{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:23:34Z","timestamp":1760059414896,"version":"build-2065373602"},"reference-count":112,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T00:00:00Z","timestamp":1749686400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft (Arne Schneidewind)","doi-asserted-by":"publisher","award":["DFG SCHN1085-2-1"],"award-info":[{"award-number":["DFG SCHN1085-2-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Faculty of Medicine, University of Regensburg","award":["DFG SCHN1085-2-1"],"award-info":[{"award-number":["DFG SCHN1085-2-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Viral evasion from effective human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-cell responses and from antiretroviral therapy through viral sequence variation is frequently accompanied by a loss in viral fitness. The impact of sequence variations on replication capacity in vitro was mostly studied by introducing single mutations into a specific clonal strain such as NL4-3. How the specific viral backbone itself impacts replicative fitness remains elusive. To test for a potential effect of the viral backbone, we constructed HIV-1 clade B clones with consensus sequences for gag and\/or pol and evaluated the infectivity of viral variants harboring well-defined cytotoxic T-lymphocyte (CTL) escape mutations or drug resistance mutations within this backbone or the clonal NL4-3 strain. Viral variants with consensus sequences were replication-competent in vitro, although at lower rates than the NL4-3 virus. Introduction of the dominant CTL escape mutation R264K into the newly constructed viruses or into NL4-3 led to a dramatic reduction in infection rates. In contrast to the NL4-3 backbone, the combination of R264K with its compensatory mutation S173A on the consensus backbone led to higher infection rates as compared to the same virus in the absence of R264K and S173A. Furthermore, 2 out of 10 drug resistance mutations in pol led to opposing effects, with an increase in infection rates on the consensus gag\/pol backbone and a reduction on NL4-3. Therefore, the effect of the respective viral backbone on infectivity observed in vitro might constitute an additional factor to explain differential kinetics of mutational evasion from immune and pharmaceutical pressure.<\/jats:p>","DOI":"10.3390\/v17060842","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T07:44:23Z","timestamp":1749714263000},"page":"842","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Consensus Sequences for Gag and Pol Introduced into HIV-1 Clade B Laboratory Strains Differentially Influence the Impact of Point Mutations Associated with Immune Escape and with Drug Resistance on Viral Replicative Capacity"],"prefix":"10.3390","volume":"17","author":[{"given":"Sven","family":"Breitschwerdt","sequence":"first","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Regensburg, 93053 Regensburg, Germany"},{"name":"Department of Internal Medicine I, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benedikt","family":"Grandel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Regensburg, 93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1056-8591","authenticated-orcid":false,"given":"Benedikt","family":"Asbach","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hygiene, University Regensburg, 93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franziska","family":"Winter","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Regensburg, 93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Todd","family":"Allen","sequence":"additional","affiliation":[{"name":"The Ragon Institute of MGH, MIT and Harvard, Boston, MA 02139, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralf","family":"Wagner","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hygiene, University Regensburg, 93053 Regensburg, Germany"},{"name":"Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, 93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernd","family":"Salzberger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Regensburg, 93053 Regensburg, Germany"},{"name":"Department of Hospital Hygiene and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arne","family":"Schneidewind","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Regensburg, 93053 Regensburg, Germany"},{"name":"Department of Internal Medicine I, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4650","DOI":"10.1128\/jvi.68.7.4650-4655.1994","article-title":"Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome","volume":"68","author":"Koup","year":"1994","journal-title":"J. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6103","DOI":"10.1128\/jvi.68.9.6103-6110.1994","article-title":"Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection","volume":"68","author":"Borrow","year":"1994","journal-title":"J. Virol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"11937","DOI":"10.1128\/JVI.01086-10","article-title":"Early selection in Gag by protective HLA alleles contributes to reduced HIV-1 replication capacity that may be largely compensated for in chronic infection","volume":"84","author":"Brockman","year":"2010","journal-title":"J. Virol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Zaunders, J., and van Bockel, D. (2013). Innate and Adaptive Immunity in Long-Term Non-Progression in HIV Disease. Front. Immunol., 4.","DOI":"10.3389\/fimmu.2013.00095"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/nm0297-205","article-title":"Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus","volume":"3","author":"Borrow","year":"1997","journal-title":"Nat. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"13239","DOI":"10.1128\/JVI.79.21.13239-13249.2005","article-title":"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","volume":"79","author":"Allen","year":"2005","journal-title":"J. Virol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Altfeld, M., Kalife, E.T., Qi, Y., Streeck, H., Lichterfeld, M., Johnston, M.N., Burgett, N., Swartz, M.E., Yang, A., and Alter, G. (2006). HLA Alleles Associated with Delayed Progression to AIDS Contribute Strongly to the Initial CD8(+) T Cell Response against HIV-1. PLoS Med., 3.","DOI":"10.1371\/journal.pmed.0030403"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1084\/jem.193.3.375","article-title":"Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses","volume":"193","author":"Kelleher","year":"2001","journal-title":"J. Exp. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1128\/JVI.02265-08","article-title":"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","volume":"83","author":"Miura","year":"2009","journal-title":"J. Virol."},{"key":"ref_10","first-page":"89","article-title":"Progression of HIV to AIDS: A protective role for HLA-B27?","volume":"6","year":"2004","journal-title":"AIDS Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.1097\/00002030-200312050-00005","article-title":"Influence of HLA-B57 on clinical presentation and viral control during acute HIV-1 infection","volume":"17","author":"Altfeld","year":"2003","journal-title":"Aids"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3133","DOI":"10.4049\/jimmunol.179.5.3133","article-title":"Viral replication capacity as a correlate of HLA B57\/B5801-associated nonprogressive HIV-1 infection","volume":"179","author":"Navis","year":"2007","journal-title":"J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/nm0496-405","article-title":"Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection","volume":"2","author":"Kaslow","year":"1996","journal-title":"Nat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1126\/science.1195271","article-title":"The major genetic determinants of HIV-1 control affect HLA class I peptide presentation","volume":"330","author":"Pereyra","year":"2010","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3952","DOI":"10.1128\/JVI.03233-12","article-title":"Frequent and variable cytotoxic-T-lymphocyte escape-associated fitness costs in the human immunodeficiency virus type 1 subtype B Gag proteins","volume":"87","author":"Boutwell","year":"2013","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"12382","DOI":"10.1128\/JVI.01543-07","article-title":"Escape from the dominant HLA-B27-restricted cytotoxic T-lymphocyte response in Gag is associated with a dramatic reduction in human immunodeficiency virus type 1 replication","volume":"81","author":"Schneidewind","year":"2007","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Gijsbers, E.F., Feenstra, K.A., van Nuenen, A.C., Navis, M., Heringa, J., Schuitemaker, H., and Kootstra, N.A. (2013). HIV-1 replication fitness of HLA-B*57\/58:01 CTL escape variants is restored by the accumulation of compensatory mutations in gag. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0081235"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Du, Y., Zhang, T.H., Dai, L., Zheng, X., Gorin, A.M., Oishi, J., Wu, T.T., Yoshizawa, J.M., Li, X., and Yang, O.O. (2017). Effects of Mutations on Replicative Fitness and Major Histocompatibility Complex Class I Binding Affinity Are Among the Determinants Underlying Cytotoxic-T-Lymphocyte Escape of HIV-1 Gag Epitopes. mBio, 8.","DOI":"10.1128\/mBio.01050-17"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"479","DOI":"10.4049\/jimmunol.0903227","article-title":"HIV immune escape at an immunodominant epitope in HLA-B*27-positive individuals predicts viral load outcome","volume":"186","author":"Ammaranond","year":"2011","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1001\/jama.283.2.229","article-title":"Drug susceptibility in HIV infection after viral rebound in patients receiving indinavir-containing regimens","volume":"283","author":"Havlir","year":"2000","journal-title":"Jama"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/S0140-6736(99)01122-8","article-title":"Clinical progression and virological failure on highly active antiretroviral therapy in HIV-1 patients: A prospective cohort study. Swiss HIV Cohort Study","volume":"353","author":"Ledergerber","year":"1999","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1086\/315334","article-title":"Sustained CD4+ T cell response after virologic failure of protease inhibitor-based regimens in patients with human immunodeficiency virus infection","volume":"181","author":"Deeks","year":"2000","journal-title":"J. Infect. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1056\/NEJM200102153440702","article-title":"Virologic and immunologic consequences of discontinuing combination antiretroviral-drug therapy in HIV-infected patients with detectable viremia","volume":"344","author":"Deeks","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10948","DOI":"10.1073\/pnas.97.20.10948","article-title":"Antiretroviral resistance during successful therapy of HIV type 1 infection","volume":"97","author":"DePasquale","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1097\/QAD.0b013e3281c615da","article-title":"Impact of genotypic drug resistance mutations on clinical and immunological outcomes in HIV-infected adults on HAART in West Africa","volume":"21","author":"Seyler","year":"2007","journal-title":"Aids"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3744","DOI":"10.1128\/JVI.73.5.3744-3752.1999","article-title":"Replicative fitness of protease inhibitor-resistant mutants of human immunodeficiency virus type 1","volume":"73","author":"Savara","year":"1999","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3300","DOI":"10.1128\/JVI.72.4.3300-3306.1998","article-title":"Loss of viral fitness associated with multiple Gag and Gag-Pol processing defects in human immunodeficiency virus type 1 variants selected for resistance to protease inhibitors in vivo","volume":"72","author":"Zennou","year":"1998","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1128\/jvi.71.2.1089-1096.1997","article-title":"Impaired fitness of human immunodeficiency virus type 1 variants with high-level resistance to protease inhibitors","volume":"71","author":"Croteau","year":"1997","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3773","DOI":"10.1128\/JVI.72.5.3773-3778.1998","article-title":"Relative replicative fitness of zidovudine-resistant human immunodeficiency virus type 1 isolates in vitro","volume":"72","author":"Harrigan","year":"1998","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8524","DOI":"10.1128\/JVI.74.18.8524-8531.2000","article-title":"Retracing the evolutionary pathways of human immunodeficiency virus type 1 resistance to protease inhibitors: Virus fitness in the absence and in the presence of drug","volume":"74","author":"Mammano","year":"2000","journal-title":"J. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8846","DOI":"10.1128\/jvi.71.11.8846-8851.1997","article-title":"Attenuated replication of human immunodeficiency virus type 1 with a didanosine-selected reverse transcriptase mutation","volume":"71","author":"Sharma","year":"1997","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1097\/COH.0b013e3280287a38","article-title":"Resistance to newly approved and investigational protease inhibitors","volume":"2","year":"2007","journal-title":"Curr. Opin. HIV AIDS"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6403","DOI":"10.1128\/JVI.02389-10","article-title":"Evolution of drug-resistant viral populations during interruption of antiretroviral therapy","volume":"85","author":"Wang","year":"2011","journal-title":"J. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1086\/496892","article-title":"Interruption of treatment with individual therapeutic drug classes in adults with multidrug-resistant HIV-1 infection","volume":"192","author":"Deeks","year":"2005","journal-title":"J. Infect. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1097\/00002030-199912240-00001","article-title":"Rapid decline in detectability of HIV-1 drug resistance mutations after stopping therapy","volume":"13","author":"Devereux","year":"1999","journal-title":"Aids"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1056\/NEJMoa035103","article-title":"Structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus","volume":"349","author":"Lawrence","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2541","DOI":"10.1097\/00002030-199912240-00007","article-title":"Interruption of reverse transcriptase inhibitors or a switch from reverse transcriptase to protease inhibitors resulted in a fast reappearance of virus strains with a reverse transcriptase inhibitor-sensitive genotype","volume":"13","author":"Verhofstede","year":"1999","journal-title":"Aids"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5662","DOI":"10.1128\/jvi.70.8.5662-5664.1996","article-title":"Human immunodeficiency virus fitness in vivo: Calculations based on a single zidovudine resistance mutation at codon 215 of reverse transcriptase","volume":"70","author":"Goudsmit","year":"1996","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1093\/jac\/dkr157","article-title":"Evolutionary pathways of transmitted drug-resistant HIV-1","volume":"66","author":"Pingen","year":"2011","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Machnowska, P., Meixenberger, K., Schmidt, D., Jessen, H., Hillenbrand, H., Gunsenheimer-Bartmeyer, B., Hamouda, O., K\u00fccherer, C., and Bannert, N. (2019). Prevalence and persistence of transmitted drug resistance mutations in the German HIV-1 Seroconverter Study Cohort. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0209605"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"8346","DOI":"10.1128\/JVI.00465-07","article-title":"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","volume":"81","author":"Crawford","year":"2007","journal-title":"J. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5594","DOI":"10.1128\/JVI.02356-07","article-title":"Structural and functional constraints limit options for cytotoxic T-lymphocyte escape in the immunodominant HLA-B27-restricted epitope in human immunodeficiency virus type 1 capsid","volume":"82","author":"Schneidewind","year":"2008","journal-title":"J. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1038\/nm0297-212","article-title":"Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS","volume":"3","author":"Goulder","year":"1997","journal-title":"Nat. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"12608","DOI":"10.1128\/JVI.01369-07","article-title":"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","volume":"81","author":"Brockman","year":"2007","journal-title":"J. Virol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6889","DOI":"10.1128\/JVI.77.12.6889-6898.2003","article-title":"The differential ability of HLA B*5701+ long-term nonprogressors and progressors to restrict human immunodeficiency virus replication is not caused by loss of recognition of autologous viral gag sequences","volume":"77","author":"Migueles","year":"2003","journal-title":"J. Virol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/354453a0","article-title":"Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition","volume":"354","author":"Phillips","year":"1991","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1126\/science.2467383","article-title":"HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy","volume":"243","author":"Larder","year":"1989","journal-title":"Science"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1093\/infdis\/171.6.1411","article-title":"Rapid changes in human immunodeficiency virus type 1 RNA load and appearance of drug-resistant virus populations in persons treated with lamivudine (3TC)","volume":"171","author":"Schuurman","year":"1995","journal-title":"J. Infect. Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1097\/00002030-198907000-00001","article-title":"Isolation of drug-resistant variants of HIV-1 from patients on long-term zidovudine therapy. Canadian Zidovudine Multi-Centre Study Group","volume":"3","author":"Rooke","year":"1989","journal-title":"Aids"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"8270","DOI":"10.1128\/jvi.70.12.8270-8276.1996","article-title":"Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor","volume":"70","author":"Condra","year":"1996","journal-title":"J. Virol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1128\/jvi.68.3.1660-1666.1994","article-title":"Nevirapine resistance mutations of human immunodeficiency virus type 1 selected during therapy","volume":"68","author":"Richman","year":"1994","journal-title":"J. Virol."},{"key":"ref_52","first-page":"135","article-title":"Resistance to AZT and ddC during long-term combination therapy in patients with advanced infection with human immunodeficiency virus","volume":"7","author":"Richman","year":"1994","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1056\/NEJM199810293391801","article-title":"Maintenance antiretroviral therapies in HIV-infected subjects with undetectable plasma HIV RNA after triple-drug therapy. AIDS Clinical Trials Group Study 343 Team","volume":"339","author":"Havlir","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Soares, E.A., Santos, A.F., Sousa, T.M., Sprinz, E., Martinez, A.M., Silveira, J., Tanuri, A., and Soares, M.A. (2007). Differential drug resistance acquisition in HIV-1 of subtypes B and C. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0000730"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.meegid.2008.10.002","article-title":"Distinct resistance mutation and polymorphism acquisition in HIV-1 protease of subtypes B and F1 from children and adult patients under virological failure","volume":"9","author":"Dumans","year":"2009","journal-title":"Infect. Genet. Evol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Cunha, R.D., Abreu, C.M., Gonzalez, L.M., Nijhuis, M., de Jong, D., Aguiar, R.S., Afonso, A.O., Brindeiro, R.M., and Tanuri, A. (2012). Differential in vitro kinetics of drug resistance mutation acquisition in HIV-1 RT of subtypes B and C. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0046622"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1128\/jvi.59.2.284-291.1986","article-title":"Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone","volume":"59","author":"Adachi","year":"1986","journal-title":"J. Virol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1089\/aid.1987.3.57","article-title":"Complete nucleotide sequences of functional clones of the AIDS virus","volume":"3","author":"Ratner","year":"1987","journal-title":"AIDS Res. Hum. Retrovir."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Foley, B., Leitner, T., Apetrei, C., Hahn, B., Mizrachi, I., Mullins, J., Rambaut, A., Wolinsky, S., and Korber, B. (2018). HIV Sequence Compendium 2018.","DOI":"10.2172\/1458915"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/nature01200","article-title":"HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus","volume":"420","author":"Altfeld","year":"2002","journal-title":"Nature"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.jviromet.2005.08.003","article-title":"Use of a novel GFP reporter cell line to examine replication capacity of CXCR4- and CCR5-tropic HIV-1 by flow cytometry","volume":"131","author":"Brockman","year":"2006","journal-title":"J. Virol. Methods"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4653","DOI":"10.1073\/pnas.94.9.4653","article-title":"A new reporter cell line to monitor HIV infection and drug susceptibility in vitro","volume":"94","author":"Gervaix","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.1128\/JVI.78.5.2581-2585.2004","article-title":"Extraepitopic compensatory substitutions partially restore fitness to simian immunodeficiency virus variants that escape from an immunodominant cytotoxic-T-lymphocyte response","volume":"78","author":"Friedrich","year":"2004","journal-title":"J. Virol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1038\/35085576","article-title":"Evolution and transmission of stable CTL escape mutations in HIV infection","volume":"412","author":"Goulder","year":"2001","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1089\/aid.2005.21.395","article-title":"A new variant cytotoxic T lymphocyte escape mutation in HLA-B27-positive individuals infected with HIV type 1","volume":"21","author":"Ammaranond","year":"2005","journal-title":"AIDS Res. Hum. Retrovir."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Das, K., Martinez, S.E., and Arnold, E. (2017). Structural Insights into HIV Reverse Transcriptase Mutations Q151M and Q151M Complex That Confer Multinucleoside Drug Resistance. Antimicrob. Agents Chemother., 61.","DOI":"10.1128\/AAC.00224-17"},{"key":"ref_67","first-page":"137","article-title":"HIV-1 multi-dideoxynucleoside resistance mutation (Q151M): Prevalence, associated resistance mutations and response to antiretroviral salvage treatment","volume":"106","author":"Bertelli","year":"2001","journal-title":"Microbios"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"583","DOI":"10.2217\/hiv.09.40","article-title":"The K65R mutation in HIV-1 reverse transcriptase: Genetic barriers, resistance profile and clinical implications","volume":"3","author":"Brenner","year":"2009","journal-title":"HIV Ther."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1128\/AAC.49.3.1139-1144.2005","article-title":"In vitro activity of structurally diverse nucleoside analogs against human immunodeficiency virus type 1 with the K65R mutation in reverse transcriptase","volume":"49","author":"Parikh","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1128\/AAC.50.1.351-354.2006","article-title":"The K101P and K103R\/V179D mutations in human immunodeficiency virus type 1 reverse transcriptase confer resistance to nonnucleoside reverse transcriptase inhibitors","volume":"50","author":"Parkin","year":"2006","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1128\/AAC.04215-14","article-title":"Impact of drug resistance-associated amino acid changes in HIV-1 subtype C on susceptibility to newer nonnucleoside reverse transcriptase inhibitors","volume":"59","author":"Basson","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1097\/QAD.0b013e3283584500","article-title":"Rilpivirine resistance mutations in HIV patients failing non-nucleoside reverse transcriptase inhibitor-based therapies","volume":"27","author":"Anta","year":"2013","journal-title":"Aids"},{"key":"ref_73","first-page":"111","article-title":"2019 update of the drug resistance mutations in HIV-1","volume":"27","author":"Wensing","year":"2019","journal-title":"Top. Antivir. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1310\/67TE-GPXQ-R1LB-BPKG","article-title":"Prevalence of HIV protease mutations on failure of nelfinavir-containing HAART: A retrospective analysis of four clinical studies and two observational cohorts","volume":"3","author":"Clotet","year":"2002","journal-title":"HIV Clin. Trials"},{"key":"ref_75","first-page":"324","article-title":"HIV-1 genotypes related to failure of nelfinavir as the first protease inhibitor treatment","volume":"9","author":"Aleixo","year":"2005","journal-title":"Braz. J. Infect. Dis."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1586\/14787210.2.1.147","article-title":"The impact of the M184V substitution on drug resistance and viral fitness","volume":"2","author":"Wainberg","year":"2004","journal-title":"Expert Rev. Anti-Infect. Ther."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1128\/JCM.43.3.1395-1400.2005","article-title":"Diminished replicative fitness of primary human immunodeficiency virus type 1 isolates harboring the K65R mutation","volume":"43","author":"Weber","year":"2005","journal-title":"J. Clin. Microbiol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"9268","DOI":"10.1128\/JVI.00695-14","article-title":"Altered viral fitness and drug susceptibility in HIV-1 carrying mutations that confer resistance to nonnucleoside reverse transcriptase and integrase strand transfer inhibitors","volume":"88","author":"Hu","year":"2014","journal-title":"J. Virol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3441","DOI":"10.1128\/AAC.00040-15","article-title":"Reduced viral fitness and lack of cross-class resistance with integrase strand transfer inhibitor and nucleoside reverse transcriptase inhibitor resistance mutations","volume":"59","author":"Andreatta","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1084\/jem.20041006","article-title":"CD8 epitope escape and reversion in acute HCV infection","volume":"200","author":"Timm","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1089\/vim.2018.0040","article-title":"CD8(+) Cytotoxic T Lymphocyte Responses and Viral Epitope Escape in Acute HIV-1 Infection","volume":"31","author":"Kim","year":"2018","journal-title":"Viral Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1073\/pnas.94.5.1890","article-title":"Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection","volume":"94","author":"Price","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"13901","DOI":"10.1128\/JVI.78.24.13901-13910.2004","article-title":"Fitness costs limit viral escape from cytotoxic T lymphocytes at a structurally constrained epitope","volume":"78","author":"Peyerl","year":"2004","journal-title":"J. Virol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"11557","DOI":"10.1128\/JVI.01955-15","article-title":"Consequences of HLA-B*13-Associated Escape Mutations on HIV-1 Replication and Nef Function","volume":"89","author":"Shahid","year":"2015","journal-title":"J. Virol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"10820","DOI":"10.1128\/JVI.01084-10","article-title":"Gag-protease-mediated replication capacity in HIV-1 subtype C chronic infection: Associations with HLA type and clinical parameters","volume":"84","author":"Wright","year":"2010","journal-title":"J. Virol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3193","DOI":"10.1128\/JVI.06682-11","article-title":"Impact of HLA-B*81-associated mutations in HIV-1 Gag on viral replication capacity","volume":"86","author":"Wright","year":"2012","journal-title":"J. Virol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/nm992","article-title":"HIV evolution: CTL escape mutation and reversion after transmission","volume":"10","author":"Leslie","year":"2004","journal-title":"Nat. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1186\/s12977-014-0101-0","article-title":"Preexisting compensatory amino acids compromise fitness costs of a HIV-1 T cell escape mutation","volume":"11","author":"Liu","year":"2014","journal-title":"Retrovirology"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Dam, E., Quercia, R., Glass, B., Descamps, D., Launay, O., Duval, X., Kr\u00e4usslich, H.G., Hance, A.J., and Clavel, F. (2009). Gag mutations strongly contribute to HIV-1 resistance to protease inhibitors in highly drug-experienced patients besides compensating for fitness loss. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000345"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.1097\/00002030-199912030-00006","article-title":"Increased fitness of drug resistant HIV-1 protease as a result of acquisition of compensatory mutations during suboptimal therapy","volume":"13","author":"Nijhuis","year":"1999","journal-title":"Aids"},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Li, S., Ouyang, J., Zhao, B., An, M., Wang, L., Ding, H., Zhang, M., and Han, X. (2020). The S68G polymorphism is a compensatory mutation associated with the drug resistance mutation K65R in CRF01_AE strains. BMC Infect. Dis., 20.","DOI":"10.1186\/s12879-020-4836-z"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1097\/QAI.0b013e3181fe9450","article-title":"Reduced replication capacity of NL4-3 recombinant viruses encoding reverse transcriptase-integrase sequences from HIV-1 elite controllers","volume":"56","author":"Brumme","year":"2011","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Murakoshi, H., Koyanagi, M., Chikata, T., Rahman, M.A., Kuse, N., Sakai, K., Gatanaga, H., Oka, S., and Takiguchi, M. (2017). Accumulation of Pol Mutations Selected by HLA-B*52:01-C*12:02 Protective Haplotype-Restricted Cytotoxic T Lymphocytes Causes Low Plasma Viral Load Due to Low Viral Fitness of Mutant Viruses. J. Virol., 91.","DOI":"10.1128\/JVI.02082-16"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Seki, S., and Matano, T. (2011). CTL Escape and Viral Fitness in HIV\/SIV Infection. Front. Microbiol., 2.","DOI":"10.3389\/fmicb.2011.00267"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"11300","DOI":"10.1128\/JVI.05584-11","article-title":"Compensation by the E138K mutation in HIV-1 reverse transcriptase for deficits in viral replication capacity and enzyme processivity associated with the M184I\/V mutations","volume":"85","author":"Xu","year":"2011","journal-title":"J. Virol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1097\/COH.0b013e328051b4e8","article-title":"Viral fitness: Relation to drug resistance mutations and mechanisms involved: Nucleoside reverse transcriptase inhibitor mutations","volume":"2","author":"Weber","year":"2007","journal-title":"Curr. Opin. HIV AIDS"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1128\/JVI.02712-06","article-title":"The fitness cost of mutations associated with human immunodeficiency virus type 1 drug resistance is modulated by mutational interactions","volume":"81","author":"Cong","year":"2007","journal-title":"J. Virol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1097\/00002030-200212060-00003","article-title":"The M184V mutation in HIV-1 reverse transcriptase reduces the restoration of wild-type replication by attenuated viruses","volume":"16","author":"Wei","year":"2002","journal-title":"Aids"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"3552","DOI":"10.1128\/AAC.48.9.3552-3555.2004","article-title":"Impact of nelfinavir resistance mutations on in vitro phenotype, fitness, and replication capacity of human immunodeficiency virus type 1 with subtype B and C proteases","volume":"48","author":"Gonzalez","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1089\/aid.2013.0038","article-title":"Differential impact of resistance-associated mutations to protease inhibitors and nonnucleoside reverse transcriptase inhibitors on HIV-1 replication capacity","volume":"29","author":"Hsieh","year":"2013","journal-title":"AIDS Res. Hum. Retrovir."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"4035","DOI":"10.1128\/JCM.00605-10","article-title":"Human immunodeficiency virus type 1 protease inhibitor drug-resistant mutants give discordant results when compared in single-cycle and multiple-cycle fitness assays","volume":"48","author":"Dykes","year":"2010","journal-title":"J. Clin. Microbiol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/978-981-16-0267-2_2","article-title":"An Update on Antiretroviral Therapy","volume":"1322","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1742-4690-6-14","article-title":"Effects of the K65R and K65R\/M184V reverse transcriptase mutations in subtype C HIV on enzyme function and drug resistance","volume":"6","author":"Xu","year":"2009","journal-title":"Retrovirology"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"F9","DOI":"10.1097\/01.aids.0000232228.88511.0b","article-title":"HIV-1 subtype C viruses rapidly develop K65R resistance to tenofovir in cell culture","volume":"20","author":"Brenner","year":"2006","journal-title":"Aids"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"25489","DOI":"10.1074\/jbc.M313534200","article-title":"A loss of viral replicative capacity correlates with altered DNA polymerization kinetics by the human immunodeficiency virus reverse transcriptase bearing the K65R and L74V dideoxynucleoside resistance substitutions","volume":"279","author":"Deval","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1074\/jbc.M308806200","article-title":"Mechanistic basis for reduced viral and enzymatic fitness of HIV-1 reverse transcriptase containing both K65R and M184V mutations","volume":"279","author":"Deval","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.virol.2016.02.008","article-title":"High fidelity simian immunodeficiency virus reverse transcriptase mutants have impaired replication in vitro and in vivo","volume":"492","author":"Lloyd","year":"2016","journal-title":"Virology"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1086\/315317","article-title":"Resistance profile of the human immunodeficiency virus type 1 reverse transcriptase inhibitor abacavir (1592U89) after monotherapy and combination therapy. CNA2001 Investigative Group","volume":"181","author":"Harrigan","year":"2000","journal-title":"J. Infect. Dis."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1128\/JVI.02154-08","article-title":"In vivo fitness cost of the M184V mutation in multidrug-resistant human immunodeficiency virus type 1 in the absence of lamivudine","volume":"83","author":"Paredes","year":"2009","journal-title":"J. Virol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"3291","DOI":"10.1128\/JVI.75.7.3291-3300.2001","article-title":"Individual contributions of mutant protease and reverse transcriptase to viral infectivity, replication, and protein maturation of antiretroviral drug-resistant human immunodeficiency virus type 1","volume":"75","author":"Bleiber","year":"2001","journal-title":"J. Virol."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Wagner, B.G., Garcia-Lerma, J.G., and Blower, S. (2012). Factors limiting the transmission of HIV mutations conferring drug resistance: Fitness costs and genetic bottlenecks. Sci. Rep., 2.","DOI":"10.1038\/srep00320"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1097\/QAD.0b013e3280187505","article-title":"Diminished efficiency of HIV-1 reverse transcriptase containing the K65R and M184V drug resistance mutations","volume":"21","author":"Frankel","year":"2007","journal-title":"AIDS"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/6\/842\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:50:38Z","timestamp":1760032238000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/17\/6\/842"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,12]]},"references-count":112,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["v17060842"],"URL":"https:\/\/doi.org\/10.3390\/v17060842","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2025,6,12]]}}}