From the Cover. Coordinate linkage of HIV evolution reveals regions of immunological vulnerability

Ragon Institute of Massachusetts General Hospital, and Harvard University, Boston, MA 02129, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2011; 108(28):11530-5. DOI: 10.1073/pnas.1105315108
Source: PubMed


Cellular immune control of HIV is mediated, in part, by induction of single amino acid mutations that reduce viral fitness, but compensatory mutations limit this effect. Here, we sought to determine if higher order constraints on viral evolution exist, because some coordinately linked combinations of mutations may hurt viability. Immune targeting of multiple sites in such a multidimensionally conserved region might render the virus particularly vulnerable, because viable escape pathways would be greatly restricted. We analyzed available HIV sequences using a method from physics to reveal distinct groups of amino acids whose mutations are collectively coordinated ("HIV sectors"). From the standpoint of mutations at individual sites, one such group in Gag is as conserved as other collectively coevolving groups of sites in Gag. However, it exhibits higher order conservation indicating constraints on the viability of viral strains with multiple mutations. Mapping amino acids from this group onto protein structures shows that combined mutations likely destabilize multiprotein structural interactions critical for viral function. Persons who durably control HIV without medications preferentially target the sector in Gag predicted to be most vulnerable. By sequencing circulating viruses from these individuals, we find that individual mutations occur with similar frequency in this sector as in other targeted Gag sectors. However, multiple mutations within this sector are very rare, indicating previously unrecognized multidimensional constraints on HIV evolution. Targeting such regions with higher order evolutionary constraints provides a novel approach to immunogen design for a vaccine against HIV and other rapidly mutating viruses.

Download full-text


Available from: Darrell J Irvine,
  • Source
    • "A fourth approach comprises eigenvalue clipping methods [13] [14] [15] whose underlying idea is to 'clean' the SCM by filtering noisy eigenvalues claimed to convey little valuable information. This approach has also been employed recently in proposing novel vaccine design strategies for infectious diseases [16] [17], and its theoretical foundations have been examined in [18]. A fifth method employs a bootstrap-corrected estimator for the optimal return and its asset allocation, which reduces the error of over-prediction of the in-sample return by bootstrapping [6]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We study the design of portfolios under a minimum risk criterion. The performance of the optimized portfolio relies on the accuracy of the estimated covariance matrix of the portfolio asset returns. For large portfolios, the number of available market returns is often of similar order to the number of assets, so that the sample covariance matrix performs poorly as a covariance estimator. Additionally, financial market data often contain outliers which, if not correctly handled, may further corrupt the covariance estimation. We address these shortcomings by studying the performance of a hybrid covariance matrix estimator based on Tyler's robust M-estimator and on Ledoit-Wolf's shrinkage estimator while assuming samples with heavy-tailed distribution. Employing recent results from random matrix theory, we develop a consistent estimator of (a scaled version of) the realized portfolio risk, which is minimized by optimizing online the shrinkage intensity. Our portfolio optimization method is shown via simulations to outperform existing methods both for synthetic and real market data.
    IEEE Transactions on Signal Processing 03/2015; DOI:10.1109/TSP.2015.2474298 · 2.79 Impact Factor
  • Source
    • "Consequently, it has been proposed that a successful vaccine would elicit responses exclusively against epitopes that are resistant to mutation or are otherwise characterized by a superior immune response [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]. Note that the need to elicit responses to multiple epitopes in a single individual may be important for effective viral control [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We describe a vaccine delivery mechanism consisting of a synthetic, non-living vector of large d,l poly(lactic-co-glycolic) acid (PLGA) microspheres that carry specific cytotoxic T lymphocyte (CTL) epitopes. We demonstrate in mice that it can be used to elicit substantial CTL responses to more than one epitope in the same individual. Our data suggest that a superior adjuvant configuration for the formulation is to place the TLR-9 agonist CpG inside the microsphere and the TLR-4 agonist MPLA in the injectate solution. This finding contrasts with the observations of others. Our approach addresses an issue that may have led to the failure of the Ad5-based HIV vaccine, in that it can elicit responses to specific epitopes thought to be protective (and exclude epitopes thought to be non-protective) by providing a means to elicit immune responses efficiently to select epitopes.
    Vaccine 06/2014; 32(33). DOI:10.1016/j.vaccine.2014.05.071 · 3.62 Impact Factor
  • Source
    • "Additional determinants beyond amino acid sequences and local secondary structures of CS are involved in Gag and GagPol processing [7]. As Gag is conserved, there are constraints on the viability of viral strains with multiple mutations due to the fact that combined mutations are likely to destabilize multiprotein structural interactions that are critical for viral function [40]. Thus, amino acid sequence conservation indicates that the specific amino acids are required to maintain basic structure and function, although other authors have suggested an important role of RNA structure in HIV-1 conservation [33], [41]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Polymorphisms at cleavage sites (CS) can influence Gag and Pol proteins processing by the viral protease (PR), restore viral fitness and influence the virological outcome of specific antiretroviral drugs. However, data of HIV-1 variant-associated CS variability is scarce. In this descriptive research, we examine the effect of HIV-1 variants on CS conservation using all 9,028 gag and 3,906 pol HIV-1 sequences deposited in GenBank, focusing on the 110 residues (10 per site) involved at 11 CS: P17/P24, P24/P2, P2/P7, P7/P1, P1/P6 (gag) , NC/TFP, TFP/P6 (pol), P6 (pol) /PR, PR/RT(p51), RT(p51)/RT(p66) and RT(p66)/IN. CS consensus amino acid sequences across HIV-1 groups (M, O, N, P), group M 9 subtypes and 51 circulating recombinant forms (CRF) were inferred from our alignments and compared to the HIV-1 consensus-of-consensuses sequence provided by GenBank. In all HIV-1 variants, the most conserved CS were PR/RT(p51), RT(p51)/RT(p66), P24/P2 and RT(p66)/IN and the least P2/P7 and P6 (pol) /PR. Conservation was significantly lower in subtypes vs. recombinants in P2/P7 and TFP/P6 (pol) and higher in P17/P24. We found a significantly higher conservation rate among Group M vs. non-M Groups HIV-1. The late processing sites at Gag (P7/P1) and GagPol precursors (PR/RT(p51)) presented a significantly higher conservation vs. the first CS (P2/P7) in the 4 HIV-1 groups. Here we show 52 highly conserved residues across HIV-1 variants in 11 CS and the amino acid consensus sequence in each HIV-1 group and HIV-1 group M variant for each 11 CS. This is the first study to describe the CS conservation level across all HIV-1 variants and 11 sites in one of the largest available sequence HIV-1 dataset. These results could help other researchers for the future design of both novel antiretroviral agents acting as maturation inhibitors as well as for vaccine targeting CS.
    PLoS ONE 02/2014; 9(2):e88099. DOI:10.1371/journal.pone.0088099 · 3.23 Impact Factor
Show more