Demographic Processes Affect HIV-1 Evolution in Primary Infection before the Onset of Selective Processes

ABSTRACT HIV-1 transmission and viral evolution in the first year of infection were studied in 11 individuals representing four transmitter-recipient pairs and three independent seroconverters. Nine of these individuals were enrolled during acute infection; all were men who have sex with men (MSM) infected with HIV-1 subtype B. A total of 475 nearly full-length HIV-1 genome sequences were generated, representing on average 10 genomes per specimen at 2 to 12 visits over the first year of infection. Single founding variants with nearly homogeneous viral populations were detected in eight of the nine individuals who were enrolled during acute HIV-1 infection. Restriction to a single founder variant was not due to a lack of diversity in the transmitter as homogeneous populations were found in recipients from transmitters with chronic infection. Mutational patterns indicative of rapid viral population growth dominated during the first 5 weeks of infection and included a slight contraction of viral genetic diversity over the first 20 to 40 days. Subsequently, selection dominated, most markedly in env and nef. Mutants were detected in the first week and became consensus as early as day 21 after the onset of symptoms of primary HIV infection. We found multiple indications of cytotoxic T lymphocyte (CTL) escape mutations while reversions appeared limited. Putative escape mutations were often rapidly replaced with mutually exclusive mutations nearby, indicating the existence of a maturational escape process, possibly in adaptation to viral fitness constraints or to immune responses against new variants. We showed that establishment of HIV-1 infection is likely due to a biological mechanism that restricts transmission rather than to early adaptive evolution during acute infection. Furthermore, the diversity of HIV strains coupled with complex and individual-specific patterns of CTL escape did not reveal shared sequence characteristics of acute infection that could be harnessed for vaccine design.

[1]  A. Rodrigo,et al.  Human immunodeficiency virus type 1 molecular evolution and the measure of selection. , 1996, AIDS research and human retroviruses.

[2]  R. Hudson,et al.  A test of neutral molecular evolution based on nucleotide data. , 1987, Genetics.

[3]  David Heckerman,et al.  Leveraging Information Across HLA Alleles/Supertypes Improves Epitope Prediction , 2006, RECOMB.

[4]  Bin Li,et al.  Rapid Reversion of Sequence Polymorphisms Dominates Early Human Immunodeficiency Virus Type 1 Evolution , 2006, Journal of Virology.

[5]  Tanmoy Bhattacharya,et al.  Modeling sequence evolution in acute HIV-1 infection. , 2009, Journal of theoretical biology.

[6]  David Heckerman,et al.  Leveraging Information Across HLA Alleles/Supertypes Improves Epitope Prediction , 2007, J. Comput. Biol..

[7]  R H Lyles,et al.  Natural history of human immunodeficiency virus type 1 viremia after seroconversion and proximal to AIDS in a large cohort of homosexual men. Multicenter AIDS Cohort Study. , 2000, The Journal of infectious diseases.

[8]  G. Shaw,et al.  Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection , 1994, Journal of virology.

[9]  Eric Delwart,et al.  Homogeneous quasispecies in 16 out of 17 individuals during very early HIV-1 primary infection , 2002, AIDS.

[10]  Cassandra B. Jabara,et al.  HIV-1 Populations in Semen Arise through Multiple Mechanisms , 2010, PLoS pathogens.

[11]  M. Bunce,et al.  Comprehensive, serologically equivalent DNA typing for HLA-B by PCR using sequence-specific primers (PCR-SSP). , 1995, Tissue antigens.

[12]  Cynthia A. Derdeyn,et al.  Inflammatory Genital Infections Mitigate a Severe Genetic Bottleneck in Heterosexual Transmission of Subtype A and C HIV-1 , 2009, PLoS pathogens.

[13]  J. Coffin,et al.  Comparison of standard PCR/cloning to single genome sequencing for analysis of HIV-1 populations. , 2010, Journal of virological methods.

[14]  S Brunak,et al.  Sensitive quantitative predictions of peptide-MHC binding by a 'Query by Committee' artificial neural network approach. , 2003, Tissue antigens.

[15]  H. Sebastian Seung,et al.  Query by committee , 1992, COLT '92.

[16]  E. Fenyö,et al.  In vivo evolution of HIV-1 co-receptor usage and sensitivity to chemokine-mediated suppression , 1997, Nature Medicine.

[17]  D. Ho,et al.  Genotypic and phenotypic characterization of HIV-1 patients with primary infection. , 1993, Science.

[18]  Eric J. Arts,et al.  Variable Fitness Impact of HIV-1 Escape Mutations to Cytotoxic T Lymphocyte (CTL) Response , 2009, PLoS pathogens.

[19]  F. Tajima Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. , 1989, Genetics.

[20]  E. Holmes,et al.  Selection for specific sequences in the external envelope protein of human immunodeficiency virus type 1 upon primary infection , 1993, Journal of virology.

[21]  Alan S. Perelson,et al.  The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection , 2009, The Journal of experimental medicine.

[22]  J. Thompson,et al.  CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. , 1994, Nucleic acids research.

[23]  B. Walker,et al.  Large-scale amplification, cloning and sequencing of near full-length HIV-1 subtype C genomes. , 2006, Journal of virological methods.

[24]  R. Swanstrom,et al.  Multiple V1/V2 env Variants Are Frequently Present during Primary Infection with Human Immunodeficiency Virus Type 1 , 2004, Journal of Virology.

[25]  Christian Brander,et al.  Selective Escape from CD8+ T-Cell Responses Represents a Major Driving Force of Human Immunodeficiency Virus Type 1 (HIV-1) Sequence Diversity and Reveals Constraints on HIV-1 Evolution , 2005, Journal of Virology.

[26]  D. Heckerman,et al.  Founder Effects in the Assessment of HIV Polymorphisms and HLA Allele Associations , 2007, Science.

[27]  Bette Korber,et al.  Tracking global patterns of N-linked glycosylation site variation in highly variable viral glycoproteins: HIV, SIV, and HCV envelopes and influenza hemagglutinin. , 2004, Glycobiology.

[28]  M. Carrington,et al.  HLA-Associated Clinical Progression Correlates with Epitope Reversion Rates in Early Human Immunodeficiency Virus Infection , 2008, Journal of Virology.

[29]  D. Nickle,et al.  Male genital tract compartmentalization of human immunodeficiency virus type 1 (HIV). , 2008, AIDS research and human retroviruses.

[30]  T. Gojobori,et al.  Evolution of pathogenic viruses with special reference to the rates of synonymous and nonsynonymous substitutions. , 1994, Idengaku zasshi.

[31]  D. Heckerman,et al.  Central Role of Reverting Mutations in HLA Associations with Human Immunodeficiency Virus Set Point , 2008, Journal of Virology.

[32]  Wayne P. Maddison,et al.  Macclade: Analysis of Phylogeny and Character Evolution/Version 3 , 1992 .

[33]  David Dunn,et al.  Molecular Phylodynamics of the Heterosexual HIV Epidemic in the United Kingdom , 2009, PLoS pathogens.

[34]  O. Lund,et al.  novel sequence representations Reliable prediction of T-cell epitopes using neural networks with , 2003 .

[35]  Julio Rozas,et al.  DnaSP version 3: an integrated program for molecular population genetics and molecular evolution analysis , 1999, Bioinform..

[36]  D. Shriner,et al.  Evolution of Human Immunodeficiency Virus Type 1 Cytotoxic T-Lymphocyte Epitopes: Fitness-Balanced Escape , 2007, Journal of Virology.

[37]  J. Mellors,et al.  Quantitation of HIV-1 RNA in Plasma Predicts Outcome after Seroconversion , 1995, Annals of Internal Medicine.

[38]  D. Ho,et al.  Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome , 1994, Journal of virology.

[39]  B. Korber,et al.  Deciphering Human Immunodeficiency Virus Type 1 Transmission and Early Envelope Diversification by Single-Genome Amplification and Sequencing , 2008, Journal of Virology.

[40]  D. Maddison,et al.  MacClade 4: analysis of phy-logeny and character evolution , 2003 .

[41]  J. Goudsmit,et al.  HIV-1 genomic RNA diversification following sexual and parenteral virus transmission. , 1992, Virology.

[42]  J. Margolick,et al.  HIV-1 variation before seroconversion in men who have sex with men: analysis of acute/early HIV infection in the multicenter AIDS cohort study. , 2008, The Journal of infectious diseases.

[43]  Christophe Fraser,et al.  HIV-1 transmission, by stage of infection. , 2008, The Journal of infectious diseases.

[44]  M. Slatkin,et al.  Pairwise comparisons of mitochondrial DNA sequences in stable and exponentially growing populations. , 1991, Genetics.

[45]  W. Li,et al.  Statistical tests of neutrality of mutations. , 1993, Genetics.

[46]  John W. Mellors,et al.  Prognosis in HIV-1 Infection Predicted by the Quantity of Virus in Plasma , 1996, Science.

[47]  J. Margolick,et al.  Improved Coreceptor Usage Prediction and GenotypicMonitoring of R5-to-X4 Transition by Motif Analysis of HumanImmunodeficiency Virus Type 1 env V3 LoopSequences , 2003, Journal of Virology.

[48]  Alan S. Perelson,et al.  High Multiplicity Infection by HIV-1 in Men Who Have Sex with Men , 2010, PLoS pathogens.

[49]  B. Walker,et al.  Human immunodeficiency virus type 1 evolution in vivo tracked by DNA heteroduplex mobility assays , 1994, Journal of virology.

[50]  Martin A. Nowak,et al.  Antigenic oscillations and shifting immunodominance in HIV-1 infections , 1995, Nature.

[51]  J. Margolick,et al.  Consistent Viral Evolutionary Changes Associated with the Progression of Human Immunodeficiency Virus Type 1 Infection , 1999, Journal of Virology.

[52]  G A Satten,et al.  Time course of viremia and antibody seroconversion following human immunodeficiency virus exposure. , 1997, The American journal of medicine.

[53]  Soung Hie Kim,et al.  An Artificial Neural Network Approach , 1993 .

[54]  O. Laeyendecker,et al.  Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. , 2005, The Journal of infectious diseases.

[55]  Lawrence Corey,et al.  Biological and Virologic Characteristics of Primary HIV Infection , 1998, Annals of Internal Medicine.

[56]  R. Byrn,et al.  HIV-1 in semen: an isolated virus reservoir , 1997, The Lancet.

[57]  D. Richman,et al.  Semen-Specific Genetic Characteristics of Human Immunodeficiency Virus Type 1 env , 2005, Journal of Virology.

[58]  Tuofu Zhu,et al.  Virus Population Homogenization following Acute Human Immunodeficiency Virus Type 1 Infection , 2002, Journal of Virology.

[59]  G. Norkrans,et al.  HIV type 1 V3 sequence diversity in contact-traced Swedish couples at the time of sexual transmission. , 1994, AIDS research and human retroviruses.

[60]  Roger Detels,et al.  Prognostic value of HIV-1 RNA, CD4 cell count, and CD4 Cell count slope for progression to AIDS and death in untreated HIV-1 infection. , 2007, JAMA.

[61]  Hui Li,et al.  Wide Variation in the Multiplicity of HIV-1 Infection among Injection Drug Users , 2010, Journal of Virology.

[62]  James I Mullins,et al.  HIV-1 Group M Conserved Elements Vaccine , 2007, PLoS pathogens.

[63]  Peter B. Gilbert,et al.  Genetic impact of vaccination on breakthrough HIV-1 sequences from the Step trial , 2011, Nature Medicine.

[64]  J. Margolick,et al.  Human Immunodeficiency Virus Type 1 Population Genetics and Adaptation in Newly Infected Individuals , 2008, Journal of Virology.

[65]  Christopher D Pilcher,et al.  Brief but efficient: acute HIV infection and the sexual transmission of HIV. , 2004, The Journal of infectious diseases.

[66]  David C. Nickle,et al.  Selection on the Human Immunodeficiency Virus Type 1 Proteome following Primary Infection , 2006, Journal of Virology.

[67]  R. Siliciano,et al.  Elite Suppressor–Derived HIV-1 Envelope Glycoproteins Exhibit Reduced Entry Efficiency and Kinetics , 2009, PLoS pathogens.

[68]  Todd M. Allen,et al.  Early Selection in Gag by Protective HLA Alleles Contributes to Reduced HIV-1 Replication Capacity That May Be Largely Compensated for in Chronic Infection , 2010, Journal of Virology.

[69]  R. Swanstrom,et al.  Quantitating the Multiplicity of Infection with Human Immunodeficiency Virus Type 1 Subtype C Reveals a Non-Poisson Distribution of Transmitted Variants , 2009, Journal of Virology.

[70]  Sergei L. Kosakovsky Pond,et al.  HyPhy: hypothesis testing using phylogenies , 2005, Bioinform..

[71]  B. Walker,et al.  Human Immunodeficiency Virus Type 1 Populations in Blood and Semen , 1998, Journal of Virology.

[72]  Michael P Busch,et al.  Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection , 2003, AIDS.

[73]  Mary Poss,et al.  Evolution of Envelope Sequences from the Genital Tract and Peripheral Blood of Women Infected with Clade A Human Immunodeficiency Virus Type 1 , 1998, Journal of Virology.

[74]  Hui Li,et al.  Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection , 2008, Proceedings of the National Academy of Sciences.

[75]  D. Nickle,et al.  Human Immunodeficiency Virus Type 1 env Evolves toward Ancestral States upon Transmission to a New Host , 2006, Journal of Virology.

[76]  David Heckerman,et al.  Adaptation of HIV-1 to human leukocyte antigen class I , 2009, Nature.

[77]  A. Perelson,et al.  Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection , 2009, The Journal of experimental medicine.

[78]  Bette Korber,et al.  HIV Evolution in Early Infection: Selection Pressures, Patterns of Insertion and Deletion, and the Impact of APOBEC , 2009, PLoS pathogens.

[79]  M. Ascher,et al.  The relationship between AIDS and immunologic tolerance. , 1992, Journal of acquired immune deficiency syndromes.

[80]  O. Gascuel,et al.  A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood. , 2003, Systematic biology.