Simian immunodeficiency virus (SIV)-specific chimeric antigen receptor-T cells engineered to target B cell follicles and suppress SIV replication

Kumudhini Preethi Haran, Agnes Hajduczki, Mary S. Pampusch, Gwantwa Mwakalundwa, Diego A. Vargas-Inchaustegui, Eva G. Rakasz, Elizabeth Connick, Edward A. Berger, Pamela J. Skinner

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

There is a need to develop improved methods to treat and potentially cure HIV infection. During chronic HIV infection, replication is concentrated within T follicular helper cells (Tfh) located within B cell follicles, where low levels of virus-specific CTL permit ongoing viral replication. We previously showed that elevated levels of simian immunodeficiency virus (SIV)-specific CTL in B cell follicles are linked to both decreased levels of viral replication in follicles and decreased plasma viral loads. These findings provide the rationale to develop a strategy for targeting follicular viral-producing (Tfh) cells using antiviral chimeric antigen receptor (CAR) T cells co-expressing the follicular homing chemokine receptor CXCR5. We hypothesize that antiviral CAR/CXCR5-expressing T cells, when infused into an SIV-infected animal or an HIV-infected individual, will home to B cell follicles, suppress viral replication, and lead to long-term durable remission of SIV and HIV. To begin to test this hypothesis, we engineered gammaretroviral transduction vectors for co-expression of a bispecific anti-SIV CAR and rhesus macaque CXCR5. Viral suppression by CAR/CXCR5-transduced T cells was measured in vitro, and CXCR5-mediated migration was evaluated using both an in vitro transwell migration assay, as well as a novel ex vivo tissue migration assay. The functionality of the CAR/CXCR5 T cells was demonstrated through their potent suppression of SIVmac239 and SIVE660 replication in in vitro and migration to the ligand CXCL13 in vitro, and concentration in B cell follicles in tissues ex vivo. These novel antiviral immunotherapy products have the potential to provide long-term durable remission (functional cure) of HIV and SIV infections.

Original languageEnglish (US)
Article number492
JournalFrontiers in immunology
Volume9
Issue numberMAR
DOIs
StatePublished - Mar 20 2018

Fingerprint

Simian Immunodeficiency Virus
Virus Replication
T-Cell Antigen Receptor
B-Lymphocytes
Antigen Receptors
Antiviral Agents
HIV
Helper-Inducer T-Lymphocytes
HIV Infections
T-Lymphocytes
Chemokine Receptors
Virus Diseases
Macaca mulatta
Viral Load
Immunotherapy
Ligands
Viruses
In Vitro Techniques

Keywords

  • B cell follicles
  • CAR-T cells
  • CD8 T cells
  • CXCR5
  • Chimeric antigen receptor
  • HIV
  • HIV cure strategies
  • Simian immunodeficiency virus

Cite this

Simian immunodeficiency virus (SIV)-specific chimeric antigen receptor-T cells engineered to target B cell follicles and suppress SIV replication. / Haran, Kumudhini Preethi; Hajduczki, Agnes; Pampusch, Mary S.; Mwakalundwa, Gwantwa; Vargas-Inchaustegui, Diego A.; Rakasz, Eva G.; Connick, Elizabeth; Berger, Edward A.; Skinner, Pamela J.

In: Frontiers in immunology, Vol. 9, No. MAR, 492, 20.03.2018.

Research output: Contribution to journalArticle

Haran, Kumudhini Preethi ; Hajduczki, Agnes ; Pampusch, Mary S. ; Mwakalundwa, Gwantwa ; Vargas-Inchaustegui, Diego A. ; Rakasz, Eva G. ; Connick, Elizabeth ; Berger, Edward A. ; Skinner, Pamela J. / Simian immunodeficiency virus (SIV)-specific chimeric antigen receptor-T cells engineered to target B cell follicles and suppress SIV replication. In: Frontiers in immunology. 2018 ; Vol. 9, No. MAR.
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abstract = "There is a need to develop improved methods to treat and potentially cure HIV infection. During chronic HIV infection, replication is concentrated within T follicular helper cells (Tfh) located within B cell follicles, where low levels of virus-specific CTL permit ongoing viral replication. We previously showed that elevated levels of simian immunodeficiency virus (SIV)-specific CTL in B cell follicles are linked to both decreased levels of viral replication in follicles and decreased plasma viral loads. These findings provide the rationale to develop a strategy for targeting follicular viral-producing (Tfh) cells using antiviral chimeric antigen receptor (CAR) T cells co-expressing the follicular homing chemokine receptor CXCR5. We hypothesize that antiviral CAR/CXCR5-expressing T cells, when infused into an SIV-infected animal or an HIV-infected individual, will home to B cell follicles, suppress viral replication, and lead to long-term durable remission of SIV and HIV. To begin to test this hypothesis, we engineered gammaretroviral transduction vectors for co-expression of a bispecific anti-SIV CAR and rhesus macaque CXCR5. Viral suppression by CAR/CXCR5-transduced T cells was measured in vitro, and CXCR5-mediated migration was evaluated using both an in vitro transwell migration assay, as well as a novel ex vivo tissue migration assay. The functionality of the CAR/CXCR5 T cells was demonstrated through their potent suppression of SIVmac239 and SIVE660 replication in in vitro and migration to the ligand CXCL13 in vitro, and concentration in B cell follicles in tissues ex vivo. These novel antiviral immunotherapy products have the potential to provide long-term durable remission (functional cure) of HIV and SIV infections.",
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AU - Mwakalundwa, Gwantwa

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