Sexually-Transmitted/Founder HIV-1 Cannot Be Directly Predicted from Plasma or PBMC-Derived Viral Quasispecies in the Transmitting Partner

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Abstract

Objective

Characterization of HIV-1 sequences in newly infected individuals is important for elucidating the mechanisms of viral sexual transmission. We report the identification of transmitted/founder viruses in eight pairs of HIV-1 sexually-infected patients enrolled at the time of primary infection (“recipients”) and their transmitting partners (“donors”).

Methods

Using a single genome-amplification approach, we compared quasispecies in donors and recipients on the basis of 316 and 376 C2V5 env sequences amplified from plasma viral RNA and PBMC-associated DNA, respectively.

Results

Both DNA and RNA sequences indicated very homogeneous viral populations in all recipients, suggesting transmission of a single variant, even in cases of recent sexually transmitted infections (STIs) in donors (n = 2) or recipients (n = 3). In all pairs, the transmitted/founder virus was derived from an infrequent variant population within the blood of the donor. The donor variant sequences most closely related to the recipient sequences were found in plasma samples in 3/8 cases and/or in PBMC samples in 6/8 cases. Although donors were exclusively (n = 4) or predominantly (n = 4) infected by CCR5-tropic (R5) strains, two recipients were infected with highly homogeneous CXCR4/dual-mixed-tropic (X4/DM) viral populations, identified in both DNA and RNA. The proportion of X4/DM quasispecies in donors was higher in cases of X4/DM than R5 HIV transmission (16.7–22.0% versus 0–2.6%), suggesting that X4/DM transmission may be associated with a threshold population of X4/DM circulating quasispecies in donors.

Conclusions

These suggest that a severe genetic bottleneck occurs during subtype B HIV-1 heterosexual and homosexual transmission. Sexually-transmitted/founder virus cannot be directly predicted by analysis of the donor’s quasispecies in plasma and/or PBMC. Additional studies are required to fully understand the traits that confer the capacity to transmit and establish infection, and determine the role of concomitant STIs in mitigating the genetic bottleneck in mucosal HIV transmission.

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Most cited references 38

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Smooth skyride through a rough skyline: Bayesian coalescent-based inference of population dynamics.

Vladimir N. Minin, Erik W Bloomquist, Marc Suchard (2008)

Kingman's coalescent process opens the door for estimation of population genetics model parameters from molecular sequences. One paramount parameter of interest is the effective population size. Temporal variation of this quantity characterizes the demographic history of a population. Because researchers are rarely able to choose a priori a deterministic model describing effective population size dynamics for data at hand, nonparametric curve-fitting methods based on multiple change-point (MCP) models have been developed. We propose an alternative to change-point modeling that exploits Gaussian Markov random fields to achieve temporal smoothing of the effective population size in a Bayesian framework. The main advantage of our approach is that, in contrast to MCP models, the explicit temporal smoothing does not require strong prior decisions. To approximate the posterior distribution of the population dynamics, we use efficient, fast mixing Markov chain Monte Carlo algorithms designed for highly structured Gaussian models. In a simulation study, we demonstrate that the proposed temporal smoothing method, named Bayesian skyride, successfully recovers "true" population size trajectories in all simulation scenarios and competes well with the MCP approaches without evoking strong prior assumptions. We apply our Bayesian skyride method to 2 real data sets. We analyze sequences of hepatitis C virus contemporaneously sampled in Egypt, reproducing all key known aspects of the viral population dynamics. Next, we estimate the demographic histories of human influenza A hemagglutinin sequences, serially sampled throughout 3 flu seasons.

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Deciphering human immunodeficiency virus type 1 transmission and early envelope diversification by single-genome amplification and sequencing.

Jesus Salazar-Gonzalez, Elizabeth Bailes, Kimmy Pham … (2008)

Accurate identification of the transmitted virus and sequences evolving from it could be instrumental in elucidating the transmission of human immunodeficiency virus type 1 (HIV-1) and in developing vaccines, drugs, or microbicides to prevent infection. Here we describe an experimental approach to analyze HIV-1 env genes as intact genetic units amplified from plasma virion RNA by single-genome amplification (SGA), followed by direct sequencing of uncloned DNA amplicons. We show that this strategy precludes in vitro artifacts caused by Taq-induced nucleotide substitutions and template switching, provides an accurate representation of the env quasispecies in vivo, and has an overall error rate (including nucleotide misincorporation, insertion, and deletion) of less than 8 x 10(-5). Applying this method to the analysis of virus in plasma from 12 Zambian subjects from whom samples were obtained within 3 months of seroconversion, we show that transmitted or early founder viruses can be identified and that molecular pathways and rates of early env diversification can be defined. Specifically, we show that 8 of the 12 subjects were each infected by a single virus, while 4 others acquired more than one virus; that the rate of virus evolution in one subject during an 80-day period spanning seroconversion was 1.7 x 10(-5) substitutions per site per day; and that evidence of strong immunologic selection can be seen in Env and overlapping Rev sequences based on nonrandom accumulation of nonsynonymous mutations. We also compared the results of the SGA approach with those of more-conventional bulk PCR amplification methods performed on the same patient samples and found that the latter is associated with excessive rates of Taq-induced recombination, nucleotide misincorporation, template resampling, and cloning bias. These findings indicate that HIV-1 env genes, other viral genes, and even full-length viral genomes responsible for productive clinical infection can be identified by SGA analysis of plasma virus sampled at intervals typical in large-scale vaccine trials and that pathways of viral diversification and immune escape can be determined accurately.

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Envelope-constrained neutralization-sensitive HIV-1 after heterosexual transmission.

Cynthia A Derdeyn, Julie Decker, Frederic Bibollet-Ruche … (2004)

Heterosexual transmission accounts for the majority of human immunodeficiency virus-1 (HIV-1) infections worldwide, yet the viral properties that determine transmission fitness or outgrowth have not been elucidated. Here we show, for eight heterosexual transmission pairs, that recipient viruses were monophyletic, encoding compact, glycan-restricted envelope glycoproteins. These viruses were also uniquely sensitive to neutralization by antibody from the transmitting partner. Thus, the exposure of neutralizing epitopes, which are lost in chronic infection because of immune escape, appears to be favored in the newly infected host. This reveals characteristics of the envelope glycoprotein that influence HIV-1 transmission and may have implications for vaccine design.

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Author and article information

Contributors

Fabrizio Mammano: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 9 July 2013

Volume: 8

Issue: 7

Electronic Location Identifier: e69144

Affiliations

[1 ]Equipe d'accueil 3620, Université Paris-Descartes, Sorbonne Paris Cité, Paris, France

[2 ]Unité d’Immunologie, Hématologie et Rhumatologie pédiatriques, Assistance Publique – Hôpitaux de Paris, Hôpital Necker-Enfants malades, Paris, France

[3 ]Institut national de la Santé et de la Recherche médicale, Centre de recherche en Epidémiologie et Santé des Populations U1018, Université Paris 11, Faculté de Médecine Paris-Sud, Service d’Epidémiologie et de Santé Publique, Assistance Publique – Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

[4 ]Institut de Biologie computationnelle, Laboratoire d'Informatique, de Robotique et de Microélectronique de Montpellier, Unité mixte de Recherche 5506, Centre national de la Recherche scientifique et Université de Montpellier 2, Montpellier, France

[5 ]Service de Médecine interne, Assistance Publique – Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

[6 ]Service de Médecine interne, Hôpital Foch, Suresnes, France

[7 ]Service des maladies infectieuses et tropicales, Centre Hospitalier Universitaire de Fort de France, Fort de France, Martinique, France

[8 ]Laboratoire de Virologie, Assistance Publique – Hôpitaux de Paris, Hôpital Necker-Enfants malades, Paris, France

INSERM, France

Author notes

* E-mail: pierre.frange@ 123456nck.aphp.fr

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: PF LM CR MLC. Performed the experiments: PF MY MG OG MLC. Analyzed the data: PF LM MJ CG OG CR MLC. Contributed reagents/materials/analysis tools: MJ DZ SA PH MG. Wrote the paper: PF LM MJ CG DZ SA PH MG OG CR MLC.

¶ Membership of the ANRS PRIMO Cohort Study Group is provided in the Acknowledgments.

Article

Publisher ID: PONE-D-13-14350

DOI: 10.1371/journal.pone.0069144

PMC ID: 3706485

PubMed ID: 23874894

SO-VID: f88e3982-74aa-44c3-97e6-48e334af4868

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 8 April 2013

Date accepted : 3 June 2013

Page count

Pages: 13

Funding

This work was supported by grants from the French National Agency for Research on AIDS and viral hepatitis [ANRS PRIMO CO06] and by a scholarship (P. Frange) from SIDACTION [BI22-1-01851]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of this manuscript.

Sexually-Transmitted/Founder HIV-1 Cannot Be Directly Predicted from Plasma or PBMC-Derived Viral Quasispecies in the Transmitting Partner

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Abstract

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Conclusions

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PLOS Climate

Most cited references 38

Smooth skyride through a rough skyline: Bayesian coalescent-based inference of population dynamics.

Deciphering human immunodeficiency virus type 1 transmission and early envelope diversification by single-genome amplification and sequencing.

Envelope-constrained neutralization-sensitive HIV-1 after heterosexual transmission.

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