There is life with HIV

HIV Cells Vulnerable to Photoimmunotherapy

Image Андрей Баклан by Pixabay

CHIV cells Vulnerable to Photoimmunotherapy represent a breakthrough! And, embroidering these questions, we propose the application of photo immunotherapy (PIT) not only against cells that express the HIV Env, but also against HIV. Previously, we showed that an anti-human gp41 antibody (7B2) conjugated to photosensitizers 

Cationic or anionic (PSs) could target and specifically kill cells expressing HIV Env. 

Here, our photolysis studies revealed that the binding of photo immunoconjugates (PICs) on the membrane of cells expressing HIV Env is sufficient to induce necrotic cell death due to physical damage to the membrane by singlet oxygen, which is independent of the type of PSs. 

This finding persuaded us to study the photo inactivation of PIC virus using two strains of HIV-1, X4 HIV-1 NL4-3 and JR-CSF virus. We note that PICs can destroy viral strains, likely via physical damage to the HIV envelope. In conclusion, we report the application of PIT as a possible dual tool for immunotherapy against HIV and ART, killing cells expressing HIV and cell-free HIV, respectively.

Recovered Viremia

HIV-infected cells persist in patients on antiretroviral therapy (ART), and viremia returns if ART is stopped. In addition, recent surveys by the World Health Organization (WHO) have revealed an alarming factor in increasing resistance to antiretrovirals crucial to HIV. (3) Currently, ART aims to keep viral loads below detection limits (BDLs) of current commercial tests, blocking viral replication and preventing the spread or growth of viral reservoirs to preserve CD4 + T cells, but its use is restricted by long-term target organ toxicities of drugs and the expansion of viral resistance.

 

Furthermore, persistent low-level viremia may remain even when on ART, potentially from tissues with low drug penetration or residual viral replication in latently infected cells. (5−7) Going further, clonal expansion of HIV-infected cells can contribute to the size of the HIV reservoir. (8) As well, defective HIV-1 proviruses, which prevail after “long-term suppressive ART” (9) (although failing to produce a complete replicative cycle), will produce HIV m-RNA and HIV proteins, which will contribute for HIV-related deleterious microinflammation despite years of plasma HIV-RNA BDL levels during ART. (10) 

 

In fact, antiproliferative drugs that will reduce the size of the HIV reservoir in lymphocytes among individuals on long-term “suppressive” ART will decrease total HIV DNA and decrease cell activation markers on CD4+ T cells. (11) Thus, this requires the design of therapeutic alternatives to ART and new strategies to directly kill latently infected cells or cells carrying defective provirus, which may address the limitations of ART and immunotherapy (IT), achieving HIV remission without the use of antiretrovirals.

Preexisting Resistance

Several immunotherapeutic strategies, with limited success, have been studied to specifically kill HIV-infected cells using antibodies targeted to HIV Env. (12) Most of these results depended on preexisting resistance of circulating/reservoir strains, and in all cases, viremia quickly recovered after MAb decay or cessation. (13) Thus, strategies to combat pre-existing and de novo development of viral resistance remain a target of antibody-based therapy for HIV. chronic infection.

 

In acute infection, the conjugation of antibodies with more toxic drugs, including chemical drugs such as doxorubicin (14) or immunogenic toxins such as ricin, (15,16) pulchelin, (17) and shiga toxin, (18) may be tolerable as a short-term solution to ensure rapid and complete cytotoxicity to treat acute infection. (19) In contrast, to treat chronic infections such as HIV infection, antibody-based immunotherapies that are more amenable to long-term use with longer-lasting effects may provide an ideal candidate.

 

Recently, we introduced HIV photo immunotherapy (HIV PIT), as an emerging anti-HIV IT by arming HIV MAbs with photosensitizers (PSs) targeting cells that express HIV Env. (20) PIT is the targeted form of conventional photodynamic therapy ( PDT), achieved through the conjugation of PS with MAbs targeting specific cell surface receptors. (21,22) 

 

Non-ionizing light of a specific wavelength can activate PSs to kill cells, generating reactive oxygen species (ROS), including hydrogen peroxide, hydroxyl radicals, superoxide, and singlet oxygen. (20,21) PIT has certain advantages over immunotoxins (ITs) or radioimmunotherapy (RIT) to eradicate infected cells. (23) 

 

In PIT, target selection is determined not only by antibodies, but also by light, in relation to time and local irradiation. In addition, PIT is a minimally invasive therapy, safer and cheaper than IT or RIT, (21) making PIT an appropriate candidate for the treatment of chronic infections such as HIV. 

MAb 7B2

Our recent findings about PIT can help add more advantages to that list.

In previous studies, we produced two different photo immunoconjugates (PICs) by conjugating an anti-human gp41 antibody (7B2) (24) with two PSs, cationic porphyrin and anionic IR700.

We employ two different strategies for antibody conjugation: Lysine conjugation using a phthalocyanine dye IRDye700DX (25) and “Click” conjugation using an azide-containing porphyrin with a tense alkyne linked by a disulfide bridge linker. (26) MAb 7B2 is a non-neutralizing antibody that recognizes virus particles and cells that express HIV Env. (27) 

 

We demonstrate that the target phototoxicity is independent of the PS payload.

In this study, the comparison between PICs is of interest with regard to physical and immunological changes in PICs during irradiation and the mechanism of in vitro cytotoxicity. Targeted phototoxicity appears to be independent of cellular internalization, although it is dependent on the generation of singlet oxygen by PSs, which physically damages both the antibody and the cell membrane. 

 

This finding persuaded us to study the photo inactivation of the virus of PICs using HIV-1 strains. Unlike other HIV immunoconjugates, we have observed that PICs kill cells expressing HIV Env and destroy viruses, so they can be considered a tool for ART.

Conclusions

 

HIV-infected cells persist in being cleared from the body very slowly despite decades of lifelong ART, (1) preventing complete elimination of HIV in a person's lifetime. 

 

Meanwhile, HIV drug resistance to ART is a serious threat to the global rise in HIV treatment. (3) Several IT strategies, using antibodies specific to the Env virus, have been investigated to activate the pathway apoptotic to kill latently infected cells. (12,43)

But these TIs are dependent on cellular internalization and fail to destroy the HIV virus.

 

This study showed that excited PSs (porphyrin and IR700) in the PS-antibody construct can cause antibody aggregation. 

 

When PICs bind to HIV Env at the cell membrane, physical changes in the structure of the irradiated PS-antibody can damage the membrane and result in necrotic cell death without internalization. We show that singlet oxygen plays a key role in this reaction. This finding persuaded us to study the possibility of destroying HIV using PICs (graphic image). Targeted phototoxicity on both HIV strains and HIV-infected cells is a possible dual combination for ART, including treatment of HIV strains resistant to antiretroviral drugs. More importantly, as specialized non-invasive IT to kill HIV infected cells and eradicate persistent reservoirs of HIV infection and potentially destroy HIV due to residual viral replication, PICs can be a critical tool for curing HIV. 

 

This mechanism can mitigate HIV-related microinflammation and/or achieve HIV remission without antiretrovirals. Furthermore, the results of this strategy could potentially translate into viral PIT against other enveloped viruses with similar mechanisms of viral replication, such as HBV and HTLV, that cause chronic yet incurable infections.

Translated by Claudio Souza's original Photoinduced Photosensitizer–Antibody Conjugates Kill HIV Env-Expressing Cells, Also Inactivating HIV in 16 / 08 / 2021

References

This article references 57 other publications.

 

  1. Daveport, MPKhoury, DSCromer, D.Lewis, SRKelleher, ADKent, SJ Functional Cure of HIV: The Scale of the ChallengeNat. Rev. Immunol. 2019194554 DOI: 10.1038/s41577-018-0085-4

  2. 2

    Ndung'u, T.McCune, JMDeeks, SG Why and Where an HIV Cure is Needed and How it might be AchievedNature 2019576397405 DOI: 10.1038/s41586-019-1841-8

  3. 3

    World Health Organization (WHO)HIV Drug Resistance Report2019.

  4. 4

    Zhang, Z.Ли, С.Gu, Y.Xia, N. Antiviral Therapy by HIV-1 Broadly Neutralizing and Inhibitory AntibodiesInt. J. Mol. Sci. 201617112 DOI: 10.3390/ijms17111901

  5. 5

    Bertrand, L.Meroth, F.Tournebize, M.Leda, ARSun, E.Toborek, M. Targeting the HIV-infected brain to improve ischemic stroke outcomeNat. Common. 2019102009  DOI: 10.1038 / s41467-019-10046-x

  6. 6

    Palmer, S.Maldarelli, F.Wiegand, A.Bernstein, B.Hanna, GJBrun, SCKempf, DJMellors, JWCoffin, JMKing, MS Low-Level Viremia Persists for at Least 7 Years in Patients on Suppressive Antiretroviral TherapyProc. Natl. Academic Sci. USA 200810538793884 DOI: 10.1073 / pnas.0800050105

  7. 7

    Anton, PAMitsuyasu, RTDeeks, SGScadden, DTWagner, B.Huang, C.Macken, C.Richman, DDChristopherson, C.Borellini, F.Lazar, R.Hege, KM Multiple Measures of HIV Burden in Blood and Tissue are Correlated with Each Other but Not with Clinical Parameters in Aviremic SubjectsAIDS 2003175363 DOI: 10.1097/00002030-200301030-00008

  8. 8

    Maldarelli, F. HIV-Infected Cells are Frequently Clonally Expanded after Prolonged Antiretroviral Therapy: Implications for HIV PersistenceJ. Virus Erad. 20151237244 DOI: 10.1016/s2055-6640(20)30930-4

  9. 9

    Samer, S.Namiyama, G.Oshiro, T.Arif, MSCardoso Da Silva, W.Sucupira, MCAJanini, LMDiaz, RS Evidence of Noncompetent HIV after Ex Vivo Purging among ART-Suppressed IndividualsAIDS Res. Hum. Retroviruses 201733993994 DOI: 10.1089/aid.2017.0036

  10. 10

    Imamichia, H.Dewar, RLAdelsberger, JWRehm, CAO'doherty, U.Paxinos, EEFauci, ASLane, HC Defective HIV-1 proviruses produce novel protein-coding RNA species in HIV-infected patients on combination antiretroviral therapyProc. Natl. Academic Sci. USA 201611387838788 DOI: 10.1073 / pnas.1609057113

  11. 11

    Diaz, RSShytaj, ILGiron, LBObermaier, B.Della Libera, E.Galinskas, J.Days, D.Hunter, J.Janini, M.Gosuen, G.Ferreira, PASucupira, MCMaricato, J.Fackler, O.Lusic, M.Savarin, A. Potential Impact of the Antirheumatic Agent Auranofin on Proviral HIV-1 DNA in Individuals under Intensified Antiretroviral Therapy: Results from a Randomized Clinical TrialInt. J. Antimicrob. agents 201954592600 DOI: 10.1016/j.ijantimicag.2019.08.001

  12. 12

    Caskey, M.Klein, F.Nussenzweig, MC Broadly Neutralizing Anti-HIV-1 Monoclonal Antibodies in the ClinicNat. Med. 201925547553 DOI: 10.1038/s41591-019-0412-8

  13. 13

    Parsons, MSLe Grand, R.Kent, SJ Neutralizing Antibody-Based Prevention of Cell-Associated HIV-1 InfectionV 201810113 DOI: 10.3390/v10060333

  14. 14

    Qiao, Z.I read, X.Kang, N.Yang, Y.Chen, C.Wu, T.Zhao, M.Liu, Y.Ji, X. The Novel Specific Anti-Cd73 Antibody Inhibits Triple-Negative Breast Cancer Cell Motility by Regulating AutophagyInt. J. Mol. Sci. 2019201057 DOI: 10.3390/ijms20051057

  15. 15

    Pincus, SHSong, K.Maresh, GAHamer, DHDimitrov, DSChen, W.Zhang, M.Ghetie, VFChan-Hui, P.-Y.Robinson, JEVitetta, ES Identification of Human Anti-HIV Gp160 Monoclonal Antibodies That Make Effective ImmunotoxinsJ.Virol. 201791JVI.01955–16  DOI: 10.1128/JVI.01955-16

  16. 16

    Sadraeian, M.Rasoul-Amini, S.Mansoorkhani, MJKMohkam, M.Ghoshoon, MBGhasemi, Y. Induction of Antitumor Immunity against Cervical Cancer by Protein HPV-16 E7 in Fusion with Ricin B Chain in Tumor-Bearing MiceInt. J. Gynecol. Cancer 201323809814 DOI: 10.1097/IGC.0b013e3182907989

  17. 17

    Sadraeian, M.Guimaraes, FEGAraújo, APUWorthylake, DKLeCour, L., Jr.Pincus, SH Selective Cytotoxicity of a Novel Immunotoxin Based on Pulchellin A Chain for Cells Expressing Expressing HIV EnvelopeSci. Rep. 201777579  DOI: 10.1038/s41598-017-08037-3

  18. 18

    Sadraeian, M.Khoshnood Mansoorkhani, MJMohkam, M.Rasoul-Amini, S.Hesaraki, M.Ghasemi, Y. Prevention and Inhibition of TC-1 Cell Growth in Tumor Bearing Mice by HPV16 E7 Protein in Fusion with Shiga Toxin B-Subunit from Shigella dysenteryCell J. 201315176181

  19. 19

    Ponziani, S.Di Vittorio, G.Pitari, G.Cimini, AMArdini, M.Gentile, R.Iacobelli, S.Room, G.Capone, E.Flavell, DJIppoliti, R.Giansanti, F. Antibody-Drug Conjugates: The New Frontier of ChemotherapyInt. J. Mol. Sci. 202021128 DOI: 10.3390/ijms21155510

  20. 20

    Sadraeian, M.Bahou, C.of the Cross, FEJanini, LMRDiaz, RSBoyle, RWChudasama, V.Guimaraes, FEG Photoimmunotherapy Using Cationic and Anionic Photosensitizer-Antibody Conjugates against HIV Env-Expressing CellsInt. J. Mol. Sci. 202021116 DOI: 10.3390/ijms21239151

  21. 21

    Sandland, J.Boyle, RW Photosensitizer Antibody-Drug Conjugates: Past, Present, and FutureBioconjugate Chem. 201930975993 DOI: 10.1021/acs.bioconjchem.9b00055

  22. 22

    Butzbach, K.Konhäuser, M.Fach, M.Bamberger, DNBreitenbach, B.Epe, B.Wich, PR Receptor-Mediated Uptake of Folic Acid-Functionalized Dextran Nanoparticles for Applications in Photodynamic TherapyPolymers (Basel) 201911810 DOI: 10.3390/polym11050896

  23. 23

    Tsukrov, D.Dadachova, E. The Potential of Radioimmunotherapy as a New Hope for HIV PatientsExpert Rev. Clin. Immunol. 201410553555 DOI: 10.1586/1744666X.2014.908706

  24. 24

    Pincus, SHFang, H.Wilkinson, RAMarcotte, TKRobinson, JEOlson, WC In Vivo Efficacy of Anti-Glycoprotein 41, but Not Anti-Glycoprotein 120, Immunotoxins in a Mouse Model of HIV InfectionJ. Immunol. 200317022362241 DOI: 10.4049/jimmunol.170.4.2236

  25. 25

    Caudle, ASYang, WTMittendorf, EAKuerer, HM Cancer Cell-Selective In Vivo Near Infrared Photoimmunotherapy Targeting Specific Membrane MoleculesNat. Med. 2016150137143 DOI: 10.1001/jamasurg.2014.1086.Feasibility

  26. 26

    Bryden, F.Maruani, A.Savoie, H.Chudasama, V.Smith, MEBCaddick, S.Boyle, RW Regioselective and Stoichiometrically Controlled Conjugation of Photodynamic Sensitizers to a HER2 Targeting Antibody FragmentBioconjugate Chem. 201425611617 DOI: 10.1021/bc5000324

  27. 27

    Santra, S.Hopefully, GDWarrier, R.Nicely, NYLiao, HXPollara, J.Liu, P.Alam, SMZhang, R.Cocklin, SLShen, X.Duffy, R.Xia, SMSchutte, RJPemble, CW, IVDennison, SMLi, H.Chao, A.Vidnovic, K.Evans, A.Klein, K.Kumar, A.Robinson, J.Landucci, G.Forthal, DNMontefiori, DCKaewkungwal, J.Nitayaphan, S.Pitisuttithum, P.Rerks-Ngarm, S.Robb, MLMichael, NLKim, JHSoderberg, KAGiorgi, EEBlair, L.Korber, BTMoog, C.Shattock, RJLetvin, NLSchmitz, JEMoody, MAGao, F.Ferrari, G.Shaw, GMHaynes, BF Human Non-Neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus MacaquesPLoS Pathhog. 201511138 DOI: 10.1371/journal.ppat.1005042

  28. 28

    Maisch, T.Baier, J.Franz, B.Maier, M.Landthaler, M.Szeimies, R.-M.Baumler, W. The Role of Singlet Oxygen and Oxygen Concentration in Photodynamic Inactivation of BacteriaProc. Natl. Academic Sci. USA 200710472237228 DOI: 10.1073 / pnas.0611328104

  29. 29

    jones, jaStarkey, JRKleinhofs, A. Toxicity and mutagenicity of sodium azide in mammalian cell culturesMutat. Res. 198077293299 DOI: 10.1016/0165-1218(80)90064-6

  30. 30

    Mitsunaga, M.Ogawa, M.Kosaka, N.Rosenblum, LTChoyke, PLKobayashi, H. Cell-Selective Cancer in Vivo near Infrared Photoimmunotherapy Targeting Specific Membrane MoleculesNat. Med. 20111716851691 DOI: 10.1038/nm.2554

  31. 31

    Debele, TAPeng, S.Tsai, H.-C. Drug Carrier for Photodynamic Cancer TherapyInt. J. Mol. Sci. 2015162209422136 DOI: 10.3390/ijms160922094

  32. 32

    Craig, RBSumma, CMCorti, M.Pincus, SH Anti-HIV Double Variable Domain Immunoglobulins Binding Both Gp41 and Gp120 for Targeted Delivery of ImmunoconjugatesPLoS One 20127113 DOI: 10.1371/journal.pone.0046778

  33. 33

    Krowicka, H.Robinson, JEClark, R.Hager, S.Broyles, S.Pincus, SH Use of Tissue Culture Cell Lines to Evaluate HIV Antiviral ResistanceAIDS Res. Hum. Retroviruses 200824957967 DOI: 10.1089/aid.2007.0242

  34. 34

    Davies, MJ Reactive Species Formed on Proteins Exposed to Singlet OxygenPhotochem. Photobiol. Sci. 200431725 DOI: 10.1039/b307576c

  35. 35

    Kobayashi, M.Harada, M.Takakura, H.Ando, ​​K.Goto, Y.Tsuneda, T.Ogawa, M.Taketsugu, T. Theoretical and Experimental Studies on the Near-Infrared Photoreaction Mechanism of a Silicon Phthalocyanine Photoimmunotherapy Dye: Photoinduced Hydrolysis by Radical Anion Generationchempluschem 202016 DOI: 10.1002/cplu.202000338

  36. 36

    Lumley, EKDyer, CEPamme, N.Boyle, RW Comparison of Photo-Oxidation Reactions in Batch and a New Photosensitizer-Immobilized Microfluidic DeviceOrg. Lett. 20121457245727 DOI: 10.1021/ol3023424

  37. 37

    Durmuş, M.Nyokong, T. Synthesis, Photophysical and Photochemical Studies of New Water-Soluble Indium(III) PhthalocyaninesPhotochem. Photobiol. Sci. 20076659668 DOI: 10.1039/b618478b

  38. 38

    Kobayashi, H.Choyke, PL Near-Infrared Photoimmunotherapy of CancerAccumulation Chem. Res. 20195223322339 DOI: 10.1021/acs.accounts.9b00273

  39. 39

    Vergara, TRCSamer, S.Santos-Oliveira, JRGiron, LBArif, MSSilva-Freitas, MLCherman, LATreitsman, MSChebabo, A.Sucupira, MCADa-Cross, AMDiaz, RS Thalidomide Is Associated With Increased T Cell Activation and Inflammation in Antiretroviral-Naive HIV-Infected Individuals in a Randomized Clinical Trial of Efficacy and Safetybiomedicine 2017235967 DOI: 10.1016/j.ebiom.2017.08.007

  40. 40

    Samer, S.Arif, MSGiron, LBZukurov, JPLHunter, J.Santillo, BTNamiyama, G.Galinskas, J.Komninakis, SVOshiro, TMSucupira, MCJanini, LMDiaz, RS Nicotinamide Activates Latent HIV-1 Ex Vivo in ART Suppressed Individuals, Revealing Higher Potency than the Association of Two Methyltransferase Inhibitors, Chaetocin and BIX01294Brazilian J. Infect. Dis. 202024150159 DOI: 10.1016/j.bjid.2020.01.005

  41. 41

    Chawla, A.Wang, C.Patton, C.Murray, M.Punekar, Y.De Ruiter, A.Steinhart, C. A Review of Long-Term Toxicity of Antiretroviral Treatment Regimens and Implications for an Aging PopulationInfected Dis. The R. 20187183195 DOI: 10.1007/s40121-018-0201-6

  42. 42

    Sohl, CDSzymanski, MRMislak, ACShumate, CKAmiralaei, S.Schinazi, RFAnderson, KSYin, YW Probing the Structural and Molecular Basis of Nucleotide Selectivity by Human Mitochondrial DNA Polymerase γProc. Natl. Academic Sci. USA 201511285968601 DOI: 10.1073 / pnas.1421733112

  43. 43

    Thymilsine, U.S.Gaur, R. Modulation of Apoptosis and Viral Latency—An Axis to Be Well Understood for Successful Cure of Human Immunodeficiency VirusJ. Gen. Virol. 201697813824 DOI: 10.1099/jgv.0.000402

  44. 44

    Kovacs, JMNoeldeke, E.Ha, HJPeng, H.Rits-Volloch, S.Harrison, SCChen, B. Stable, Uncleaved HIV-1 Envelope Glycoprotein Gp140 Forms a Tightly Folded Trimer with a Native-like StructureProc. Natl. Academic Sci. USA 20141111854218547 DOI: 10.1073 / pnas.1422269112

  45. 45

    Madani, N.Millette, R.Platt, EJMarin, M.Kozak, SLBloch, DBKabat, D. Implication of the Lymphocyte-Specific Nuclear Body Protein Sp140 in an Innate Response to Human Immunodeficiency Virus Type 1J.Virol. 2002761113311138 DOI: 10.1128/jvi.76.21.11133-11138.2002

  46. 46

    Koyanagi, Y.Miles, S.Mitsuyasu, RTMerrill, JEVinters, HVChen, ISY Dual Infection of the Central Nervous System by AIDS Viruses with Distinct Cellular TropismsScience 1987236819822 DOI: 10.1126 / science.3646751

  47. 47

    Pincus, SHWehrly, K. AZT Demonstrates Anti-HIV-l Activity in Persistently Infected Cell Lines: Implications for Combination Chemotherapy and ImmunotherapyJ. Infect. Dis. 199016212331238 DOI: 10.1093/infdis/162.6.1233

  48. 48

    Pincus, SHMcClure, J. Soluble CD4 Enhances the Efficacy of Immunotoxins Directed against Gp41 of the Human Immunodeficiency VirusProc. Natl. Academic Sci. USA 199390332336 DOI: 10.1073 / pnas.90.1.332

  49. 49

    Mchugh, L.Hu, S.Lee, BKSantora, K.Kennedy, PEBerger, EAPastan, I.Hamer, DH Increased Affinity and Stability of an Anti-HIV-1 Envelope Immunotoxin by Structure-Based MutagenesisJ. Biol. Chem. 20022773438334390 DOI: 10.1074/jbc.M205456200

  50. 50

    Bahou, C.Richards, DAMaruani, A.Love, EAJavaid, F.Caddick, S.Baker, JRChudasama, V. Highly Homogeneous Antibody Modification through Optimization of the Synthesis and Conjugation of Functionalized DibromopyridazinedionesOrg. Biomol. Chem. 20181613591366 DOI: 10.1039/c7ob03138f

  51. 51

    Castaneda, L.Wright, ZVFMarcuse, C.Tran, TMChudasama, V.Maruani, A.Hull, EANunes, JPMFitzmaurice, RJSmith, MEBJones, LHCaddick, S.Baker, JR A Mild Synthesis of N-Functionalised Bromomaleimides, Thiomaleimides and BromopyridazinedionesTetrahedron Lett. 20135434933495 DOI: 10.1016/j.tetlet.2013.04.088

  52. 52

    Robinson, E.Nunes, JPMVassileva, V.Maruani, A.Walnut, JCFSmith, MEBPedley, RBCaddick, S.Baker, JRChudasama, V. Pyridazinediones Deliver Potent, Stable, Targeted and Efficacious Antibody-Drug Conjugates (ADCs) with a Controlled Loading of 4 Drugs per AntibodyRSC Adv. 2017790739077 DOI: 10.1039/c7ra00788d

  53. 53

    Mello, BLAlessi, AMRiaño-Pachón, DMDeAzevedo, ERGuimaraes, FEGHoly Spirit, MCMcQueen-Mason, S.Bruce, NCPolikarpov, I. Targeted Metatranscriptomics of Compost-Derived Consortia Reveals a GH11 Exerting an Unusual Exo-1,4-β-Xylanase ActivityBiotechnol. Biofuels 201710117 DOI: 10.1186/s13068-017-0944-4

  54. 54

    Marine, RDSSSanz Duro, RLSantos, GLHunter, J.Teles, MDARBrustulin, R.From Padua Miracles, FASabino, ECDiaz, RSKomninakis, SV Detection of Coinfection with Chikungunya Virus and Dengue Virus Serotype 2 in Serum Samples of Patients in State of Tocantins, BrazilJ. Infect. Public Health 202013724729 DOI: 10.1016/j.jiph.2020.02.034

  55. 55

    Komninakis, SVsaints, DEMSantos, C.Oliveros, MPRSanabani, S.Diaz, RS HIV-1 Proviral DNA Loads (as Determined by Quantitative PCR) in Patients Subjected to Structured Treatment Interruption after Antiretroviral Therapy FailureJ. Clin. Microbiol. 20125021322133 DOI: 10.1128/JCM.00393-12

  56. 56

    Kumar, AMFernandez, JBSinger, EJCommins, D.Waldrop-Valverde, D.Ownby, RLKumar, M. Human Immunodeficiency Virus Type 1 in the Central Nervous System Leads to Decreased Dopamine in Different Regions of Postmortem Human BrainsJ. Neurovirol. 200915257274 DOI: 10.1080 / 13550280902973952

  57. 57

    Brenner, S.Horne, R. A Negative Staining Method For High Resolution Electron Microscopy Of VirusesBiochim. Biophys. Minutes 195934103110 DOI: 10.1016/0006-3002(59)90237-9


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