 HIV subtype B Gag sequences (500 amino acids long) from the Los Alamos laboratories database and identify events where mutations occur together more frequently than would be expected from their independent distributions. A correlation matrix of all possible combinations of polymorphic amino acid sites is then produced. Where mutations become linked a cluster is defined, called an “eigenvector,” which itself has an “eigenvalue” to reflect the strength of correlations linking the individual sites. The authors, however, had to account for noise and phylogenetic relationships between sites (which give the strongest eigenvectors), because this can lead to misleading associations. This is where RMT came in useful, to define the boundary between eigenvectors that represented noise from those representing true signal. Although they identified 289 sites in HIV Gag that did not coevolve, they found collections of mutating sites (sectors) that did. A key point is that HLA-associated footprint sites—i.e., those that reflect viral adaptation to CTL-imposed immune pressure—were only weakly associated with sectors and were effectively excluded. The use of RMT to “clean” the resulting matrix of coevolving sites of noise resulted in some interesting trends. The authors identify five sectors within the HIV-1 Gag proteome that have evolved independently of each other. These five sectors contain conserved amino acid loci (mean conservation within the sectors of at least 95%), although they vary in the degree to which sites covary. In particular, sites with a “negative correlation” (i.e., mutations that are found together less frequently than might be expected from their individual frequencies) are felt to be important because they reflect evolutionary constraint. Of the five sectors, the authors identify Gag sector 3—a collection of 57 amino acid sites—to have the strongest negative correlations, suggesting that this is the region of the HIV proteome under greatest conservation and therefore a good target for a vaccine. The identification of sector 3 is supported by structural modeling showing that 68% of the associated amino acid sites are at key interfaces of the p24 protein hexamers, potentially explaining the observed evolutionary constraint. This result confirms how we need to consider the “nonlinearity” of the HIV genome and how amino acids that are some distance apart in protein sequence may have critical interactions within a three-dimensional structure. An intriguing result in this paper is that the HLA class I alleles enriched among “elite HIV controllers”—i.e., those individuals who maintain low or undetectable viral loads without therapy—target epitopes that contain more sites from sector 3 than the other four sectors. This result is surprising because the selection of sites within the sectors has been cleaned or corrected for those that vary because of HLA class I-imposed selection, and so this finding reflects a separate pressure driving coevolution. The argument is that controllers target immune responses against highly structurally conserved epitopes, and therefore escape mutations—particularly multiple mutations—extract a cost from HIV-1 so rendering it either nonviable or of very low replication capacity. Although this is not a new argument (these authors and others have previously reported associations of viral fitness and immune escape), this paper is unique because it uses predictive mathematics derived from physics and financial forecasting. Could these approaches contribute to the design of an effective HIV vaccine? The authors selected known epitopes within the HIV proteome from an experimental data set, which, although limited, is representative for common HLA class I alleles. By choosing a selection of epitopes that contain the most sites from sector 3 and which cover the most common HLA class I alleles, the authors propose that an immunogen could be designed that could invoke T cell responses in the majority of the population and for which immune escape would be limited by structural constraint and fitness costs. Although other approaches have tackled this question—and many papers on HIV-1 fitness conclude by advocating the consideration of fitness in vaccine design—in this paper, a multidimensional approach has been applied. How can this approach be taken forward? It is well known that virus sequenced from HIV controllers frequently contains immune escape mutations within key protective epitopes—often at sites associated with fitness costs—and yet virological control is maintained (Miura et al., 2009Miura T. Brumme C.J. Brockman M.A. Brumme Z.L. Pereyra F. Block B.L. Trocha A. John M. Mallal S. Harrigan P.R. Walker B.D. J. Virol. 2009; 83: 3407-3412Crossref PubMed Scopus (59) Google Scholar). It is unlikely to be coincidence that many of these escape mutations often lie adjacent to many of the sites in sector 3, although they are cleaned out by the RMT method, which removes HLA-associated sites. It might be interesting therefore to consider sites not as independent amino acids but rather as moving “epitope windows” of 8–10 amino acids and see whether the same sector structures are realized. They may not be—complete escape from an immune response can result from a mutation at a single amino acid within a 10 amino acid epitope, with the other nine being highly conserved. An effective HIV vaccine—whether protective or therapeutic—is likely to be required to confer both humoral and cell-mediated protection. With the sorts of polydimensional mathematical approaches described by Dahirel et al., 2011Dahirel V. Shekhar K. Pereyra F. Miura T. Artyomov M. Talsania S. Allen T.M. Altfeld M. Carrington M. Irvine D.J. et al.Proc. Natl. Acad. Sci. USA. 2011; (in press. Published online June 20, 2011)https://doi.org/10.1073/pnas.1105315108Crossref PubMed Scopus (141) Google Scholar, one might envisage how the costs of all viral adaptation could be considered together—including adaptation to CTLs, broadly neutralizing antibodies, and even antiretroviral drugs—to predict a truly universal immunogen. RMT is closely associated with John von Neumann (von Neumann and Goldstine, 1947von Neumann J. Goldstine H.H. Bull. Am. Math. Soc. 1947; 53: 1021-1099Crossref Scopus (185) Google Scholar), who was also involved in the Manhattan Project working out of Los Alamos and the first atomic bomb. The decision to apply this concept to HIV sequence data also from Los Alamos is reminiscent of beating swords into ploughshares. What would von Neumann make of this application of his theory? Effective HIV vaccines remain elusive but we are sure von Neumann would approve of this meritorious application of his theory to data archived at Los Alamos for the betterment, not the destruction, of mankind." @default.
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• W2079069987 title "Beating Atomic Swords into Immunological Ploughshares" @default.
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