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HIV-1 Gag Mutations in Protease Inhibitors Resistance
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HIV protease inhibitors against the viral protease are often hampered by drug resistance mutations in protease and in the viral substrate Gag. To overcome this drug resistance and inhibit viral maturation, targeting Gag alongside protease rather than targeting protease alone may be more efficient. 

HIV-1 Gag Gag inhibitors protease protease inhibitors drug resistance mutations
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Subjects: Virology
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Update Time: 29 Mar 2022

1. Introduction

Many anti-HIV drugs interfere directly with the viral life cycle by targeting key viral enzymes[1], e.g., reverse transcriptase inhibitors[2][3][4], integrase inhibitors[5][6], and protease inhibitors[7][8]. While such efforts are already hampered by the emergence of drug resistance mutations in the enzymes (e.g., in [9]), the scenario further worsens when viral enzyme substrates, such as Gag (HIV protease substrate), are found to synergistically contribute to drug resistance.
Gag and protease play key roles in the viral maturation process[10] where the immature HIV virion matures into the infectious virion after budding from the infected cell for the next replication cycle. Proteolysis of Gag by protease occurs during the early stage of this maturation (Figure 1A), in which the intact full length Gag precursor polyprotein is cleaved by the viral protease into functional subunits[10] . To inhibit this proteolysis, protease inhibitors (PIs) block protease activity in a competitive manner with Gag for protease binding[11].
Figure 1. An overview of the Gag and Protease relationship. (A) A schematic of the early stage of viral maturation where HIV-1 Protease cleaves Gag into the functional subunits: Matrix (MA), capsid (CA), nucleocapsid (NC), p6, and two spacer peptides p1 and p2. (B) To inhibit viral maturation, protease inhibitors (PIs in green) are used to competitively inhibit protease binding of Gag. PI resistant mutations are denoted by colored stars, where those in the protease catalytic site are in blue, while those in Gag are red for cleavage sites, and purple for non-cleavage sites.

2. Possible Targets in Gag

The Gag polyprotein consists of components matrix (MA), capsid (CA), nucleocapsid (NC), p6, and two spacer peptides p1 and p2. The MA subunit, located at the N-terminus, is essential for targeting Gag to the cell membrane, while the CA forms a shell to protect the viral RNA genome and other core proteins during maturation. The NC is responsible for RNA packing and encapsidation [12] while the two spacer peptides p1 and p2 regulate the rate and the sequential cleavage process of Gag by protease[13]. This process of viral assembly is complemented by viral budding moderated by the small Proline-rich p6. Mutations at either the N-terminal or C-terminal of these core proteins were reported to block viral assembly and impair Gag binding to plasma membrane, thereby inhibiting viral budding [12].
Since the Gag cleavage sites do not share a consensus sequence (Figure 2), the recognition of the cleavage sites by protease is likely to be based on their asymmetric three-dimensional structures[14] that would fit into the substrate-binding pocket of protease[15]. The cleavage of these scissile bonds (seven-residue peptide sequences unique for each cleavage site) are highly regulated and occur at differing rates [16][13][17]. The first cleavage occurs at the site between the p2 peptide and NC domain (Figure 2), followed by the MA from CA–p2 at a rate that is ~14-fold slower than that of the first cleavage, before proceeding to release p6 from the NC-p1 domain (at a rate ~9-fold slower than the first cleavage). At the last step, the two spacer peptides p1 and p2 are cleaved from NC-p1 and CA–p2 at rates ~350-fold and ~400-fold, respectively, slower than the initial cleavage[16][13][15][17].
Figure 2. The sequential Gag proteolysis by Protease. The cleavage sites are marked by the 7-residues, along with the estimated cleavage rates [13] marked by arrows. For easy comparison, the initial cleavage site rate is set to the value of 1, while the other cleavage site values depict the reduced normalized rate. The cleavage site sequences are colored based on their physicochemical properties, e.g., hydrophobic (black), charged (positive: blue, negative: red), polar (other colors), and varied in text sizes based on positional conservation, using WebLogo[18][19]. Structural surface presentations of the cleavage sites are also attached for visualization.
To date, there are nine PIs, i.e., Saquinavir (SQV), Ritonavir (RTV), Indinavir (IDV), Nelfinavir (NFV), Fos/Amprenavir (FPV/APV), Lopinavir (LPV), Atazanavir (ATV), Tipranavir (TPV), and Darunavir (DRV) in clinical treatment regimes [15]. With increasing PI resistance[20][21][22][23] and cross-resistance[16][21][24][25] conferred by protease mutations that compromise viral fitness, there is a compromise between enzymatic activity and drug inhibition by protease within its 99-residue homodimer subunits. Mapped to the resistance to several current PIs[26][27][28][29], many mutations were found to spontaneously arise as part of the natural variance[30] selected for during the treatment regimes. These mutations directly intervene with PI binding via steric perturbation at the active site, and those distant from the active site allosterically modulated protease activity[31][32][33][34][35][36][37][38][39][40][41]. However, such mutations often reduce viral fitness, resulting in future repertoires of viruses with compromised fitness[42]. This fitness trade-off is then compensated by additional mutations that restore enzymatic activity to an extent [33][37][38][43].
To fully study the Gag–protease synergy, there is a need to study the limitations and mechanisms by which Gag mutations arise. Although the sequencing of clinical samples is the predominant source of HIV sequences, there are attempts to study and generate novel mutations [47][45][46][46]) for various HIV proteins. One example of such an effort[47] involved subjecting the Gag mRNA transcript to HIV reverse transcriptase (RT) to explore the repertoire of possible Gag mutations in the absence of drug or immune selection pressures. It was shown that clinically reported mutations could be generated and that the location and type of mutations incidentally avoided crucial locations and drastic changes. While such selection-free platforms can reveal the possible repertoires of Gag mutations for inhibitor design against emerging resistance, the large permutations require focusing through structural analysis for comparison to known clinical mutations taking into consideration the in-built mutational biases in the genetic code.
Characterized clinical Gag mutations[48][49][50][24][51][16] are sparse, with many reported to restore reduced binding to mutated proteases[48][49][50][24][51][16][52]. The lack of a high-resolution structure of full-length Gag for study of these mutations makes it difficult to analyze structurally the effects of these mutations on the whole Gag during its binding to protease. Fortunately, the recent full length model of Gag[53][54] allowed some investigation of non-cleavage site mutations.

3. The Role of Gag Mutations in Restoring Gag–Protease Synergy in PI Resistance

The mapping of Gag mutations associated with protease drug resistant mutations are summarized in Table 1. Gag cleavage site mutations at the p1/p6 (L449F) and NC/p1 (L449F-Q430R-A431V) sections were found to be associated to protease mutation I84V[16][55]. Similarly, Gag mutations A431V and I437V were mapped to protease mutation V82A [16][56]. Apart from compensating the loss of viral fitness, mutations P453L (Gag) and I50V (Protease) synergistically mitigated Amprenavir effectiveness (e.g., increasing IC50 value of Amprenavir) and Gag mutations A431V-I437V together with protease V82A were found to lead to Indinavir resistance[16] .
Table 1. Gag and Protease paired mutations compensating for viral fitness and viral replication. Gag mutations are colored according to domains: MA (red), CA (green), NC (magenta), and p6 (orange).
   

Molecules 24 03243 i001

Molecules 24 03243 i002

Inhibitor

Strain or Lab Clone

Mutations on Gag

Mutations on Protease

Amprenavir

HIV-1 NL4-3 (pNL4-3)

V35IL75RH219Q

L10F–V32I–M46I–I84V

Amprenavir

HIV-1 NL4-3 (pNL4-3)

L75RH219QR409KL449F–E468K

L10F–V32I–M46I–I84V

Amprenavir

HIV-1 NL4-3 (pNL4-3)

E12KV35IL75RH219QV390DR409KL449F–E468K

L10F–V32I–M46I–I54M–A71V–I84V

JE–2147

HIV-1 NL4-3 (pNL4-3)

H219QV390D

M46I–I84V

JE–2147

HIV-1 NL4-3 (pNL4-3)

H219QV390DR409KL449F

V32I–M46I–I47V–V82I–I84V

KNI–272

HIV-1 NL4-3 (pNL4-3)

V35IE40KG123EH219QG381SR409KA431V

V32I–M46I–A71V–V82I–I84V

UIC–94003

HIV-1 NL4-3 (pNL4-3)

E12KE40KG123EQ199HH219QR409KG412DL449F–E468K

L10F–M46I–I50V–A71V

Amprenavir

HIV-1 HXB2

P453L

I50V

BILA–1906BS

HIV-1 strain IIIB

L449F

M46L–A71V–I84V

BILA–2185BS

HIV-1 strain IIIB

L449FQ430RA431V

L23I–V32I–M46I–I47V–I54M–A71V–I84V

Indinavir

HIV-1 pNL4.3

A431V–I437V

V82A

Ritonavir/Saquinavir

HIV-1 subtype B #

A431VL449F

I84V

# the study involves patients.
Non-cleavage site mutations associated with PI resistance [57][51], included H219Q and R409K for Amprenavir, JE-2147, KNI-272, and UIC-94003 resistance. Gag L75R and H219Q together with Protease mutation I84V, led to Amprenavir and JE-2147 resistance. Together, these non-cleavage site mutations (synergistically with E12K, V390D, and R409K) delayed resistance to other PIs, e.g., Ritonavir and Nelfinavir[57]. Interestingly, most of these Gag non-cleavage site mutations are located on the MA–CA or p1–p6 domains. Gag MA domain mutations (e.g., R76K, Y79F, and T81A) were suggested to enhance Protease accessibility to Gag cleavage sites[58][59]. Nonetheless, the exact mechanism of such non-cleavage mutations remains elusive due to the lack of full-length Gag structure and its sequentially cleaved subunits.
Limited structural research[34][36][53][60] have revealed an underlying allosteric mechanism in resistance development by Gag non-cleavage mutations that allosterically rendered the first cleavage site to be more flexible[53]. When coupled with protease mutations, several Gag compensatory mutations recovered protease binding affinities. Thus, the Gag and protease mutations synergistically formed a resistance network against multiple PIs[26][60][61]. By mapping these Gag–protease resistance relationships (Figure 3) onto our previously constructed PI cross-resistance network[60], similar combinations of Gag mutations were found to resist varied PIs, independent of their diverse chemical scaffolds[62].
Figure 3. A schematic map of associated Gag–Protease drug resistant mutations. Mutation hotspots are shown on both the Gag and Protease, and representatives of paired combinations of Gag and Protease mutations are shown in boxes. More details can be found in Table 1. Gag mutations are colored according to domains: MA (red), CA (green), NC (magenta), and p6 (orange).

References

  1. Adnan Bashir Bhatti; Muhammad Usman; Venkataramana Kandi; Current Scenario of HIV/AIDS, Treatment Options, and Major Challenges with Compliance to Antiretroviral Therapy. Cureus 2016, 8, e515, 10.7759/cureus.515.
  2. Mohammad A. Rai; Sam Pannek; Carl J. Fichtenbaum; Emerging reverse transcriptase inhibitors for HIV-1 infection. Expert Opinion on Emerging Drugs 2018, 23, 149-157, 10.1080/14728214.2018.1474202.
  3. Ron Zhi-Hui Chiang; Samuel Ken-En Gan; Chinh Tran-To Su; A computational study for rational HIV-1 non-nucleoside reverse transcriptase inhibitor selection and the discovery of novel allosteric pockets for inhibitor design. Bioscience Reports 2018, 38, 1, 10.1042/bsr20171113.
  4. Kwok-Fong Chan; Chinh Su; Alexander Krah; Ser-Xian Phua; Joshua Yeo; Wei-Li Ling; Peter Bond; Samuel Gan; An Alternative HIV-1 Non-Nucleoside Reverse Transcriptase Inhibition Mechanism: Targeting the p51 Subunit. Molecules 2020, 25, 5902, 10.3390/molecules25245902.
  5. Zeger Debyser; Gerlinde VanSant; Anne Bruggemans; Julie Janssens; Frauke Christ; Insight in HIV Integration Site Selection Provides a Block-and-Lock Strategy for a Functional Cure of HIV Infection. Viruses 2018, 11, 12, 10.3390/v11010012.
  6. Charlotte Charpentier; Diane Descamps; Resistance to HIV Integrase Inhibitors: About R263K and E157Q Mutations. Viruses 2018, 10, 41, 10.3390/v10010041.
  7. Graziella Favarato; Claire L. Townsend; Heather Bailey; Helen Peters; Pat A. Tookey; Graham P. Taylor; Claire Thorne; Protease inhibitors and preterm delivery. AIDS 2018, 32, 243-252, 10.1097/qad.0000000000001694.
  8. Yong Wang; Zhengtong Lv; Yuan Chu; HIV protease inhibitors: a review of molecular selectivity and toxicity. HIV/AIDS - Research and Palliative Care 2015, 7, 95-104, 10.2147/hiv.s79956.
  9. Louise Castain; Marine Perrier; Charlotte Charpentier; Romain Palich; Nathalie Desire; Marc Wirden; Diane Descamps; Sophie Sayon; Roland Landman; Marc-Antoine Valantin; et al. New mechanisms of resistance in virological failure to protease inhibitors: selection of non-described protease, Gag and Gp41 mutations. Journal of Antimicrobial Chemotherapy 2019, 74, 2019-2023, 10.1093/jac/dkz151.
  10. Eric O. Freed; HIV-1 assembly, release and maturation. Nature Reviews Microbiology 2015, 13, 484-496, 10.1038/nrmicro3490.
  11. Arun K. Ghosh; Heather L. Osswald; Gary Prato; Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS. Journal of Medicinal Chemistry 2016, 59, 5172-5208, 10.1021/acs.jmedchem.5b01697.
  12. Eric O. Freed; HIV-1 Gag Proteins: Diverse Functions in the Virus Life Cycle. Virology 1998, 251, 1-15, 10.1006/viro.1998.9398.
  13. Steve Pettit; M D Moody; R S Wehbie; A H Kaplan; P V Nantermet; C A Klein; R Swanstrom; The p2 domain of human immunodeficiency virus type 1 Gag regulates sequential proteolytic processing and is required to produce fully infectious virions. Journal of Virology 1994, 68, 8017-8027, 10.1128/jvi.68.12.8017-8027.1994.
  14. Moses Prabu-Jeyabalan; Ellen Nalivaika; Celia A. Schiffer; Substrate Shape Determines Specificity of Recognition for HIV-1 Protease: Analysis of Crystal Structures of Six Substrate Complexes. Structure 2002, 10, 369-381, 10.1016/s0969-2126(02)00720-7.
  15. Axel Fun; Annemarie Mj Wensing; Jens Verheyen; Monique Nijhuis; Human Immunodeficiency Virus gag and protease: partners in resistance. Retrovirology 2012, 9, 63-63, 10.1186/1742-4690-9-63.
  16. François Clavel; Fabrizio Mammano; Role of Gag in HIV Resistance to Protease Inhibitors. Viruses 2010, 2, 1411-1426, 10.3390/v2071411.
  17. Steve C Pettit; Jeffrey N Lindquist; Andrew H Kaplan; Ronald Swanstrom; Processing sites in the human immunodeficiency virus type 1 (HIV-1) Gag-Pro-Pol precursor are cleaved by the viral protease at different rates. Retrovirology 2005, 2, 66-66, 10.1186/1742-4690-2-66.
  18. Gavin E. Crooks; Gary Hon; John-Marc Chandonia; Steven E. Brenner; WebLogo: A Sequence Logo Generator: Figure 1. Genome Research 2004, 14, 1188-1190, 10.1101/gr.849004.
  19. Thomas Schneider; R. Michael Stephens; Sequence logos: a new way to display consensus sequences. Nucleic Acids Research 1990, 18, 6097-6100, 10.1093/nar/18.20.6097.
  20. Michele W. Tang; Robert W. Shafer; HIV-1 Antiretroviral Resistance. Drugs 2012, 72, e1-e25, 10.2165/11633630-000000000-00000.
  21. Kwok-Fong Chan; Stelios Koukouravas; Joshua Yi Yeo; Darius Wen-Shuo Koh; Samuel Ken-En Gan; Probability of change in life: Amino acid changes in single nucleotide substitutions. Biosystems 2020, 193-194, 104135, 10.1016/j.biosystems.2020.104135.
  22. E. Fumero; D. Podzamczer; New patterns of HIV-1 resistance during HAART. Clinical Microbiology and Infection 2003, 9, 1077-1084, 10.1046/j.1469-0691.2003.00730.x.
  23. Pierre Loulergue; Constance Delaugerre; Vincent Jullien; Jean-Paul Viard; Letter to the Editor [HIV Drug Resistance on HAART Despite an Undetectable Viral Load]. Current HIV Research 2011, 9, 623-624, 10.2174/157016211798998817.
  24. Michael F. Maguire; Rosario Guinea; Philip Griffin; Sarah Macmanus; Robert C. Elston; Josie Wolfram; Naomi Richards; Mary H. Hanlon; David J. T. Porter; Terri Wrin; et al. Changes in Human Immunodeficiency Virus Type 1 Gag at Positions L449 and P453 Are Linked to I50V Protease Mutants In Vivo and Cause Reduction of Sensitivity to Amprenavir and Improved Viral Fitness In Vitro. Journal of Virology 2002, 76, 7398-7406, 10.1128/jvi.76.15.7398-7406.2002.
  25. Axel Fun; Noortje M van Maarseveen; Jana Pokorná; Renée Em Maas; Pauline J Schipper; Jan Konvalinka; Monique Nijhuis; HIV-1 protease inhibitor mutations affect the development of HIV-1 resistance to the maturation inhibitor bevirimat. Retrovirology 2011, 8, 70-70, 10.1186/1742-4690-8-70.
  26. Art F. Y. Poon; Sergei L. Kosakovsky Pond; Douglas D. Richman; Simon Frost; Mapping Protease Inhibitor Resistance to Human Immunodeficiency Virus Type 1 Sequence Polymorphisms within Patients. Journal of Virology 2007, 81, 13598-13607, 10.1128/jvi.01570-07.
  27. Jose-Luis Blanco; Vici Varghese; Soo-Yon Rhee; Jose M. Gatell; Robert W. Shafer; HIV-1 Integrase Inhibitor Resistance and Its Clinical Implications. The Journal of Infectious Diseases 2011, 203, 1204-1214, 10.1093/infdis/jir025.
  28. Hiroaki Mitsuya; Kenji Maeda; Debananda Das; Arun K. Ghosh; Development of Protease Inhibitors and the Fight with Drug‐Resistant HIV‐1 Variants. A New Era of Catecholamines in the Laboratory and Clinic 2007, 56, 169-197, 10.1016/s1054-3589(07)56006-0.
  29. Joel E Gallant; Initial therapy of HIV infection. Journal of Clinical Virology 2002, 25, 317-333, 10.1016/s1386-6532(02)00024-0.
  30. Kimberly A. Barrie; Elena E. Perez; Susanna L. Lamers; William G. Farmerie; Ben M. Dunn; John W. Sleasman; Maureen M. Goodenow; Natural Variation in HIV-1 Protease, Gag p7 and p6, and Protease Cleavage Sites within Gag/Pol Polyproteins: Amino Acid Substitutions in the Absence of Protease Inhibitors in Mothers and Children Infected by Human Immunodeficiency Virus Type 1. Virology 1996, 219, 407-416, 10.1006/viro.1996.0266.
  31. Joon H. Park; Jane M. Sayer; Annie Aniana; Xiaxia Yu; Irene T. Weber; Robert W. Harrison; John M. Louis; Binding of Clinical Inhibitors to a Model Precursor of a Rationally Selected Multidrug Resistant HIV-1 Protease Is Significantly Weaker Than That to the Released Mature Enzyme. Biochemistry 2016, 55, 2390-2400, 10.1021/acs.biochem.6b00012.
  32. Yuqi Yu; Jinan Wang; Qiang Shao; Jiye Shi; Weiliang Zhu; Effects of drug-resistant mutations on the dynamic properties of HIV-1 protease and inhibition by Amprenavir and Darunavir. Scientific Reports 2015, 5, 10517, 10.1038/srep10517.
  33. Masaaki Nakashima; Hirotaka Ode; Koji Suzuki; Masayuki Fujino; Masami Maejima; Yuki Kimura; Takashi Masaoka; Junko Hattori; Masakazu Matsuda; Atsuko Hachiya; et al. Unique Flap Conformation in an HIV-1 Protease with High-Level Darunavir Resistance. Frontiers in Microbiology 2016, 7, 61, 10.3389/fmicb.2016.00061.
  34. Rajeswari Appadurai; Sanjib Senapati; Dynamical Network of HIV-1 Protease Mutants Reveals the Mechanism of Drug Resistance and Unhindered Activity. Biochemistry 2016, 55, 1529-1540, 10.1021/acs.biochem.5b00946.
  35. Chen-Hsiang Shen; Yu-Chung Chang; Johnson Agniswamy; Robert Harrison; Irene T. Weber; Conformational variation of an extreme drug resistant mutant of HIV protease. Journal of Molecular Graphics and Modelling 2015, 62, 87-96, 10.1016/j.jmgm.2015.09.006.
  36. Debra A. Ragland; Ellen A. Nalivaika; Madhavi N. L. Nalam; Kristina L. Prachanronarong; Hong Cao; Rajintha M. Bandaranayake; Yufeng Cai; Nese Kurt-Yilmaz; Celia A. Schiffer; Drug Resistance Conferred by Mutations Outside the Active Site through Alterations in the Dynamic and Structural Ensemble of HIV-1 Protease. Journal of the American Chemical Society 2014, 136, 11956-11963, 10.1021/ja504096m.
  37. Jeffrey D. Carter; Estrella G. Gonzales; Xi Huang; Adam Smith; Ian Mitchelle de Vera; Peter D'Amore; James R. Rocca; Maureen M. Goodenow; Ben M. Dunn; Gail E. Fanucci; et al. Effects of PRE and POST therapy drug-pressure selected mutations on HIV-1 protease conformational sampling. FEBS Letters 2014, 588, 3123-3128, 10.1016/j.febslet.2014.06.051.
  38. Xi Huang; Manuel D. Britto; Jamie L. Kear-Scott; Christopher D. Boone; James R. Rocca; Carlos Simmerling; Robert Mckenna; Michael Bieri; Paul Gooley; Ben M. Dunn; et al. The Role of Select Subtype Polymorphisms on HIV-1 Protease Conformational Sampling and Dynamics. Journal of Biological Chemistry 2014, 289, 17203-17214, 10.1074/jbc.m114.571836.
  39. Rui Duan; Raudah Lazim; Dawei Zhang; Understanding the basis of I50V-induced affinity decrease in HIV-1 protease via molecular dynamics simulations using polarized force field. Journal of Computational Chemistry 2015, 36, 1885-1892, 10.1002/jcc.24020.
  40. Dinler Antunes; Mauricio Menegatti Rigo; Marialva Sinigaglia; Rúbia M. De Medeiros; Dennis M. Junqueira; Sabrina E. M. Almeida; Gustavo F. Vieira; New Insights into the In Silico Prediction of HIV Protease Resistance to Nelfinavir. PLOS ONE 2014, 9, e87520, 10.1371/journal.pone.0087520.
  41. Ankita Gupta; Salma Jamal; Sukriti Goyal; Ritu Jain; Divya Wahi; Abhinav Grover; Structural studies on molecular mechanisms of Nelfinavir resistance caused by non-active site mutation V77I in HIV-1 protease. BMC Bioinformatics 2015, 16, S10-S10, 10.1186/1471-2105-16-s19-s10.
  42. Feng Gao; David L. Robertson; Catherine D. Carruthers; Sandra G. Morrison; Bixi Jian; Yalu Chen; Françoise Barré-Sinoussi; Marc Girard; Alagarsamy Srinivasan; Alash’Le G. Abimiku; et al. A Comprehensive Panel of Near-Full-Length Clones and Reference Sequences for Non-Subtype B Isolates of Human Immunodeficiency Virus Type 1. Journal of Virology 1998, 72, 5680-5698, 10.1128/jvi.72.7.5680-5698.1998.
  43. Javier Martinez-Picado; Anu V. Savara; Lorraine Sutton; Richard T. D’Aquila; Replicative Fitness of Protease Inhibitor-Resistant Mutants of Human Immunodeficiency Virus Type 1. Journal of Virology 1999, 73, 3744-3752, 10.1128/jvi.73.5.3744-3752.1999.
  44. Joshua Yi Yeo; Darius Wen-Shuo Koh; Ping Yap; Ghin-Ray Goh; Samuel Ken-En Gan; Spontaneous Mutations in HIV-1 Gag, protease, RT p66 in the first replication cycle and how they appear: Insights from an in vitro BSL2 assay on mutation rates and types. null 2019, NA, 679852, 10.1101/679852.
  45. Ron Geller; Pilar Domingo-Calap; Jose Cuevas; Paola Rossolillo; Matteo Negroni; Rafael Sanjuán; The external domains of the HIV-1 envelope are a mutational cold spot. Nature Communications 2015, 6, 8571, 10.1038/ncomms9571.
  46. Michael E. Abram; Andrea L. Ferris; Wei Shao; W. Gregory Alvord; Stephen H. Hughes; Nature, Position, and Frequency of Mutations Made in a Single Cycle of HIV-1 Replication. Journal of Virology 2010, 84, 9864-9878, 10.1128/jvi.00915-10.
  47. Joshua Yeo; Darius Koh; Ping Yap; Ghin-Ray Goh; Samuel Gan; Spontaneous Mutations in HIV-1 Gag, Protease, RT p66 in the First Replication Cycle and How They Appear: Insights from an In Vitro Assay on Mutation Rates and Types. International Journal of Molecular Sciences 2020, 22, 370, 10.3390/ijms22010370.
  48. Elisabeth Dam; Romina Quercia; Bärbel Glass; Diane Descamps; Odile Launay; Xavier Duval; Hans-Georg Kräusslich; Allan J. Hance; François Clavel; ANRS 109 Study Group; et al. Gag Mutations Strongly Contribute to HIV-1 Resistance to Protease Inhibitors in Highly Drug-Experienced Patients besides Compensating for Fitness Loss. PLOS Pathogens 2009, 5, e1000345, 10.1371/journal.ppat.1000345.
  49. Chris M. Parry; Arinder Kohli; Christine J. Boinett; Greg J. Towers; Adele L. McCormick; Deenan Pillay; Gag Determinants of Fitness and Drug Susceptibility in Protease Inhibitor-Resistant Human Immunodeficiency Virus Type 1. Journal of Virology 2009, 83, 9094-9101, 10.1128/jvi.02356-08.
  50. Sadahiro Tamiya; Sek Mardy; Mark F. Kavlick; Kazuhisa Yoshimura; Hiroaki Mistuya; Amino Acid Insertions near Gag Cleavage Sites Restore the Otherwise Compromised Replication of Human Immunodeficiency Virus Type 1 Variants Resistant to Protease Inhibitors. Journal of Virology 2004, 78, 12030-12040, 10.1128/jvi.78.21.12030-12040.2004.
  51. Hiroyuki Gatanaga; Yasuhiro Suzuki; Hsinyi Tsang; Kazuhisa Yoshimura; Mark F. Kavlick; Kunio Nagashima; Robert J. Gorelick; Sek Mardy; Chun Tang; Michael F. Summers; et al. Amino Acid Substitutions in Gag Protein at Non-cleavage Sites Are Indispensable for the Development of a High Multitude of HIV-1 Resistance against Protease Inhibitors. Journal of Biological Chemistry 2002, 277, 5952-5961, 10.1074/jbc.m108005200.
  52. Frank Bally; Raquel Martinez; Solange Peters; Philippe Sudre; Amalio Telenti; Polymorphism of HIV Type 1 Gag p7/p1 and p1/p6 Cleavage Sites: Clinical Significance and Implications for Resistance to Protease Inhibitors. AIDS Research and Human Retroviruses 2000, 16, 1209-1213, 10.1089/08892220050116970.
  53. Chinh Tran-To Su; Chee-Keong Kwoh; Chandra Shekhar Verma; Samuel Ken-En Gan; Modeling the full length HIV-1 Gag polyprotein reveals the role of its p6 subunit in viral maturation and the effect of non-cleavage site mutations in protease drug resistance. Journal of Biomolecular Structure and Dynamics 2017, 36, 4366-4377, 10.1080/07391102.2017.1417160.
  54. Firdaus Samsudin; Samuel Ken-En Gan; Peter J. Bond; The impact of Gag non-cleavage site mutations on HIV-1 viral fitness from integrative modelling and simulations. Computational and Structural Biotechnology Journal 2020, 19, 330-342, 10.1016/j.csbj.2020.12.022.
  55. L Doyon; G Croteau; D Thibeault; F Poulin; L Pilote; D Lamarre; Second locus involved in human immunodeficiency virus type 1 resistance to protease inhibitors. Journal of Virology 1996, 70, 3763-3769, 10.1128/jvi.70.6.3763-3769.1996.
  56. Isabelle Malet; Bénédicte Roquebert; Cécile Dalban; Marc Wirden; Bahia Amellal; Rachid Agher; Anne Simon; Christine Katlama; Dominique Costagliola; Vincent Calvez; et al. Association of Gag cleavage sites to protease mutations and to virological response in HIV-1 treated patients. Journal of Infection 2007, 54, 367-374, 10.1016/j.jinf.2006.06.012.
  57. Manabu Aoki; David J. Venzon; Yasuhiro Koh; Hiromi Aoki-Ogata; Toshikazu Miyakawa; Kazuhisa Yoshimura; Kenji Maeda; Hiroaki Mitsuya; Non-Cleavage Site Gag Mutations in Amprenavir-Resistant Human Immunodeficiency Virus Type 1 (HIV-1) Predispose HIV-1 to Rapid Acquisition of Amprenavir Resistance but Delay Development of Resistance to Other Protease Inhibitors. Journal of Virology 2009, 83, 3059-3068, 10.1128/jvi.02539-08.
  58. William F. Flynn; Max W. Chang; Zhiqiang Tan; Glenn Oliveira; Jinyun Yuan; Jason F. Okulicz; Bruce E. Torbett; Ronald M. Levy; Deep Sequencing of Protease Inhibitor Resistant HIV Patient Isolates Reveals Patterns of Correlated Mutations in Gag and Protease. PLOS Computational Biology 2015, 11, e1004249, 10.1371/journal.pcbi.1004249.
  59. Chris M. Parry; Madhavi Kolli; Richard E. Myers; Patricia A. Cane; Celia Schiffer; Deenan Pillay; Three Residues in HIV-1 Matrix Contribute to Protease Inhibitor Susceptibility and Replication Capacity. Antimicrobial Agents and Chemotherapy 2011, 55, 1106-1113, 10.1128/aac.01228-10.
  60. Chinh Tran-To Su; Wei-Li Ling; Wai-Heng Lua; Yu-Xuan Haw; Samuel Ken-En Gan; Structural analyses of 2015-updated drug-resistant mutations in HIV-1 protease: an implication of protease inhibitor cross-resistance. BMC Bioinformatics 2016, 17, 219-228, 10.1186/s12859-016-1372-3.
  61. Soo-Yon Rhee; Jonathan Taylor; W. Jeffrey Fessel; David Kaufman; William Towner; Paolo Troia; Peter Ruane; James Hellinger; Vivian Shirvani; Andrew Zolopa; et al. HIV-1 Protease Mutations and Protease Inhibitor Cross-Resistance. Antimicrobial Agents and Chemotherapy 2010, 54, 4253-4261, 10.1128/aac.00574-10.
  62. Akbar Ali; Rajintha M. Bandaranayake; Yufeng Cai; Nancy M. King; Madhavi Kolli; Seema Mittal; Jennifer F. Murzycki; Madhavi N.L. Nalam; Ellen A. Nalivaika; Ayşegül Özen; et al. Molecular Basis for Drug Resistance in HIV-1 Protease. Viruses 2010, 2, 2509-2535, 10.3390/v2112509.
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    Koh, D.W.S.; Gan, S. HIV-1 Gag Mutations in Protease Inhibitors Resistance. Encyclopedia. Available online: https://encyclopedia.pub/entry/17172 (accessed on 03 October 2022).
    Koh DWS, Gan S. HIV-1 Gag Mutations in Protease Inhibitors Resistance. Encyclopedia. Available at: https://encyclopedia.pub/entry/17172. Accessed October 03, 2022.
    Koh, Darius Wen Shuo, Samuel Gan. "HIV-1 Gag Mutations in Protease Inhibitors Resistance," Encyclopedia, https://encyclopedia.pub/entry/17172 (accessed October 03, 2022).
    Koh, D.W.S., & Gan, S. (2021, December 15). HIV-1 Gag Mutations in Protease Inhibitors Resistance. In Encyclopedia. https://encyclopedia.pub/entry/17172
    Koh, Darius Wen Shuo and Samuel Gan. ''HIV-1 Gag Mutations in Protease Inhibitors Resistance.'' Encyclopedia. Web. 15 December, 2021.
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