Despite the fact that people diagnosed with HIV who adhere to combination antiretroviral therapy can expect long-term survival, HIV persists in CD4+ T cells due to stable integration into the host genome, even in patients with undetectable viral load. A major objective in the field is to eradicate this latent viral reservoir. The current work by Yang and colleagues, representing a combined effort by an academic group and a biotechnology company, brings us one step closer to achieving this goal.
The authors draw upon a technology that they previously developed for redirecting T cells against cancer. They produced bispecific protein constructs comprising a pan–T cell antigen CD3 recognition domain on one side and a T cell receptor (TCR) against an immunodominant epitope of the HIV protein Gag, in the context of a common MHC class I molecule, on the other side. The TCR-peptide-MHC affinity was such that even very low amounts of the HIV protein could be recognized, which is important because the CD4+ T cells that harbor the viral reservoir tend to express only low levels of Gag. Binding CD3 conferred the ability to recruit polyclonal cytotoxic T cells, thus considerably increasing the pool of T cells that are capable of recognizing HIV. In a series of in vitro experiments, the authors showed that the redirected T cells could eliminate HIV-infected CD4+ T cells much more efficiently than the patients’ own naturally primed CD8+ T cells that were specific for the same Gag epitope. They also demonstrated that redirected CD8+ T cells inhibit HIV replication and clear HIV from resting CD4+ T cells.
One additional observation was that patients’ autologous T cells were less efficient than healthy donor T cells at attacking the viral reservoir. This observation is consistent with the known T cell exhaustion that occurs in chronically infected individuals and represents an important limitation of this technology. However, a distinct strength of this approach is the modular design of these bispecific constructs, which means that in future it will be possible to treat patients with cocktails of constructs that recruit T cells against a variety of HIV-associated epitopes, thus potentially circumventing HIV’s known propensity for developing escape mutants.
H. Yang et al., Elimination of latently HIV-infected cells from antiretroviral therapy-suppressed subjects by engineered immune-mobilizing T-cell receptors. Mol. Ther. 10.1038/mt.2016.114 (2016). [Abstract]
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