Restoring Potent Antiviral Immune Responses (RePAIR) to Treat HIV Disease

Significance 

Millions of people worldwide are living with HIV/AIDS. For four decades antiretroviral drugs have restored quality of life to persons living with HIV and, in some cases, have even been used to prevent new infections. However, no approved treatments have yet cured HIV disease. A new cell and gene therapy targets an important reason why HIV remains uncured.

HIV infection causes a reduction in CD4 T cells and a near-complete destruction of HIV-specific CD4 T cells that are not recovered even after prolonged antiretroviral therapy. The loss of specific T cells inhibits all aspects of the antiviral immune response and allows HIV to persist and cause chronic disease. Previous studies showed that CD4 T cells play important roles in sustaining the responses of anti-HIV CD8 T cells and provide help to B cells that improves production of antibodies against HIV. HIV-specific CD4 T cells also manifest cell-mediated toxicity restricted to MHC class II expressing cells, an activity important for clearing persistent virus infections like HIV. Virus-specific CD4 and CD8 T cells have been used successfully for treating virus reactivation following bone marrow transplantation, chronic virus infections and cancer. It has been suggested that virus-specific CD4 T cells might be useful for controlling HIV and reducing the dependence on antiretroviral therapy. Despite years of virus-suppressive antiretroviral therapy in persons with HIV disease, the restoration of antigen-specific memory CD4 T cells falls far short of levels needed to support virus eradication and this explains why HIV persists in the body. To re-constitute immunity against HIV, therapeutic restoration of antigen-specific CD4 T cells is necessary. Reported studies on HIV-specific CD4 T cell therapy are few mainly due to challenges associated with obtaining amounts of HIV-specific and HIV-resistant CD4 T cells sufficient to treat the disease.

To address this challenge, scientists at American Gene Technologies International: Haishan Li, Tyler Lahusen, Lingzhi Xiao, Nidal Muvarak and led by C. David Pauza, PhD, together with Jana Blazkova and Tae-Wook Chun from the National Institute of Allergy and Infectious Diseases developed a process for efficient manufacturing of HIV-specific CD4 T cells that are resistant to HIV destruction. The study is published in the Journal Molecular Therapy: Methods and Clinical Development.

The research team devised a recombinant lentivirus vector (designated AGT103) that encodes inhibitory RNA targeted to the HIV coreceptor C-C chemokine receptor type 5 (CCR5) and HIV sequences in the Vif/Tat coding regions. They found that AGT103 reduced CCR5 levels on JC53 cells by more than 98%. AGT103 also reduced the expression of CCR5 without affecting other common cell-surface molecules, and expression of HIV Tat RNA or Vif protein was inhibited significantly by AGT103.

Transduction of JC53 cells with AGT103 caused the cells to resist CCR5-tropic HIV infection with protection of up to 93%. J1.1 cells, a model for inducible, latent HIV, were transduced with AGT103-GFP that lowered the amount of infectious HIV released after induction with TNF-α. In addition, transduction of primary human CD4 T cells with AGT103 provided dose dependent protection against HIV replication. The AGT103 vector also provided potent protection for primary CD4 T cells against a challenge with infectious CXCR4-tropic HIV.

Authors of this study designed and optimized a protocol to scale-up manufacturing of the cell product AGT103-T. The protocol involves increasing the levels of rare Gag-specific CD4 T cells found in peripheral blood mononuclear cells (PBMC) by nearly 1,000-times in the final product. This remarkable enrichment of HIV-specific CD4 T cells was achieved by stimulating PBMC with Gag peptides, then deleting non-target cells before transduction with the lentivirus vector AGT103. Final products are >90% CD4 T cells with up to 30% being Gag-specific CD4 T cells.

AGT103 is a promising new cell and gene therapy designed to treat HIV with a genetically modified cell product made from a person’s own T cells. With this study, the authors developed a novel, effective, and practical manufacturing platform for clinical cell products used as immunotherapeutic agents for treating HIV disease. The cell and gene therapeutic product is now being evaluated in a clinical trial (trial number NCT04561258, https://www.clinicaltrials.gov/).

 

Reference

Li H, Lahusen T, Xiao L, Muvarak N, Blazkova J, Chun TW, Pauza CD. Preclinical Development and Clinical-Scale Manufacturing of HIV Gag-Specific, Lentivirus Modified CD4 T Cells for HIV Functional Cure. Mol Ther Methods Clin Dev. 2020 May 3;17:1048-1060.

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