Mamuka Kvaratskhelia, PhD

Professional Titles

• Professor

Research Interests

Research Overview The research in our laboratory focuses on the molecular mechanisms for retroviral integration into the host genome, discovery of HIV-1 integrase inhibitors with allosteric mechanisms of action and virus-host interactions. We employ innovative and complementary biochemistry, biophysics, structural biology, pharmacology, molecular biology and virology approaches. Structure and function of HIV-1 integrase. We are investigating structural determinants for how a key HIV-1 enzyme integrase carries out concerted integration of reverse transcribed viral cDNA into chromatin of infected cells (1,2). Furthermore, we have recently discovered an unexpected, non-catalytic role of integrase in HIV-1 biology, which includes its ability to bind and localize the viral RNA genome within the protective cone-shaped capsid core during virion maturation (3). Our current efforts are focused on dissecting structural and mechanistic basis for highly specific interactions of integrase with select sites on the viral RNA genome. Allosteric HIV-1 integrase inhibitors (ALLINIs). Evolution of HIV-1 strains resistant to current therapies is a major clinical problem in the fight against AIDS. Therefore, new inhibitors with unexploited mechanisms of action are needed. One such mechanism investigated by our group is to allosterically modulate HIV-1 integrase multimerization. In proof-of-concept studies (4,5) we reported a compound that binds at the IN dimer interface, “locking” interacting subunits into an inactive conformation. More recently, we have elucidated the mechanism of action of ALLINIs, which are currently in clinical trials (6-8). These inhibitors potently blocked HIV-1 replication by inducing hyper- or aberrant- integrase multimerization in virions and resulted in eccentric particle maturation with the ribonucleoprotein complex being mislocalized between the capsid core and the particle membrane. These studies have delineated the significance of correctly ordered integrase structure for HIV-1 particle morphogenesis and demonstrated the feasibility of exploiting integrase multimerization as a therapeutic target. Our current efforts are centered on developing novel integrase inhibitors with unique structural scaffolds for their potential clinical use. Virus-host interactions. Host cell factors regulate retroviral replication. We have identified bromodomain and extraterminal domain (BET) proteins (Brd2, 3, 4) as principal cellular-binding partners of gammaretroviral murine leukemia virus (MLV) integrase and demonstrated their importance for targeting MLV integration to transcription start sites (9). These findings inform ongoing efforts to develop safer retroviral vectors for human gene therapy. In addition, we are studying how LEDGF/p75, a key cellular binding partner of lentiviral integrases, navigates HIV-1 preintegration complexes to active genes during integration (10,11). Furthermore, we have recently discovered and are currently investigating molecular mechanisms of novel critical co-factors for HIV-1 infection. References: 1. Passos, D. O., Li, M., Yang, R., Rebensburg, S. V., Ghirlando, R., Jeon, Y., Shkriabai, N., Kvaratskhelia, M., Craigie, R., and Lyumkis, D. (2017) Cryo-EM structures and atomic model of the HIV-1 strand transfer complex intasome. Science 355, 89-92 2. Kessl, J. J., Li, M., Ignatov, M., Shkriabai, N., Eidahl, J. O., Feng, L., Musier-Forsyth, K., Craigie, R., and Kvaratskhelia, M. (2011) FRET analysis reveals distinct conformations of IN tetramers in the presence of viral DNA or LEDGF/p75. Nucleic Acids Res. 39, 9009-9022 3. Kessl, J. J., Kutluay, S. B., Townsend, D., Rebensburg, S., Slaughter, A., Larue, R. C., Shkriabai, N., Bakouche, N., Fuchs, J. R., Bieniasz, P. D., and Kvaratskhelia, M. (2016) HIV-1 Integrase Binds the Viral RNA Genome and Is Essential during Virion Morphogenesis. Cell 166, 1257-1268 e1212 4. Shkriabai, N., Patil, S. S., Hess, S., Budihas, S. R., Craigie, R., Burke, T. R., Jr., Le Grice, S. F., and Kvaratskhelia, M. (2004) Identification of an inhibitor-binding site to HIV-1 integrase with affinity acetylation and mass spectrometry. Proceedings of the National Academy of Sciences of the United States of America 101, 6894-6899 5. Kessl, J. J., Eidahl, J. O., Shkriabai, N., Zhao, Z., McKee, C. J., Hess, S., Burke, T. R., Jr., and Kvaratskhelia, M. (2009) An allosteric mechanism for inhibiting HIV-1 integrase with a small molecule. Mol. Pharmacol. 76, 824-832 6. Jurado, K. A., Wang, H., Slaughter, A., Feng, L., Kessl, J. J., Koh, Y., Wang, W., Ballandras-Colas, A., Patel, P. A., Fuchs, J. R., Kvaratskhelia, M., and Engelman, A. (2013) Allosteric integrase inhibitor potency is determined through the inhibition of HIV-1 particle maturation. Proceedings of the National Academy of Sciences of the United States of America 110, 8690-8695 7. Sharma, A., Slaughter, A., Jena, N., Feng, L., Kessl, J. J., Fadel, H. J., Malani, N., Male, F., Wu, L., Poeschla, E., Bushman, F. D., Fuchs, J. R., and Kvaratskhelia, M. (2014) A New Class of Multimerization Selective Inhibitors of HIV-1 Integrase. PLoS Pathog 10, e1004171 8. Koneru, P. C., Francis, A. C., Deng, N., Rebensburg, S. V., Hoyte, A. C., Lindenberger, J., Adu-Ampratwum, D., Larue, R. C., Wempe, M. F., Engelman, A. N., Lyumkis, D., Fuchs, J. R., Levy, R. M., Melikyan, G. B., and Kvaratskhelia, M. (2019) HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors. Elife 8 9. Sharma, A., Larue, R. C., Plumb, M. R., Malani, N., Male, F., Slaughter, A., Kessl, J. J., Shkriabai, N., Coward, E., Aiyer, S. S., Green, P. L., Wu, L., Roth, M. J., Bushman, F. D., and Kvaratskhelia, M. (2013) BET proteins promote efficient murine leukemia virus integration at transcription start sites. Proceedings of the National Academy of Sciences of the United States of America 110, 12036-12041 10. Eidahl, J. O., Crowe, B. L., North, J. A., McKee, C. J., Shkriabai, N., Feng, L., Plumb, M., Graham, R. L., Gorelick, R. J., Hess, S., Poirier, M. G., Foster, M. P., and Kvaratskhelia, M. (2013) Structural basis for high-affinity binding of LEDGF PWWP to mononucleosomes. Nucleic Acids Res. 41, 3924-3936 11. Singh, P. K., Plumb, M. R., Ferris, A. L., Iben, J. R., Wu, X., Fadel, H. J., Luke, B. T., Esnault, C., Poeschla, E. M., Hughes, S. H., Kvaratskhelia, M., and Levin, H. L. (2015) LEDGF/p75 interacts with mRNA splicing factors and targets HIV-1 integration to highly spliced genes. Genes Dev. 29, 2287-2297

Publications

• Tedbury PR, Mahboubi D, Puray-Chavez M, Shah R, Ukah OB, Wahoski CC, Fadel HJ, Poeschla EM, Gao X, McFadden WM, Gaitanidou M, Kesesidis N, Kirby KA, Vanderford TH, Kvaratskhelia M, Achuthan V, Behrens RT, Engelman AN, Sarafianos SG. Disruption of LEDGF/p75-directed integration derepresses antisense transcription of the HIV-1 genome. bioRxiv. 2024 Dec 6. PubMed PMID: 39677798
• Huang SW, Briganti L, Annamalai AS, Greenwood J, Shkriabai N, Haney R, Armstrong ML, Wempe MF, Singh SP, Francis AC, Engelman AN, Kvaratskhelia M. The primary mechanism for highly potent inhibition of HIV-1 maturation by lenacapavir. bioRxiv. 2024 Dec 7. PubMed PMID: 39677622
• Briganti L, Annamalai AS, Bester SM, Wei G, Andino-Moncada JR, Singh SP, Kleinpeter AB, Tripathi M, Nguyen B, Radhakrishnan R, Singh PK, Greenwood J, Schope LI, Haney R, Huang SW, Freed EO, Engelman AN, Francis AC, Kvaratskhelia M. Structural and Mechanistic Bases for Resistance of the M66I Capsid Variant to Lenacapavir. bioRxiv. 2024 Nov 25. PubMed PMID: 39651162
• Dinh T, Tber Z, Rey JS, Mengshetti S, Annamalai AS, Haney R, Briganti L, Amblard F, Fuchs JR, Cherepanov P, Kim K, Schinazi RF, Perilla JR, Kim B, Kvaratskhelia M. The structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir. mBio. 2024 Nov 13;15(11):e0046524. PubMed PMID: 39404354
• Patacchini E, Madia VN, Albano A, Ruggieri G, Messore A, Ialongo D, Saccoliti F, Scipione L, Cosconati S, Koneru PC, Haney R, Kvaratskhelia M, Di Santo R, Costi R. Quinolinonyl Derivatives as Dual Inhibitors of the HIV-1 Integrase Catalytic Site and Integrase-RNA interactions. ACS Med Chem Lett. 2024 Sep 12;15(9):1533-1540. PubMed PMID: 39291012
• Layish B, Goli R, Flick H, Huang SW, Zhang RZ, Kvaratskhelia M, Kane M. Virus specificity and nucleoporin requirements for MX2 activity are affected by GTPase function and capsid-CypA interactions. PLoS Pathog. 2024 Mar;20(3):e1011830. PubMed PMID: 38512975
• Jing T, Shan Z, Dinh T, Biswas A, Jang S, Greenwood J, Li M, Zhang Z, Gray G, Shin HJ, Zhou B, Passos D, Aiyer S, Li Z, Craigie R, Engelman AN, Kvaratskhelia M, Lyumkis D. Oligomeric HIV-1 Integrase Structures Reveal Functional Plasticity for Intasome Assembly and RNA Binding. bioRxiv. 2024 Jan 27. PubMed PMID: 38328132
• Layish B, Goli R, Flick H, Huang SW, Zhang RZ, Kvaratskhelia M, Kane M. Virus specificity and nucleoporin requirements for MX2 activity are affected by GTPase function and capsid-CypA interactions. bioRxiv. 2023 Nov 17. PubMed PMID: 38014352
• Smith S, Seth J, Midkiff A, Stahl R, Syu YC, Shkriabai N, Kvaratskhelia M, Musier-Forsyth K, Jain P, Green PL, Panfil AR. The Pleiotropic Effects of YBX1 on HTLV-1 Transcription. Int J Mol Sci. 2023 Aug 23;24(17). PubMed PMID: 37685922
• Li M, Oliveira Passos D, Shan Z, Smith SJ, Sun Q, Biswas A, Choudhuri I, Strutzenberg TS, Haldane A, Deng N, Li Z, Zhao XZ, Briganti L, Kvaratskhelia M, Burke TR Jr, Levy RM, Hughes SH, Craigie R, Lyumkis D. Mechanisms of HIV-1 integrase resistance to dolutegravir and potent inhibition of drug-resistant variants. Sci Adv. 2023 Jul 21;9(29):eadg5953. PubMed PMID: 37478179
• Singer MR, Dinh T, Levintov L, Annamalai AS, Rey JS, Briganti L, Cook NJ, Pye VE, Taylor IA, Kim K, Engelman AN, Kim B, Perilla JR, Kvaratskhelia M, Cherepanov P. The Drug-Induced Interface That Drives HIV-1 Integrase Hypermultimerization and Loss of Function. mBio. 2023 Feb 28;14(1):e0356022. PubMed PMID: 36744954
• Singer MR, Dinh T, Levintov L, Annamalai AS, Rey JS, Briganti L, Cook NJ, Pye VE, Taylor IA, Kim K, Engelman AN, Kim B, Perilla JR, Kvaratskhelia M, Cherepanov P. The Drug-Induced Interface That Drives HIV-1 Integrase Hypermultimerization and Loss of Function. mBio. 2023 Feb 6;:e0356022. [Epub ahead of print] PubMed PMID: 36744954
• Wei G, Iqbal N, Courouble VV, Francis AC, Singh PK, Hudait A, Annamalai AS, Bester S, Huang SW, Shkriabai N, Briganti L, Haney R, KewalRamani VN, Voth GA, Engelman AN, Melikyan GB, Griffin PR, Asturias F, Kvaratskhelia M. Prion-like low complexity regions enable avid virus-host interactions during HIV-1 infection. Nat Commun. 2022 Oct 6;13(1):5879. PubMed PMID: 36202818
• Bester SM, Adu-Ampratwum D, Annamalai AS, Wei G, Briganti L, Murphy BC, Haney R, Fuchs JR, Kvaratskhelia M. Structural and Mechanistic Bases of Viral Resistance to HIV-1 Capsid Inhibitor Lenacapavir. mBio. 2022 Oct 26;13(5):e0180422. PubMed PMID: 36190128
• Sapp N, Burge N, Cox K, Prakash P, Balasubramaniam M, Thapa S, Christensen D, Li M, Linderberger J, Kvaratskhelia M, Pandhare J, Craigie R, Poirier MG, Dash C. HIV-1 Preintegration Complex Preferentially Integrates the Viral DNA into Nucleosomes Containing Trimethylated Histone 3-Lysine 36 Modification and Flanking Linker DNA. J Virol. 2022 Sep 28;96(18):e0101122. PubMed PMID: 36094316
• Shema Mugisha C, Dinh T, Kumar A, Tenneti K, Eschbach JE, Davis K, Gifford R, Kvaratskhelia M, Kutluay SB. Emergence of Compensatory Mutations Reveals the Importance of Electrostatic Interactions between HIV-1 Integrase and Genomic RNA. mBio. 2022 Oct 26;13(5):e0043122. PubMed PMID: 35975921
• Engelman AN, Kvaratskhelia M. Multimodal Functionalities of HIV-1 Integrase. Viruses. 2022 Apr 28;14(5). PubMed PMID: 35632668
• Adu-Ampratwum D, Pan Y, Koneru PC, Antwi J, Hoyte AC, Kessl J, Griffin PR, Kvaratskhelia M, Fuchs JR, Larue RC. Identification and Optimization of a Novel HIV-1 Integrase Inhibitor. ACS Omega. 2022 Feb 8;7(5):4482-4491. PubMed PMID: 35155940
• Liu S, Koneru PC, Li W, Pathirage C, Engelman AN, Kvaratskhelia M, Musier-Forsyth K. HIV-1 integrase binding to genomic RNA 5'-UTR induces local structural changes in vitro and in virio. Retrovirology. 2021 Nov 22;18(1):37. PubMed PMID: 34809662
• Maehigashi T, Ahn S, Kim UI, Lindenberger J, Oo A, Koneru PC, Mahboubi B, Engelman AN, Kvaratskhelia M, Kim K, Kim B. A highly potent and safe pyrrolopyridine-based allosteric HIV-1 integrase inhibitor targeting host LEDGF/p75-integrase interaction site. PLoS Pathog. 2021 Jul;17(7):e1009671. PubMed PMID: 34293041
• Li Z, Wang-Heaton H, Cartwright BM, Makinwa Y, Hilton BA, Musich PR, Shkriabai N, Kvaratskhelia M, Guan S, Chen Q, Yu X, Zou Y. ATR prevents Ca(2 ) overload-induced necrotic cell death through phosphorylation-mediated inactivation of PARP1 without DNA damage signaling. FASEB J. 2021 May;35(5):e21373. PubMed PMID: 33811702
• Rebensburg SV, Wei G, Larue RC, Lindenberger J, Francis AC, Annamalai AS, Morrison J, Shkriabai N, Huang SW, KewalRamani V, Poeschla EM, Melikyan GB, Kvaratskhelia M. Sec24C is an HIV-1 host dependency factor crucial for virus replication. Nat Microbiol. 2021 Apr;6(4):435-444. PubMed PMID: 33649557
• Elliott JL, Eschbach JE, Koneru PC, Li W, Puray-Chavez M, Townsend D, Lawson DQ, Engelman AN, Kvaratskhelia M, Kutluay SB. (2020) Integrase-RNA interactions underscore the critical role of integrase in HIV-1 virion morphogenesis. eLife 9:e54311. PMID: 32960169.
• Tse C, Wickstrom L, Kvaratskhelia M, Gallicchio E, Levy R, Deng N (2020) Exploring the Free-Energy Landscape and Thermodynamics of Protein-Protein Association Biophys J. 119(6):1226-1238. PMID: 32877664
• Bester SM, Wei G, Zhao H, Adu-Ampratwum D, Iqbal N, Courouble VV, Francis AC, Annamalai AS, Singh PK, Shkriabai N, Van Blerkom P, Morrison J, Poeschla EM, Engelman AN, Melikyan GB, Griffin PR, Fuchs JR, Asturias FJ, Kvaratskhelia M. (2020) Structural and mechanistic bases for a potent HIV-1 capsid inhibitor. Science 370(6514):360-364. (PMID: 33060363).
• Esposito F, Sechi M, Pala N, Sanna A, Koneru PC, Kvaratskhelia M, Naesens L, Corona A, Grandi N, di Santo R, D'Amore VM, Di Leva FS, Novellino E, Cosconati S, Tramontano E. Discovery of dihydroxyindole-2-carboxylic acid derivatives as dual allosteric HIV-1 Integrase and Reverse Transcriptase associated Ribonuclease H inhibitors. Antiviral Res. 2019 Dec 5;174:104671. [Epub ahead of print] PubMed PMID: 31812637
• Koneru PC, Francis AC, Deng N, Rebensburg SV, Hoyte AC, Lindenberger J, Adu-Ampratwum D, Larue RC, Wempe MF, Engelman AN, Lyumkis D, Fuchs JR, Levy RM, Melikyan GB, Kvaratskhelia M. HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors. Elife. 2019 May 23;8. PubMed PMID: 31120420
• Al-Saleem J, Dirksen WP, Martinez MP, Shkriabai N, Kvaratskhelia M, Ratner L, Green PL. HTLV-1 Tax-1 interacts with SNX27 to regulate cellular localization of the HTLV-1 receptor molecule, GLUT1. PLoS One. 2019;14(3):e0214059. PubMed PMID: 30897179
• Wilson TA, Koneru PC, Rebensburg SV, Lindenberger JJ, Kobe MJ, Cockroft NT, Adu-Ampratwum D, Larue RC, Kvaratskhelia M, Fuchs JR. An Isoquinoline Scaffold as a Novel Class of Allosteric HIV-1 Integrase Inhibitors. ACS Med Chem Lett. 2019 Feb 14;10(2):215-220. PubMed PMID: 30783506
• Rivieccio E, Tartaglione L, Esposito V, Dell'Aversano C, Koneru PC, Scuotto M, Virgilio A, Mayol L, Kvaratskhelia M, Varra M. Structural studies and biological evaluation of T30695 variants modified with single chiral glycerol-T reveal the importance of LEDGF/p75 for the aptamer anti-HIV-integrase activities. Biochim Biophys Acta Gen Subj. 2019 Feb;1863(2):351-361. PubMed PMID: 30414444
• Zhao XZ, Métifiot M, Kiselev E, Kessl JJ, Maddali K, Marchand C, Kvaratskhelia M, Pommier Y, Burke TR Jr. (2018) HIV-1 Integrase-Targeted Short Peptides Derived from a Viral Protein R Sequence. Molecules. pii: E1858. PMID: 30049955.
• Lu W, Tirumuru N, St Gelais C, Koneru PC, Liu C, Kvaratskhelia M, He C, Wu L. (2018) N6-Methyladenosine-binding proteins suppress HIV-1 infectivity and viral production. J Biol Chem. 293(34):12992-13005. PMID: 29976753
• Panfil AR, Al-Saleem J, Howard CM, Shkriabai N, Kvaratskhelia M, Green PL. (2018) Stability of the HTLV-1 Antisense-Derived Protein, HBZ, Is Regulated by the E3 Ubiquitin-Protein Ligase, UBR5. Front Microbiol. 9:80. PMID: 29441057.
• Panfil AR, Al-Saleem J, Howard CM, Shkriabai N, Kvaratskhelia M, Green PL. (2018) Stability of the HTLV-1 Antisense-Derived Protein, HBZ, Is Regulated by the E3 Ubiquitin-Protein Ligase, UBR5. Front Microbiol. 9:80. PMID: 29441057.
• Rivieccio E, Tartaglione L, Esposito V, Dell'Aversano C, Koneru PC, Scuotto M, Virgilio A, Mayol L, Kvaratskhelia M, Varra M. Structural Studies and Biological Evaluation of T30695 Variants Modified with Single Chiral Glycerol-T Reveal the Importance of LEDGF/p75 for the Aptamer Anti-HIV-Integrase Activities. Biochim Biophys Acta Gen Subj. pii: S0304-4165(18)30349-0. PMID: 30414444.
• Hoyte AC, Jamin AV, Koneru PC, Kobe MJ, Larue RC, Fuchs JR, Engelman AN, Kvaratskhelia M. Resistance to pyridine-based inhibitor KF116 reveals an unexpected role of integrase in HIV-1 Gag-Pol polyprotein proteolytic processing. J Biol Chem. 2017 Dec 1;292(48):19814-19825. PubMed PMID: 28972144
• Madison MK, Lawson DQ, Elliott J, Ozantürk AN, Koneru PC, Townsend D, Errando M, Kvaratskhelia M, Kutluay SB. Allosteric HIV-1 Integrase Inhibitors Lead to Premature Degradation of the Viral RNA Genome and Integrase in Target Cells. J Virol. 2017 Sep 1;91(17). PubMed PMID: 28615207
• Al-Saleem J, Kvaratskhelia M, Green PL. Methods for Identifying and Examining HTLV-1 HBZ Post-translational Modifications. Methods Mol Biol. 2017;1582:111-126. PubMed PMID: 28357666
• Winans S, Larue RC, Abraham CM, Shkriabai N, Skopp A, Winkler D, Kvaratskhelia M, Beemon KL. The FACT Complex Promotes Avian Leukosis Virus DNA Integration. J Virol. 2017 Apr 1;91(7). PubMed PMID: 28122976
• Ablenas CJ, Liu HW, Shkriabai N, Kvaratskhelia M, Cosa G, Götte M. Dynamic Interconversions of HCV Helicase Binding Modes on the Nucleic Acid Substrate. ACS Infect Dis. 2017 Jan 13;3(1):99-109. PubMed PMID: 28081608
• Passos DO, Li M, Yang R, Rebensburg SV, Ghirlando R, Jeon Y, Shkriabai N, Kvaratskhelia M, Craigie R, Lyumkis D. Cryo-EM structures and atomic model of the HIV-1 strand transfer complex intasome. Science. 2017 Jan 6;355(6320):89-92. PubMed PMID: 28059769
• Rebensburg SV, Wei G, Larue RC, Lindenberger J, Francis AC, Annamalai AS, Morrison J, Shkriabai N, Huang SW, KewalRamani V, Poeschla EM, Melikyan GB, Kvaratskhelia M. (2021) Sec24C is an HIV-1 host dependency factor crucial for virus replication. Nature Microbiology In press.

Practice Locations

UCHealth University of Colorado Hospital (UCH)
12605 E. 16th Ave
Aurora, CO 80045
720-848-0000