Impact of immune escape mutations on HIV-1 fitness in the context of the cognate transmitted/founder genome

Retrovirology

Feng Gao⁸  Barton F Haynes⁸  Beatrice H Hahn⁵  George M Shaw⁵  Alan S Perelson⁹  Andrew McMichael¹  Guido Ferrari⁷  M Anthony Moody⁶  Joy Pickeral⁷  Josh Eudailey⁴  Mark S Drinker⁴  Bhavna Hora⁴  Anna Berg⁴  Michael KP Liu¹  Nilu Goonetilleke¹  Julie M Decker²  Katharine J Bar³  Shilpa S Iyer³  Hui Li³  Tanmoy Bhattacharya⁹  Fangping Cai⁴  Jeffrey W Pavlicek⁴  Hongshuo Song⁴ 

[1] Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, England, OX3 9DS, UK;Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA;Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA;Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA;Department of Microbiology, University of Pennsylvania, Philadelphia, PA, 19104, USA;Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA;Department of Surgery, Duke University Medical Center, Durham, NC, 27710, USA;Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA;Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM, 87545, USA

关键词: Mathematical model;    Transmitted/founder virus;    Immune escape mutation;    Cytotoxic T lymphocytes;    Viral fitness;    Human immunodeficiency virus type I;   

Others  :  1209253
DOI  :  10.1186/1742-4690-9-89

 received in 2012-06-03, accepted in 2012-10-07,  发布年份 2012

【 摘 要 】

Background

A modest change in HIV-1 fitness can have a significant impact on viral quasispecies evolution and viral pathogenesis, transmission and disease progression. To determine the impact of immune escape mutations selected by cytotoxic T lymphocytes (CTL) on viral fitness in the context of the cognate transmitted/founder (T/F) genome, we developed a new competitive fitness assay using molecular clones of T/F genomes lacking exogenous genetic markers and a highly sensitive and precise parallel allele-specific sequencing (PASS) method.

Results

The T/F and mutant viruses were competed in CD4⁺ T-cell enriched cultures, relative proportions of viruses were assayed after repeated cell-free passage, and fitness costs were estimated by mathematical modeling. Naturally occurring HLA B57-restricted mutations involving the TW10 epitope in Gag and two epitopes in Tat/Rev and Env were assessed independently and together. Compensatory mutations which restored viral replication fitness were also assessed. A principal TW10 escape mutation, T242N, led to a 42% reduction in replication fitness but V247I and G248A mutations in the same epitope restored fitness to wild-type levels. No fitness difference was observed between the T/F and a naturally selected variant carrying the early CTL escape mutation (R355K) in Env and a reversion mutation in the Tat/Rev overlapping region.

Conclusions

These findings reveal a broad spectrum of fitness costs to CTL escape mutations in T/F viral genomes, similar to recent findings reported for neutralizing antibody escape mutations, and highlight the extraordinary plasticity and adaptive potential of the HIV-1 genome. Analysis of T/F genomes and their evolved progeny is a powerful approach for assessing the impact of composite mutational events on viral fitness.

【 授权许可】

   
2012 Song et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

【 参考文献 】

• [1]Abraha A, Nankya IL, Gibson R, Demers K, Tebit DM, Johnston E, Katzenstein D, Siddiqui A, Herrera C, Fischetti L, et al.: CCR5- and CXCR4-tropic subtype C human immunodeficiency virus type 1 isolates have a lower level of pathogenic fitness than other dominant group M subtypes: implications for the epidemic. J Virol 2009, 83:5592-5605.
• [2]Arien KK, Troyer RM, Gali Y, Colebunders RL, Arts EJ, Vanham G: Replicative fitness of historical and recent HIV-1 isolates suggests HIV-1 attenuation over time. AIDS 2005, 19:1555-1564.
• [3]Quinones-Mateu ME, Ball SC, Marozsan AJ, Torre VS, Albright JL, Vanham G, van Der Groen G, Colebunders RL, Arts EJ: A dual infection/competition assay shows a correlation between ex vivo human immunodeficiency virus type 1 fitness and disease progression. J Virol 2000, 74:9222-9233.
• [4]Rodriguez MA, Ding M, Ratner D, Chen Y, Tripathy SP, Kulkarni SS, Chatterjee R, Tarwater PM, Gupta P: High replication fitness and transmission efficiency of HIV-1 subtype C from India: Implications for subtype C predominance. Virology 2009, 385:416-424.
• [5]Shakirzyanova M, Ren W, Zhuang K, Tasca S, Cheng-Mayer C: Fitness disadvantage of transitional intermediates contributes to dynamic change in the infecting-virus population during coreceptor switch in R5 simian/human immunodeficiency virus-infected macaques. J Virol 2010, 84:12862-12871.
• [6]Troyer RM, Collins KR, Abraha A, Fraundorf E, Moore DM, Krizan RW, Toossi Z, Colebunders RL, Jensen MA, Mullins JI, et al.: Changes in human immunodeficiency virus type 1 fitness and genetic diversity during disease progression. J Virol 2005, 79:9006-9018.
• [7]Chopera DR, Woodman Z, Mlisana K, Mlotshwa M, Martin DP, Seoighe C, Treurnicht F, de Rosa DA, Hide W, Karim SA, et al.: Transmission of HIV-1 CTL escape variants provides HLA-mismatched recipients with a survival advantage. PLoS Pathog 2008, 4:e1000033.
• [8]Crawford H, Lumm W, Leslie A, Schaefer M, Boeras D, Prado JG, Tang J, Farmer P, Ndung'u T, Lakhi S, et al.: Evolution of HLA-B*5703 HIV-1 escape mutations in HLA-B*5703-positive individuals and their transmission recipients. J Exp Med 2009, 206:909-921.
• [9]Goepfert PA, Lumm W, Farmer P, Matthews P, Prendergast A, Carlson JM, Derdeyn CA, Tang J, Kaslow RA, Bansal A, et al.: Transmission of HIV-1 Gag immune escape mutations is associated with reduced viral load in linked recipients. J Exp Med 2008, 205:1009-1017.
• [10]Coffin JM: HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 1995, 267:483-489.
• [11]Goonetilleke N, Liu MK, Salazar-Gonzalez JF, Ferrari G, Giorgi E, Ganusov VV, Keele BF, Learn GH, Turnbull EL, Salazar MG, et al.: The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection. J Exp Med 2009, 206:1253-1272.
• [12]Ganusov VV, Goonetilleke N, Liu MK, Ferrari G, Shaw GM, McMichael AJ, Borrow P, Korber BT, Perelson AS: Fitness costs and diversity of the cytotoxic T lymphocyte (CTL) response determine the rate of CTL escape during acute and chronic phases of HIV infection. J Virol 2011, 85:10518-10528.
• [13]Troyer RM, McNevin J, Liu Y, Zhang SC, Krizan RW, Abraha A, Tebit DM, Zhao H, Avila S, Lobritz MA, et al.: Variable fitness impact of HIV-1 escape mutations to cytotoxic T lymphocyte (CTL) response. PLoS Pathog 2009, 5:e1000365.
• [14]Martinez-Picado J, Prado JG, Fry EE, Pfafferott K, Leslie A, Chetty S, Thobakgale C, Honeyborne I, Crawford H, Matthews P, et al.: Fitness cost of escape mutations in p24 Gag in association with control of human immunodeficiency virus type 1. J Virol 2006, 80:3617-3623.
• [15]Brockman MA, Schneidewind A, Lahaie M, Schmidt A, Miura T, Desouza I, Ryvkin F, Derdeyn CA, Allen S, Hunter E, et al.: Escape and compensation from early HLA-B57-mediated cytotoxic T-lymphocyte pressure on human immunodeficiency virus type 1 Gag alter capsid interactions with cyclophilin A. J Virol 2007, 81:12608-12618.
• [16]Miura T, Brockman MA, Schneidewind A, Lobritz M, Pereyra F, Rathod A, Block BL, Brumme ZL, Brumme CJ, Baker B, et al.: HLA-B57/B*5801 human immunodeficiency virus type 1 elite controllers select for rare gag variants associated with reduced viral replication capacity and strong cytotoxic T-lymphocyte [corrected] recognition. J Virol 2009, 83:2743-2755.
• [17]Maree AF, Keulen W, Boucher CA, De Boer RJ: Estimating relative fitness in viral competition experiments. J Virol 2000, 74:11067-11072.
• [18]Armstrong KL, Lee TH, Essex M: Replicative fitness costs of nonnucleoside reverse transcriptase inhibitor drug resistance mutations on HIV subtype C. Antimicrob Agents Chemother 2011, 55:2146-2153.
• [19]Hu Z, Giguel F, Hatano H, Reid P, Lu J, Kuritzkes DR: Fitness comparison of thymidine analog resistance pathways in human immunodeficiency virus type 1. J Virol 2006, 80:7020-7027.
• [20]Wu H, Huang Y, Dykes C, Liu D, Ma J, Perelson AS, Demeter LM: Modeling and estimation of replication fitness of human immunodeficiency virus type 1 in vitro experiments by using a growth competition assay. J Virol 2006, 80:2380-2389.
• [21]Quinones-Mateu ME, Arts EJ: Fitness of drug resistant HIV-1: methodology and clinical implications. Drug Resist Updat 2002, 5:224-233.
• [22]Croteau G, Doyon L, Thibeault D, McKercher G, Pilote L, Lamarre D: Impaired fitness of human immunodeficiency virus type 1 variants with high-level resistance to protease inhibitors. J Virol 1997, 71:1089-1096.
• [23]Martinez-Picado J, Savara AV, Shi L, Sutton L, D'Aquila RT: Fitness of human immunodeficiency virus type 1 protease inhibitor-selected single mutants. Virology 2000, 275:318-322.
• [24]Levy DN, Aldrovandi GM, Kutsch O, Shaw GM: Dynamics of HIV-1 recombination in its natural target cells. Proc Natl Acad Sci USA 2004, 101:4204-4209.
• [25]Zhuang J, Mukherjee S, Ron Y, Dougherty JP: High rate of genetic recombination in murine leukemia virus: implications for influencing proviral ploidy. J Virol 2006, 80:6706-6711.
• [26]Dykes C, Wu H, Sims M, Holden-Wiltse J, Demeter LM: Human immunodeficiency virus type 1 protease inhibitor drug-resistant mutants give discordant results when compared in single-cycle and multiple-cycle fitness assays. J Clin Microbiol 2010, 48:4035-4043.
• [27]Kosalaraksa P, Kavlick MF, Maroun V, Le R, Mitsuya H: Comparative fitness of multi-dideoxynucleoside-resistant human immunodeficiency virus type 1 (HIV-1) in an In vitro competitive HIV-1 replication assay. J Virol 1999, 73:5356-5363.
• [28]Cai F, Chen H, Hicks CB, Bartlett JA, Zhu J, Gao F: Detection of minor drug-resistant populations by parallel allele-specific sequencing. Nat Methods 2007, 4:123-125.
• [29]Salazar-Gonzalez JF, Salazar MG, Keele BF, Learn GH, Giorgi EE, Li H, Decker JM, Wang S, Baalwa J, Kraus MH, et al.: Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection. J Exp Med 2009, 206:1273-1289.
• [30]Wang D, Hicks CB, Goswami ND, Tafoya E, Ribeiro RM, Cai F, Perelson AS, Gao F: Evolution of Drug-Resistant Viral Populations during Interruption of Antiretroviral Therapy. J Virol 2011, 85:6403-6415.
• [31]Liu M, Hawkins N, Ritchie A, Ganusov V, Whale V, Brackenridge S, Li H, Pavelick J, Cai F, Rose-Abrahams M, et al.: T cell immunodominance, breadth and epitope entropy are the major determinants of virus escape rate in acute HIV-1 infection. J Clin InvestIn press
• [32]Crawford H, Prado JG, Leslie A, Hue S, Honeyborne I, Reddy S, van der Stok M, Mncube Z, Brander C, Rousseau C, et al.: Compensatory mutation partially restores fitness and delays reversion of escape mutation within the immunodominant HLA-B*5703-restricted Gag epitope in chronic human immunodeficiency virus type 1 infection. J Virol 2007, 81:8346-8351.
• [33]Kelleher AD, Long C, Holmes EC, Allen RL, Wilson J, Conlon C, Workman C, Shaunak S, Olson K, Goulder P, et al.: Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses. J Exp Med 2001, 193:375-386.
• [34]Dimitrov DS, Willey RL, Sato H, Chang LJ, Blumenthal R, Martin MA: Quantitation of human immunodeficiency virus type 1 infection kinetics. J Virol 1993, 67:2182-2190.
• [35]Bar KJ, Tsao C-y, Iyer S, Decker JM, Yang Y, Mao Y, Bonsignori M, Chen X, Hwang K-K, Montefiori DC, et al.: Early Appearance of Low-Titer Neutralizing Antibodies Selects for HIV-1 Escape. PLoS PathogSubmitted
• [36]Gao F, Chen Y, Levy DN, Conway JA, Kepler TB, Hui H: Unselected mutations in the human immunodeficiency virus type 1 genome are mostly nonsynonymous and often deleterious. J Virol 2004, 78:2426-2433.
• [37]Mansky LM, Temin HM: Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol 1995, 69:5087-5094.
• [38]Neher RA, Leitner T: Recombination rate and selection strength in HIV intra-patient evolution. PLoS Comput Biol 2010, 6:e1000660.
• [39]Batorsky R, Kearney MF, Palmer SE, Maldarelli F, Rouzine IM, Coffin JM: Estimate of effective recombination rate and average selection coefficient for HIV in chronic infection. Proc Natl Acad Sci U S A 2011, 108:5661-5666.
• [40]Leslie AJ, Pfafferott KJ, Chetty P, Draenert R, Addo MM, Feeney M, Tang Y, Holmes EC, Allen T, Prado JG, et al.: HIV evolution: CTL escape mutation and reversion after transmission. Nat Med 2004, 10:282-289.
• [41]Novitsky V, Wang R, Margolin L, Baca J, Moyo S, Musonda R, Essex M: Dynamics and timing of in vivo mutations at Gag residue 242 during primary HIV-1 subtype C infection. Virology 2010, 403:37-46.
• [42]Schneidewind A, Tang Y, Brockman MA, Ryland EG, Dunkley-Thompson J, Steel-Duncan JC, St John MA, Conrad JA, Kalams SA, Noel F, et al.: Maternal transmission of human immunodeficiency virus escape mutations subverts HLA-B57 immunodominance but facilitates viral control in the haploidentical infant. J Virol 2009, 83:8616-8627.
• [43]Robertson DL, Sharp PM, McCutchan FE, Hahn BH: Recombination in HIV-1. Nature 1995, 374:124-126.
• [44]Jiang C, Parrish NF, Wilen CB, Li H, Chen Y, Pavlicek JW, Berg A, Lu X, Song H, Tilton JC, et al.: Primary Infection by a Human Immunodeficiency Virus with Atypical Coreceptor Tropism. J Virol 2011, 85:10669-10681.
• [45]Liu J, Miller MD, Danovich RM, Vandergrift N, Cai F, Hicks CB, Hazuda DJ, Gao F: Analysis of low frequency mutations associated with drug-resistance to raltegravir before antiretroviral treatment. Antimicrob Agents Chemother 2011, 55:1114-1119.
• [46]Nagylaki T: Introduction to Theoretical Population Genetics. Springer, Berlin; 1992.
• [47]Layne SP, Merges MJ, Dembo M, Spouge JL, Conley SR, Moore JP, Raina JL, Renz H, Gelderblom HR, Nara PL: Factors underlying spontaneous inactivation and susceptibility to neutralization of human immunodeficiency virus. Virology 1992, 189:695-714.