title: Accurate predictions of population-level changes in sequence and structural properties of HIV-1 Env using a volatility-controlled diffusion model.
abstract: The envelope glycoproteins (Envs) of HIV-1 continuously evolve in the host by random mutations and recombination events. The resulting diversity of Env variants circulating in the population and their continuing diversification process limit the efficacy of AIDS vaccines. We examined the historic changes in Env sequence and structural features (measured by integrity of epitopes on the Env trimer) in a geographically defined population in the United States. As expected, many Env features were relatively conserved during the 1980s. From this state, some features diversified whereas others remained conserved across the years. We sought to identify "clues" to predict the observed historic diversification patterns. Comparison of viruses that cocirculate in patients at any given time revealed that each feature of Env (sequence or structural) exists at a defined level of variance. The in-host variance of each feature is highly conserved among individuals but can vary between different HIV-1 clades. We designate this property "volatility" and apply it to model evolution of features as a linear diffusion process that progresses with increasing genetic distance. Volatilities of different features are highly correlated with their divergence in longitudinally monitored patients. Volatilities of features also correlate highly with their population-level diversification. Using volatility indices measured from a small number of patient samples, we accurately predict the population diversity that developed for each feature over the course of 30 years. Amino acid variants that evolved at key antigenic sites are also predicted well. Therefore, small "fluctuations" in feature values measured in isolated patient samples accurately describe their potential for population-level diversification. These tools will likely contribute to the design of population-targeted AIDS vaccines by effectively capturing the diversity of currently circulating strains and addressing properties of variants expected to appear in the future.
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Orlando
authors.initials: O
authors.lastname: DeLeon
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Hagit
authors.initials: H
authors.lastname: Hodis
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: O'Malley
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Jacklyn
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Hamid
authors.initials: H
authors.lastname: Salimi
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Yinjie
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Winter
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Claire
authors.initials: C
authors.lastname: Remec
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Noah
authors.initials: N
authors.lastname: Eichelberger
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Brandon
authors.initials: B
authors.lastname: Van Cleave
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Ramya
authors.initials: R
authors.lastname: Puliadi
authors.affiliation: Center for AIDS Research (CFAR) at the University of Washington, Seattle, Washington, United States of America.
authors.forename: Robert D
authors.initials: RD
authors.lastname: Harrington
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.|Veterans Affairs Medical Center, Iowa City, Iowa, United States of America.
authors.forename: Jack T
authors.initials: JT
authors.lastname: Stapleton
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors.forename: Hillel
authors.initials: H
authors.lastname: Haim
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D000940:Antigenic Variation; D002460:Cell Line; D003430:Cross-Sectional Studies; D004058:Diffusion; D004285:Dogs; D000939:Epitopes; D015699:HIV Envelope Protein gp120 / Q000097:blood / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000097:blood / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015658:HIV Infections / Q000097:blood / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology* / Q000302:isolation & purification / Q000378:metabolism; D006801:Humans; D007484:Iowa; D008137:Longitudinal Studies; D008958:Models, Molecular; D010802:Phylogeny; D020836:Protein Structure, Quaternary; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D014861:Washington
chemical_list: D000939:Epitopes; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; C039919:RNA, recombinant; D011993:Recombinant Fusion Proteins; C514793:gp120 protein, Human immunodeficiency virus 1; C514787:gp41 protein, Human immunodeficiency virus 1; D012313:RNA