CAR-T therapy for durable remission of HIV

Suppressing HIV with a patient’s own cells 

We are developing a one-time treatment for the durable remission of HIV.  The treatment will enhance a patient’s own immune system to be able to kill HIV in places where it hides.  After this treatment, some patients may not need to continue treatment with other medications, including antiretrovirals.

Therapeutic Approach

We modify the patient’s own T cells to express a chimeric antigen receptor (CAR), which allows T cells to penetrate B cell follicles and which enhances the ability of the T cells to kill HIV and HIV infected cells.

CAR/CXCR5 T Cell Therapy Infographic

Features of the immune system

The therapy works by employing several components of the patient’s immune system:

Cytotoxic T cells (T lymphocytes, CTL) function to kill HIV and HIV infected cells.

Secondary lymphoid organs, such as the spleen and lymph nodes, are the sites where most HIV replication is concentrated.

B cell follicles are a part of secondary lymphoid organs such as the spleen and lymph nodes. HIV is adept at hiding in B cell follicles, allowing it to escape immune surveillance from CTL, and causing persistent infection.

A sufficient number of CTL targeted to B cell follicles could result in the ability to keep viral loads low without other medications.

Related Publications

  1. Pampusch MS, Haran KP, Hart G, Rakasz EG, Berger EA, Connick E, Skinner PJ. Rapid transduction and expansion of transduced T cells with maintenance of central memory populations. Mol Ther Methods Clin Dev. 2020;16:1–10. doi: 10.1016/j.omtm.2019.09.007. 
  2. Shengbin Li, Joy M Folkvord, Katalin J Kovacs, Reece K Wagstaff, Gwantwa Mwakalundwa, Aaron K Rendahl, Eva G Rakasz, Elizabeth Connick, Pamela J Skinner, Absence of SIV-specific CD8+ T cells in germinal centers may set the stage for persistent infection, PLoS Pathogens 2019, 15 (3), e1007311
  3. Haran KP, Hajduczki A, Pampusch MS, Mwakalundwa G, Vargas-Inchaustegui DA, Rakasz EG, Connick E, Berger EA, Skinner PJ. Simian immunodeficiency virus (SIV)-specific chimeric antigen receptor-T cells engineered to target B cell follicles and suppress SIV replication. Front Immunol. 2018;9:492. doi:10.3389/fimmu.2018.00492 
  4. Skinner PJ. Targeting reservoirs of HIV replication in lymphoid follicles with cellular therapies to cure HIV. Adv Cell Gene Ther. 2018;2(2) 76–84. doi:10.1002/acg2.27
  5. Li S, Mwakalundwa G, Skinner PJ. In situ MHC-tetramer staining and quantitative analysis to determine the location, abundance, and phenotype of antigen-specific CD8 T cells in tissues video link. J Vis Exp. 2017;5613037915(12710):1–8. doi:10.3791/56130
  6. Shengbin Li, Joy M. Folkvord, Eva G. Rakasz, Hadia M. Abdelaal, Reece K. Wagstaff, Katalin J. Kovacs, Hyeon O. Kim, Ryoko Sawahata, Samantha MaWhinney, David Masopust, Elizabeth Connick, and Pamela J. Skinner, Simian Immunodeficiency Virus-Producing Cells in Follicles Are Partially Suppressed by CD8+ Cells In Vivo, Journal of Virology, 2016, 90 (24), 11168-11180.
  7. Dileepan T, Kim HO, Cleary PP, Skinner PJ. In Situ peptide-MHC-II tetramer staining of antigen-specific CD4+ T cells in tissues. PLoS One. 2015 Jun 11;10(6):e0128862. doi: 10.1371/journal.pone.0128862. 
  8. Connick E, Folkvord JM, Lind KT, Rakasz EG, Miles B, Wilson NA, Santiago ML, Stephens EB, Kim HO, Wagstaff R, Li S, Abdelaal HM, Kemp N, Watkins DI, MaWhinney S, Skinner PJ. Compartmentalization of simian immunodeficiency virus replication within secondary lymphoid tissues of rhesus macaques is linked to disease stage and inversely related to localization of virus-specific CTL. J Immunol. 2014;193(11):5613–5625. doi:10.4049/jimmunol.1401161
  9. Skinner PJ, Connick E. Overcoming the immune privilege of B cell follicles to cure HIV-1 infection. J Hum Virol Retrovirol. 2014;1(1):8–10. doi:10.15406/jhvrv.2014.01.00001 
  10. Li Q, Skinner PJ, Ha S-J, Duan L, Mattila TL, Hage A, White C, Barber DL, O’Mara L, Southern PJ, Reilly CS, Miller CJ, Ahmed R, Haase AT. Visualizing antigen-specific and infected cells in situ predicts outcomes in early viral infection. Science.  2009;323(5922):1726–1729. doi:10.1126/science.1168676 
  11. Connick E, Mattila T, Folkvord JM, Schlichtemeier R, Meditz AL, Hage A, White C, and Skinner PJ.  CTL fail to accumulate at sites of HIV-1 replication in lymphoid tissue. J Immunol. 2007;178(11):6975-6983. doi:10.4049/jimmunol.178.11.6975 
  12. Skinner PJ, Daniels MA, Schmidt CS, Jameson SC, and Haase AT. Cutting edge: In situ tetramer staining of antigen-specific T cells in tissues. J Immunol. 2000;165(2):613–7. doi:10.4049/jimmunol.165.2.613