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Paul R Clapham PhD

TitleProfessor Emeritus
InstitutionUMass Chan Medical School
DepartmentProgram in Molecular Medicine
AddressUMass Chan Medical School
373 Plantation Street Two Biotech Suite 315
Worcester MA 01605
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    Other Positions
    InstitutionT.H. Chan School of Medicine
    DepartmentMicrobiology and Physiological Systems

    InstitutionT.H. Chan School of Medicine
    DepartmentProgram in Molecular Medicine

    Collapse Biography 
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    King's College London, London, , United KingdomBSCMicrobiology
    University of Reading, Reading, , United KingdomMSCVirology
    University of London, London, , United KingdomPHDPhilosophy

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    The HIV envelope: Biology, Receptors and Cellular Tropisms

    HIV uses cell surface receptors to attach to and enter cells. Interactions with CD4 and a coreceptor are usually required for HIV to efficiently enter cells. Coreceptors are seven-transmembrane receptors that belong to the chemokine receptor family. Viruses transmitted and present in the asymptomatic stages of infection use the chemokine receptor CCR5 as a coreceptor, while variants that use CXCR4 emerge later in disease in up to 50% of AIDS patients. More than a dozen other coreceptors have been identified that confer infection in vitro for various HIV and SIV strains. However, these are not currently believed to be significant for HIV replication in vivo.Dr. Paul Clapham

    Our group is investigating how HIV-1 adapts for replication in different environments and cell types in vivo. We use PCR to amplify envelopes from patient tissue. This avoids viral culture that may introduce mutations into envelope genes. We have shown that CCR5-using envelopes vary substantially in tropism and capacity to exploit low levels of CD4 and/or CCR5 for infection. Thus, envelopes from brain tissue are predominantly highly macrophage-tropic and can exploit low levels of CD4 for infection. In contrast, the majority of envelopes from immune tissue required high levels of CD4 for infection and were non-macrophage-tropic. Current research aims to evaluate whether highly macrophage-tropic variants evolve at different sites in vivo. For example, if highly macrophage-tropic variants are present in semen, they may confer more efficient transmission. We are also investigating the selective pressures that confer macrophage-tropic and non-macrophage-tropic phenotypes for CCR5-using HIV-1. Do these phenotypes simply reflect adaptation for replication in T-cells in immune tissue and for macrophages in the brain? Or do the phenotypes result from different immune pressures conferred by neutralizing antibodies in immune tissue, contrasting with brain tissue where neutralizing antibodies are usually excluded by the blood brain barrier.

    Projects that examine other aspects of the biology of the HIV-1 envelope are also ongoing to investigate (1) the trafficking of newly synthesized envelope glycoproteins to the sites of virus budding and (2) vpu regulation of envelope expression and maturation in vitro and in vivo.

    Paul Clapham, PhD

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    Rotation Projects

    Rotation projects are available in support of our research. See the research description section of this page.

    Collapse Bibliographic 
    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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    1. Verdejo-Torres O, Vargas-Pavia T, Fatima S, Clapham PR, Duenas-Decamp MJ. Implications of the 375W mutation for HIV-1 tropism and vaccine development. J Virol. 2024 Jan 23; 98(1):e0152223. PMID: 38169306.
      Citations:    Fields:    Translation:HumansCells
    2. Quitadamo B, Peters PJ, Koch M, Luzuriaga K, Cheng-Mayer C, Clapham PR, Gonzalez-Perez MP. No detection of CD4-independent human immunodeficiency virus 1 envelope glycoproteins in brain tissue of patients with or without neurological complications. Arch Virol. 2019 Feb; 164(2):473-482. PMID: 30415390.
      Citations:    Fields:    Translation:HumansCells
    3. Brese RL, Gonzalez-Perez MP, Koch M, O'Connell O, Luzuriaga K, Somasundaran M, Clapham PR, Dollar JJ, Nolan DJ, Rose R, Lamers SL. Ultradeep single-molecule real-time sequencing of HIV envelope reveals complete compartmentalization of highly macrophage-tropic R5 proviral variants in brain and CXCR4-using variants in immune and peripheral tissues. J Neurovirol. 2018 08; 24(4):439-453. PMID: 29687407.
      Citations: 12     Fields:    Translation:HumansCells
    4. Quitadamo B, Peters PJ, Repik A, O'Connell O, Mou Z, Koch M, Somasundaran M, Brody R, Luzuriaga K, Wallace A, Wang S, Lu S, McCauley S, Luban J, Duenas-Decamp M, Gonzalez-Perez MP, Clapham PR. HIV-1 R5 Macrophage-Tropic Envelope Glycoprotein Trimers Bind CD4 with High Affinity, while the CD4 Binding Site on Non-macrophage-tropic, T-Tropic R5 Envelopes Is Occluded. J Virol. 2018 01 15; 92(2). PMID: 29118121.
      Citations: 9     Fields:    Translation:HumansCells
    5. Gonzalez-Perez MP, Peters PJ, O'Connell O, Silva N, Harbison C, Cummings Macri S, Kaliyaperumal S, Luzuriaga K, Clapham PR. Identification of Emerging Macrophage-Tropic HIV-1 R5 Variants in Brain Tissue of AIDS Patients without Severe Neurological Complications. J Virol. 2017 10 15; 91(20). PMID: 28768859.
      Citations: 11     Fields:    Translation:HumansCells
    6. Wang S, Chou TH, Hackett A, Efros V, Wang Y, Han D, Wallace A, Chen Y, Hu G, Liu S, Clapham P, Arthos J, Montefiori D, Lu S. Screening of primary gp120 immunogens to formulate the next generation polyvalent DNA prime-protein boost HIV-1 vaccines. Hum Vaccin Immunother. 2017 12 02; 13(12):2996-3009. PMID: 28933684.
      Citations: 6     Fields:    Translation:Animals
    7. Beauparlant D, Rusert P, Magnus C, Kadelka C, Weber J, Uhr T, Zagordi O, Oberle C, Duenas-Decamp MJ, Clapham PR, Metzner KJ, G?nthard HF, Trkola A. Delineating CD4 dependency of HIV-1: Adaptation to infect low level CD4 expressing target cells widens cellular tropism but severely impacts on envelope functionality. PLoS Pathog. 2017 03; 13(3):e1006255. PMID: 28264054.
      Citations: 16     Fields:    Translation:HumansCells
    8. Soto ER, O'Connell O, Dikengil F, Peters PJ, Clapham PR, Ostroff GR. Targeted Delivery of Glucan Particle Encapsulated Gallium Nanoparticles Inhibits HIV Growth in Human Macrophages. J Drug Deliv. 2016; 2016:8520629. PMID: 27965897.
    9. Duenas-Decamp M, Jiang L, Bolon D, Clapham PR. Saturation Mutagenesis of the HIV-1 Envelope CD4 Binding Loop Reveals Residues Controlling Distinct Trimer Conformations. PLoS Pathog. 2016 Nov; 12(11):e1005988. PMID: 27820858.
      Citations: 14     Fields:    Translation:HumansCells
    10. Peters PJ, Gonzalez-Perez MP, Musich T, Moore Simas TA, Lin R, Morse AN, Shattock RJ, Derdeyn CA, Clapham PR. Infection of ectocervical tissue and universal targeting of T-cells mediated by primary non-macrophage-tropic and highly macrophage-tropic HIV-1 R5 envelopes. Retrovirology. 2015 Jun 09; 12:48. PMID: 26055104.
      Citations: 4     Fields:    Translation:HumansCells
    11. Musich T, O'Connell O, Gonzalez-Perez MP, Derdeyn CA, Peters PJ, Clapham PR. HIV-1 non-macrophage-tropic R5 envelope glycoproteins are not more tropic for entry into primary CD4+ T-cells than envelopes highly adapted for macrophages. Retrovirology. 2015 Mar 14; 12:25. PMID: 25809903.
      Citations: 10     Fields:    Translation:HumansCells
    12. Peters PJ, Richards K, Clapham P. Human immunodeficiency viruses: propagation, quantification, and storage. Curr Protoc Microbiol. 2013; Chapter 15:Unit 15J.1. PMID: 23408133.
      Citations: 1     Fields:    Translation:HumansCells
    13. O'Connell O, Repik A, Reeves JD, Gonzalez-Perez MP, Quitadamo B, Anton ED, Duenas-Decamp M, Peters P, Lin R, Zolla-Pazner S, Corti D, Wallace A, Wang S, Kong XP, Lu S, Clapham PR. Efficiency of bridging-sheet recruitment explains HIV-1 R5 envelope glycoprotein sensitivity to soluble CD4 and macrophage tropism. J Virol. 2013 Jan; 87(1):187-98. PMID: 23055568.
      Citations: 17     Fields:    Translation:HumansCells
    14. Gonzalez-Perez MP, O'Connell O, Lin R, Sullivan WM, Bell J, Simmonds P, Clapham PR. Independent evolution of macrophage-tropism and increased charge between HIV-1 R5 envelopes present in brain and immune tissue. Retrovirology. 2012 Mar 15; 9:20. PMID: 22420378.
      Citations: 28     Fields:    Translation:HumansCells
    15. Due?as-Decamp MJ, O'Connell OJ, Corti D, Zolla-Pazner S, Clapham PR. The W100 pocket on HIV-1 gp120 penetrated by b12 is not a target for other CD4bs monoclonal antibodies. Retrovirology. 2012 Jan 27; 9:9. PMID: 22284192.
      Citations: 8     Fields:    Translation:HumansCells
    16. Clapham PR, Lu S. Vaccinology: precisely tuned antibodies nab HIV. Nature. 2011 Sep 21; 477(7365):416-7. PMID: 21938063.
      Citations: 17     Fields:    Translation:HumansCells
    17. Kishko M, Somasundaran M, Brewster F, Sullivan JL, Clapham PR, Luzuriaga K. Genotypic and functional properties of early infant HIV-1 envelopes. Retrovirology. 2011 Aug 15; 8:67. PMID: 21843318.
      Citations: 24     Fields:    Translation:HumansCellsPHPublic Health
    18. Shen R, Meng G, Ochsenbauer C, Clapham PR, Grams J, Novak L, Kappes JC, Smythies LE, Smith PD. Stromal down-regulation of macrophage CD4/CCR5 expression and NF-?B activation mediates HIV-1 non-permissiveness in intestinal macrophages. PLoS Pathog. 2011 May; 7(5):e1002060. PMID: 21637819.
      Citations: 27     Fields:    Translation:HumansCells
    19. Brown RJ, Peters PJ, Caron C, Gonzalez-Perez MP, Stones L, Ankghuambom C, Pondei K, McClure CP, Alemnji G, Taylor S, Sharp PM, Clapham PR, Ball JK. Intercompartmental recombination of HIV-1 contributes to env intrahost diversity and modulates viral tropism and sensitivity to entry inhibitors. J Virol. 2011 Jun; 85(12):6024-37. PMID: 21471230.
      Citations: 39     Fields:    Translation:HumansCells
    20. Vaine M, Duenas-Decamp M, Peters P, Liu Q, Arthos J, Wang S, Clapham P, Lu S. Two closely related Env antigens from the same patient elicited different spectra of neutralizing antibodies against heterologous HIV-1 isolates. J Virol. 2011 May; 85(10):4927-36. PMID: 21411542.
      Citations: 10     Fields:    Translation:HumansAnimalsCellsPHPublic Health
    21. Musich T, Peters PJ, Duenas-Decamp MJ, Gonzalez-Perez MP, Robinson J, Zolla-Pazner S, Ball JK, Luzuriaga K, Clapham PR. A conserved determinant in the V1 loop of HIV-1 modulates the V3 loop to prime low CD4 use and macrophage infection. J Virol. 2011 Mar; 85(5):2397-405. PMID: 21159865.
      Citations: 45     Fields:    Translation:HumansCells
    22. Duenas-Decamp MJ, Clapham PR. HIV-1 gp120 determinants proximal to the CD4 binding site shift protective glycans that are targeted by monoclonal antibody 2G12. J Virol. 2010 Sep; 84(18):9608-12. PMID: 20610714.
      Citations: 19     Fields:    Translation:HumansCells
    23. Duenas-Decamp MJ, Peters PJ, Repik A, Musich T, Gonzalez-Perez MP, Caron C, Brown R, Ball J, Clapham PR. Variation in the biological properties of HIV-1 R5 envelopes: implications of envelope structure, transmission and pathogenesis. Future Virol. 2010 Jul; 5(4):435-451. PMID: 20930940.
    24. Richards KH, Aasa-Chapman MM, McKnight A, Clapham PR. Modulation of HIV-1 macrophage-tropism among R5 envelopes occurs before detection of neutralizing antibodies. Retrovirology. 2010 May 27; 7:48. PMID: 20507591.
      Citations: 10     Fields:    Translation:HumansCells
    25. Zhang S, Alexander L, Wang T, Agler M, Zhou N, Fang H, Kadow J, Clapham P, Lin PF. Protection against HIV-envelope-induced neuronal cell destruction by HIV attachment inhibitors. Arch Virol. 2010 May; 155(5):777-81. PMID: 20300783.
      Citations: 6     Fields:    Translation:HumansCells
    26. Agrawal L, Maxwell CR, Peters PJ, Clapham PR, Liu SM, Mackay CR, Strayer DS. Complexity in human immunodeficiency virus type 1 (HIV-1) co-receptor usage: roles of CCR3 and CCR5 in HIV-1 infection of monocyte-derived macrophages and brain microglia. J Gen Virol. 2009 Mar; 90(Pt 3):710-722. PMID: 19218218.
      Citations: 5     Fields:    Translation:HumansAnimalsCells
    27. Shen R, Richter HE, Clements RH, Novak L, Huff K, Bimczok D, Sankaran-Walters S, Dandekar S, Clapham PR, Smythies LE, Smith PD. Macrophages in vaginal but not intestinal mucosa are monocyte-like and permissive to human immunodeficiency virus type 1 infection. J Virol. 2009 Apr; 83(7):3258-67. PMID: 19153236.
      Citations: 114     Fields:    Translation:HumansCells
    28. Duenas-Decamp MJ, Peters PJ, Burton D, Clapham PR. Determinants flanking the CD4 binding loop modulate macrophage tropism of human immunodeficiency virus type 1 R5 envelopes. J Virol. 2009 Mar; 83(6):2575-83. PMID: 19129457.
      Citations: 55     Fields:    Translation:HumansCells
    29. Repik A, Clapham PR. Plugging gp120s cavity. Structure. 2008 Nov 12; 16(11):1603-4. PMID: 19000812.
      Citations: 3     Fields:    Translation:HumansCells
    30. Duenas-Decamp MJ, Peters P, Burton D, Clapham PR. Natural resistance of human immunodeficiency virus type 1 to the CD4bs antibody b12 conferred by a glycan and an arginine residue close to the CD4 binding loop. J Virol. 2008 Jun; 82(12):5807-14. PMID: 18385254.
      Citations: 42     Fields:    Translation:HumansCells
    31. Peters PJ, Duenas-Decamp MJ, Sullivan WM, Brown R, Ankghuambom C, Luzuriaga K, Robinson J, Burton DR, Bell J, Simmonds P, Ball J, Clapham PR. Variation in HIV-1 R5 macrophage-tropism correlates with sensitivity to reagents that block envelope: CD4 interactions but not with sensitivity to other entry inhibitors. Retrovirology. 2008 Jan 18; 5:5. PMID: 18205925.
      Citations: 59     Fields:    Translation:HumansCells
    32. Richards KH, Clapham PR. Effects of vpu start-codon mutations on human immunodeficiency virus type 1 replication in macrophages. J Gen Virol. 2007 Oct; 88(Pt 10):2780-2792. PMID: 17872532.
      Citations: 12     Fields:    Translation:HumansCells
    33. Repik A, Richards KH, Clapham PR. The promise of CCR5 antagonists as new therapies for HIV-1. Curr Opin Investig Drugs. 2007 Feb; 8(2):130-9. PMID: 17328229.
      Citations: 3     Fields:    Translation:HumansAnimalsCells
    34. Gorry PR, Dunfee RL, Mefford ME, Kunstman K, Morgan T, Moore JP, Mascola JR, Agopian K, Holm GH, Mehle A, Taylor J, Farzan M, Wang H, Ellery P, Willey SJ, Clapham PR, Wolinsky SM, Crowe SM, Gabuzda D. Changes in the V3 region of gp120 contribute to unusually broad coreceptor usage of an HIV-1 isolate from a CCR5 Delta32 heterozygote. Virology. 2007 May 25; 362(1):163-78. PMID: 17239419.
      Citations: 28     Fields:    Translation:HumansCells
    35. Peters PJ, Due?as-Decamp MJ, Sullivan WM, Clapham PR. Variation of macrophage tropism among HIV-1 R5 envelopes in brain and other tissues. J Neuroimmune Pharmacol. 2007 Mar; 2(1):32-41. PMID: 18040824.
      Citations: 24     Fields:    Translation:HumansAnimalsCells
    36. Richards KH, Clapham PR. Human immunodeficiency viruses: propagation, quantification, and storage. Curr Protoc Microbiol. 2006 Sep; Chapter 15:Unit15J.1. PMID: 18770581.
      Citations: 3     Fields:    Translation:HumansAnimalsCells
    37. Peters PJ, Sullivan WM, Duenas-Decamp MJ, Bhattacharya J, Ankghuambom C, Brown R, Luzuriaga K, Bell J, Simmonds P, Ball J, Clapham PR. Non-macrophage-tropic human immunodeficiency virus type 1 R5 envelopes predominate in blood, lymph nodes, and semen: implications for transmission and pathogenesis. J Virol. 2006 Jul; 80(13):6324-32. PMID: 16775320.
      Citations: 71     Fields:    Translation:HumansCells
    38. Bhattacharya J, Repik A, Clapham PR. Gag regulates association of human immunodeficiency virus type 1 envelope with detergent-resistant membranes. J Virol. 2006 Jun; 80(11):5292-300. PMID: 16699009.
      Citations: 45     Fields:    Translation:HumansCells
    39. Ho HT, Fan L, Nowicka-Sans B, McAuliffe B, Li CB, Yamanaka G, Zhou N, Fang H, Dicker I, Dalterio R, Gong YF, Wang T, Yin Z, Ueda Y, Matiskella J, Kadow J, Clapham P, Robinson J, Colonno R, Lin PF. Envelope conformational changes induced by human immunodeficiency virus type 1 attachment inhibitors prevent CD4 binding and downstream entry events. J Virol. 2006 Apr; 80(8):4017-25. PMID: 16571818.
      Citations: 39     Fields:    Translation:HumansCells
    40. Willey S, Peters PJ, Sullivan WM, Dorr P, Perros M, Clapham PR. Inhibition of CCR5-mediated infection by diverse R5 and R5X4 HIV and SIV isolates using novel small molecule inhibitors of CCR5: effects of viral diversity, target cell and receptor density. Antiviral Res. 2005 Nov; 68(2):96-108. PMID: 16157392.
      Citations: 11     Fields:    Translation:HumansCells
    41. Cilliers T, Willey S, Sullivan WM, Patience T, Pugach P, Coetzer M, Papathanasopoulos M, Moore JP, Trkola A, Clapham P, Morris L. Use of alternate coreceptors on primary cells by two HIV-1 isolates. Virology. 2005 Aug 15; 339(1):136-44. PMID: 15992849.
      Citations: 20     Fields:    Translation:HumansCells
    42. Neil SJ, Aasa-Chapman MM, Clapham PR, Nibbs RJ, McKnight A, Weiss RA. The promiscuous CC chemokine receptor D6 is a functional coreceptor for primary isolates of human immunodeficiency virus type 1 (HIV-1) and HIV-2 on astrocytes. J Virol. 2005 Aug; 79(15):9618-24. PMID: 16014924.
      Citations: 34     Fields:    Translation:HumansCells
    43. Elvin SJ, Williamson ED, Scott JC, Smith JN, P?rez De Lema G, Chilla S, Clapham P, Pfeffer K, Schl?ndorff D, Luckow B. Evolutionary genetics: Ambiguous role of CCR5 in Y. pestis infection. Nature. 2004 Jul 22; 430(6998):417. PMID: 15272490.
      Citations: 16     Fields:    Translation:HumansAnimalsCells
    44. Peters PJ, Bhattacharya J, Hibbitts S, Dittmar MT, Simmons G, Bell J, Simmonds P, Clapham PR. Biological analysis of human immunodeficiency virus type 1 R5 envelopes amplified from brain and lymph node tissues of AIDS patients with neuropathology reveals two distinct tropism phenotypes and identifies envelopes in the brain that confer an enhanced tropism and fusigenicity for macrophages. J Virol. 2004 Jul; 78(13):6915-26. PMID: 15194768.
      Citations: 131     Fields:    Translation:HumansCells
    45. Bhattacharya J, Peters PJ, Clapham PR. Human immunodeficiency virus type 1 envelope glycoproteins that lack cytoplasmic domain cysteines: impact on association with membrane lipid rafts and incorporation onto budding virus particles. J Virol. 2004 May; 78(10):5500-6. PMID: 15113929.
      Citations: 56     Fields:    Translation:Cells
    46. Willey SJ, Reeves JD, Hudson R, Miyake K, Dejucq N, Schols D, De Clercq E, Bell J, McKnight A, Clapham PR. Identification of a subset of human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strains able to exploit an alternative coreceptor on untransformed human brain and lymphoid cells. J Virol. 2003 Jun; 77(11):6138-52. PMID: 12743271.
      Citations: 26     Fields:    Translation:HumansAnimalsCells
    47. Thomas ER, Shotton C, Weiss RA, Clapham PR, McKnight A. CD4-dependent and CD4-independent HIV-2: consequences for neutralization. AIDS. 2003 Feb 14; 17(3):291-300. PMID: 12556682.
      Citations: 17     Fields:    Translation:HumansCells
    48. Reynolds L, Ullman C, Moore M, Isalan M, West MJ, Clapham P, Klug A, Choo Y. Repression of the HIV-1 5' LTR promoter and inhibition of HIV-1 replication by using engineered zinc-finger transcription factors. Proc Natl Acad Sci U S A. 2003 Feb 18; 100(4):1615-20. PMID: 12574502.
      Citations: 38     Fields:    Translation:AnimalsCells
    49. Bhattacharya J, Peters PJ, Clapham PR. CD4-independent infection of HIV and SIV: implications for envelope conformation and cell tropism in vivo. AIDS. 2003; 17 Suppl 4:S35-43. PMID: 15080178.
      Citations: 22     Fields:    Translation:HumansAnimalsCells
    50. Clapham PR, McKnight ?. Cell surface receptors, virus entry and tropism of primate lentiviruses. J Gen Virol. 2002 Aug; 83(Pt 8):1809-1829. PMID: 12124446.
      Citations: 67     Fields:    Translation:HumansAnimalsCells
    51. Dejucq N, Simmons G, Clapham PR. T-cell line adaptation of human immunodeficiency virus type 1 strain SF162: effects on envelope, vpu and macrophage-tropism. J Gen Virol. 2000 Dec; 81(Pt 12):2899-2904. PMID: 11086121.
      Citations: 18     Fields:    Translation:HumansCells
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