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HIV CAR Design and Construction

All products and services are For Research Use Only and CANNOT be used in the treatment or diagnosis of disease.

For decades, the treatment of HIV infection through cell and gene therapy has been a goal. Broadly neutralizing monoclonal antibodies (bNAbs) specific for HIV envelope glycoproteins provide a promising means of targeting HIV-infected cells. However, the HIV reservoir is still an obstacle to overcome difficulties to achieve HIV treatment. Several strategies to clear the reservoir have been developed, including the "kick-and-kill" method, which is based on the concept that reactivating the latent reservoir will allow the host's anti-HIV immune cells to be subsequently cleared. Robust immune response to reactivated HIV expressing cells is critical to the work of this strategy. The current focus of enhancing immunity against HIV is through the use of chimeric antigen receptors (CARs).

The latest advances in gene editing and chimeric antigen receptor (CAR) technology have created new therapeutic possibilities for many diseases. Currently, HIV-specific CARs are being applied to peripheral T cells, NK cells, and stem cells to enhance the ability to recognize and kill HIV-infected cells. At Creative Biolabs, we have a thorough understanding of the important aspects of anti-HIV CAR T cell development and provide a variety of new generation HIV directed CARs to promote the elimination of HIV.

Strategies to Optimize HIV CAR T Structure

Different types of anti-HIV chimeric antigen receptors.Figure 1. Different types of anti-HIV chimeric antigen receptors.

1. Optimized CAR T Structure: From Single to Multiple

CAR is composed of extracellular antigen binding domain, hinge, transmembrane domain, and intracellular signal transduction domain. The first-generation anti-HIV CAR used contains the extracellular domain of the CD4 molecule, which is connected to the single intracellular signaling domain CD3ζ. CD4-based CAR T cells have great advantages in binding affinity, and the possibility of virus escape is extremely small because CD4 is a natural ligand of HIV and is essential for virus replication. Recent studies have developed CD4ζCAR with advanced CAR design based on the concept that complete T cell activation depends on signal transduction through T cell receptors and costimulatory molecules. By including the intracellular signaling domain of costimulatory molecules (such as CD28, 4-1BB, CD127, and OX40), CAR T cells exhibit optimized survival, proliferation, and cytotoxic phenotypes. Another general strategy for HIV-infected cells is to use single-chain variable fragments (scFvs) of Env-specific antibodies as the extracellular part of the CAR. The ability to identify an increasing number of broadly neutralizing antibodies (bNAbs) against HIV has enhanced this strategy. These antibodies target various vulnerable sites of gp120 and gp41, including CD4 binding sites, V1/V2 loops, V3 ring, and gp41 membrane-outer region. Compared with CD4-based strategies, it has advantages because it eliminates the sensitivity of CAR T cells to HIV infection.

To reduce the potential threat of pre-existing escape mutants, bispecific CARs-duoCAR were developed, which are characterized by simultaneously recognizing two different Env epitopes. duoCAR is created by encoding a two-molecular CAR structure in a single lentiviral vector that can target HIV-1 envelope glycoproteins to multiple sites of a wide range of susceptibility. Multispecific anti-HIV duoCARs have shown significant efficacy in inhibiting cellular HIV infection, but they can also effectively eliminate peripheral blood mononuclear cells infected with bNAb-resistant HIV strains. Therefore, designing a multispecific anti-HIV duoCAR may be a promising method to overcome the HIV escape mechanism.

2. Protecting CAR T cells from HIV infection

Due to the extensive sequence diversity within Env, the binding affinity of the chimeric protein is directly proportional to its cytotoxic efficiency. By fusing the CAR structure into the sequence encoding HIV-1 fusion inhibitor (such as membrane-anchored C peptide or gp41 heptapeptide repeat 2 domain peptide), novel CAR has been developed to protect T cells from HIV infection. The integration of CAR into the CCR5 locus represents two fascinating birds, one stone approach for the production of uniform HIV-1-specific CAR T cells not recognized by HIV.

3. Guaranteed safety of anti-HIV CAR T cells

Cytokine storms are unlikely to occur in HIV-1-infected individuals because of the minimal amounts of antigen present on ART. Compared with bNAb-CAR, CD4-CAR may have more safety hazards, and CD4 is a natural ligand of MHC class II. However, a clinical trial showed that CD4 CAR T cells cannot target cells that express MHC class II. Even if anti-HIV CAR T cells fail to control viral rebound after treatment with potential reservoir activators, there are effective means to control the resulting cytokine storm, such as IL-6 blockade, and renewed ART treatment would be sufficient to suppress the rebound virus. The safety of anti-HIV CAR T cells can be further improved by carrying inducible suicide genes (such as herpes simplex virus TK and iCasp9), which can be used as a safety switch to 'turn off' anti-HIV CAR T cells if needed.

HIV CARs at Creative Biolabs

As the leading cell therapeutics biotech that provides cell therapy related services, Creative Biolabs masters the most advanced CAR design technology. We always keep in pace with the most advanced knowledge in the field and are capable of offering a broad range of CARs to meet your needs:

  • Multispecific HIV duoCAR
  • CD4 CAR
  • bNAb-based CAR
  • convertible CAR
  • CCR5 disruption HIV CAR

We also offer customized CAR design and construction services. For more detailed information, please feel free to contact us or directly sent us an inquiry.

All products and services are For Research Use Only and CANNOT be used in the treatment or diagnosis of disease.

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All products and services are For Research Use Only and CANNOT be used in the treatment or diagnosis of disease.

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