Skip to main content
SpringerLink
Log in

Modeling HIV-1 Mucosal Transmission and Prevention in Humanized Mice

  • Protocol
HIV Protocols

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1354))

Abstract

The new generation humanized mice (hu-mice) that permit continuous de novo generation of human hematopoietic cells have led to novel strategies in studying HIV-1 pathogenesis, prevention and therapies. HIV-1 infection of hu-mice results in chronic viremia and CD4+ T cell loss, thus mimicking key aspects of the disease progression. In addition, the new generation hu-mice are permissive for HIV-1 sexual transmission by vaginal and rectal routes thus allowing in vivo efficacy testing of new anti-HIV-1 drugs for prevention. Two leading models are currently being used, namely the hu-HSC mice and the BLT mice. Here we describe the methodology for generating both hu-HSC and BLT mice and their use in the study of HIV-1 transmission and prevention of infection by topical and oral administration of anti-retroviral drugs. Practical aspects of the methodologies are emphasized.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Akkina R (2013) New generation humanized mice for virus research: comparative aspects and future prospects. Virology 435:14–28. doi:10.1016/j.virol.2012.10.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Brehm MA, Wiles MV, Greiner DL, Shultz LD (2014) Generation of improved humanized mouse models for human infectious diseases. J Immunol Methods 410C:3–17. doi:10.1016/j.jim.2014.02.011

    Article  Google Scholar 

  3. Denton PW, Garcia JV (2011) Humanized mouse models of HIV infection. AIDS Rev 13(3):135–148

    PubMed  PubMed Central  Google Scholar 

  4. Garcia S, Freitas AA (2012) Humanized mice: current states and perspectives. Immunol Lett 146:1–7. doi:10.1016/j.imlet.2012.03.009

    Article  CAS  PubMed  Google Scholar 

  5. Maartens G, Celum C, Lewin SR (2014) HIV infection: epidemiology, pathogenesis, treatment, and prevention. Lancet 384:258–271. doi:10.1016/S0140-6736(14)60164-1

    Article  PubMed  Google Scholar 

  6. Romano J, Kashuba A, Becker S, Cummins J, Turpin J, Veronese F, Antiretroviral Pharmacology In HIVPTTP (2013) Pharmacokinetics and pharmacodynamics in HIV prevention; current status and future directions: a summary of the DAIDS and BMGF sponsored think tank on pharmacokinetics (PK)/pharmacodynamics (PD) in HIV prevention. AIDS Res Hum Retroviruses 29:1418–1427. doi:10.1089/AID.2013.0122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Baeten JM, Celum C (2013) Antiretroviral preexposure prophylaxis for HIV prevention. N Engl J Med 368:83–84

    PubMed  Google Scholar 

  8. Hankins CA, Dybul MR (2013) The promise of pre-exposure prophylaxis with antiretroviral drugs to prevent HIV transmission: a review. Curr Opin HIV AIDS 8:50–58. doi:10.1097/COH.0b013e32835b809d

    Article  CAS  PubMed  Google Scholar 

  9. Veazey RS (2013) Animal models for microbicide safety and efficacy testing. Curr Opin HIV AIDS 8:295–303. doi:10.1097/COH.0b013e328361d096

    PubMed  PubMed Central  Google Scholar 

  10. Trezza CR, Kashuba AD (2014) Pharmacokinetics of antiretrovirals in genital secretions and anatomic sites of HIV transmission: implications for HIV prevention. Clin Pharmacokinet 53:611–624. doi:10.1007/s40262-014-0148-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Veselinovic M, Yang KH, LeCureux J, Sykes C, Remling-Mulder L, Kashuba AD, Akkina R (2014) HIV pre-exposure prophylaxis: mucosal tissue drug distribution of RT inhibitor Tenofovir and entry inhibitor Maraviroc in a humanized mouse model. Virology 464–465:253–263. doi:10.1016/j.virol.2014.07.008

    Article  PubMed  Google Scholar 

  12. Akkina RK, Rosenblatt JD, Campbell AG, Chen IS, Zack JA (1994) Modeling human lymphoid precursor cell gene therapy in the SCID-hu mouse. Blood 84:1393–1398

    CAS  PubMed  Google Scholar 

  13. Berges BK, Akkina SR, Folkvord JM, Connick E, Akkina R (2008) Mucosal transmission of R5 and X4 tropic HIV-1 via vaginal and rectal routes in humanized Rag2-/- gammac -/- (RAG-hu) mice. Virology 373:342–351. doi:10.1016/j.virol.2007.11.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Berges BK, Akkina SR, Remling L, Akkina R (2010) Humanized Rag2(-/-)gammac(-/-) (RAG-hu) mice can sustain long-term chronic HIV-1 infection lasting more than a year. Virology 397:100–103. doi:10.1016/j.virol.2009.10.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Berges BK, Wheat WH, Palmer BE, Connick E, Akkina R (2006) HIV-1 infection and CD4 T cell depletion in the humanized Rag2-/-gamma c-/- (RAG-hu) mouse model. Retrovirology 3:76. doi:10.1186/1742-4690-3-76

    Article  PubMed  PubMed Central  Google Scholar 

  16. Lan P, Tonomura N, Shimizu A, Wang S, Yang YG (2006) Reconstitution of a functional human immune system in immunodeficient mice through combined human fetal thymus/liver and CD34+ cell transplantation. Blood 108:487–492. doi:10.1182/blood-2005-11-4388

    Article  CAS  PubMed  Google Scholar 

  17. Bristol GC, Gao LY, Zack JA (1997) Preparation and maintenance of SCID-hu mice for HIV research. Methods 12:343–347

    Article  CAS  PubMed  Google Scholar 

  18. Denton PW, Estes JD, Sun Z, Othieno FA, Wei BL, Wege AK, Powell DA, Payne D, Haase AT, Garcia JV (2008) Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice. PLoS Med 5:e16. doi:10.1371/journal.pmed.0050016

    Article  PubMed  PubMed Central  Google Scholar 

  19. Denton PW, Garcia JV (2012) Mucosal HIV-1 transmission and prevention strategies in BLT humanized mice. Trends Microbiol 20:268–274. doi:10.1016/j.tim.2012.03.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rouet F, Ekouevi DK, Chaix ML, Burgard M, Inwoley A, Tony TD, Danel C, Anglaret X, Leroy V, Msellati P, Dabis F, Rouzioux C (2005) Transfer and evaluation of an automated, low-cost real-time reverse transcription-PCR test for diagnosis and monitoring of human immunodeficiency virus type 1 infection in a West African resource-limited setting. J Clin Microbiol 43:2709–2717. doi:10.1128/JCM.43.6.2709-2717.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Neff CP, Ndolo T, Tandon A, Habu Y, Akkina R (2010) Oral pre-exposure prophylaxis by anti-retrovirals raltegravir and maraviroc protects against HIV-1 vaginal transmission in a humanized mouse model. PLoS One 5:e15257. doi:10.1371/journal.pone.0015257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Neff CP, Kurisu T, Ndolo T, Fox K, Akkina R (2011) A topical microbicide gel formulation of CCR5 antagonist maraviroc prevents HIV-1 vaginal transmission in humanized RAG-hu mice. PLoS One 6:e20209. doi:10.1371/journal.pone.0020209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Denton PW, Othieno F, Martinez-Torres F, Zou W, Krisko JF, Fleming E, Zein S, Powell DA, Wahl A, Kwak YT, Welch BD, Kay MS, Payne DA, Gallay P, Appella E, Estes JD, Lu M, Garcia JV (2011) One percent tenofovir applied topically to humanized BLT mice and used according to the CAPRISA 004 experimental design demonstrates partial protection from vaginal HIV infection, validating the BLT model for evaluation of new microbicide candidates. J Virol 85:7582–7593. doi:10.1128/JVI.00537-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chateau ML, Denton PW, Swanson MD, McGowan I, Garcia JV (2013) Rectal transmission of transmitted/founder HIV-1 is efficiently prevented by topical 1% tenofovir in BLT humanized mice. PLoS One 8:e60024. doi:10.1371/journal.pone.0060024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Denton PW, Long JM, Wietgrefe SW, Sykes C, Spagnuolo RA, Snyder OD, Perkey K, Archin NM, Choudhary SK, Yang K, Hudgens MG, Pastan I, Haase AT, Kashuba AD, Berger EA, Margolis DM, Garcia JV (2014) Targeted cytotoxic therapy kills persisting HIV infected cells during ART. PLoS Pathog 10:e1003872. doi:10.1371/journal.ppat.1003872

    Article  PubMed  PubMed Central  Google Scholar 

  26. Choudhary SK, Rezk NL, Ince WL, Cheema M, Zhang L, Su L, Swanstrom R, Kashuba AD, Margolis DM (2009) Suppression of human immunodeficiency virus type 1 (HIV-1) viremia with reverse transcriptase and integrase inhibitors, CD4+ T-cell recovery, and viral rebound upon interruption of therapy in a new model for HIV treatment in the humanized Rag2-/-{gamma}c-/- mouse. J Virol 83:8254–8258. doi:10.1128/JVI.00580-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Stoddart CA, Bales CA, Bare JC, Chkhenkeli G, Galkina SA, Kinkade AN, Moreno ME, Rivera JM, Ronquillo RE, Sloan B, Black PL (2007) Validation of the SCID-hu Thy/Liv mouse model with four classes of licensed antiretrovirals. PLoS One 2:e655. doi:10.1371/journal.pone.0000655

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Work reported here was supported by NIH grants RO1AI100845, R56AI095101, and RO1AI111891. We thank the NIH AIDS Research and Reference Reagents Program for supplying some of the reagents outlined in this protocol.

Author information

Authors and Affiliations

  1. Department of Microbiology, Immunology and Pathology, Colorado State University, 1682 Campus Delivery, Fort Collins, CO, 80523, USA

    Milena Veselinovic, Paige Charlins & Ramesh Akkina

Authors
  1. Milena Veselinovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paige Charlins
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ramesh Akkina
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ramesh Akkina .

Editor information

Editors and Affiliations

  1. Department of Microbiology & Immunology, Albert Einstein College of Medicine, BRONX, New York, USA

    Vinayaka R. Prasad

  2. Department of Genetics, Albert Einstein College of Medicine, BRONX, New York, USA

    Ganjam V. Kalpana

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media New York

About this protocol

Cite this protocol

Veselinovic, M., Charlins, P., Akkina, R. (2016). Modeling HIV-1 Mucosal Transmission and Prevention in Humanized Mice. In: Prasad, V., Kalpana, G. (eds) HIV Protocols. Methods in Molecular Biology, vol 1354. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3046-3_14

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-3046-3_14

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-3045-6

  • Online ISBN: 978-1-4939-3046-3

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation