HIV-Resistant Anti-HIV CAR T Cells
Cancer immunotherapy has been revolutionized by the development of chimeric antigen receptor T cells (CAR T cells). CAR T cells offer a potential novel mechanism by which prolonged immune surveillance, recognition, and killing of HIV-infected cells can be achieved, particularly when combined with latency-reversing agents. Anti-HIV CAR lymphocytes are attractive because they have potential to kill HIV-infected cells that have escaped endogenous immune responses, have been shown to have persistent activity for months to years, cross the blood brain barrier, and enter lymphoid tissue and bone marrow. This project investigates the potential of defined populations of “gene protected” anti-HIV CAR T cells to be a major component of a successful cure for HIV.
eCD4-Ig Based Therapy For
As a complementary approach to reducing the HIV reservoir, and to facilitate control of virus reactivating from a reduced but not fully eradicated reservoir, we are targeting reactivated reservoir cells for destruction by antibody-dependent cell-mediated cytotoxicity (ADCC) using eCD4-Ig, an extremely potent synthetic antibody constructed from the receptor and co-receptor structures recognized by HIV. eCD4-Ig has extremely broad reactivity, and we have shown that it may serve as a universal strategy for killing reactivated reservoir cells. In addition, eCD4-Ig works well as an AAV-expressed transgene, can be stably expressed in pre-clinical models for more than a year at concentrations that are protective against infection, and which may help suppress a reactivation of latent infection, thus contributing to a curative therapy.
Genetic Protection of T Cells After Therapeutic Vaccination
Developing a cure for HIV infection by clearing virus reservoirs, or preventing virus rebound following interruption of ART (post-treatment control), requires novel intervention strategies. Inducing a durable and effective HIV-specific immune response in the host, and making host cells resistant to infection, could prevent virus spread once residual latent viruses are activated. Our team has made great progress in genetic protection of stem cells and T cells, specifically through CCR5 disruption. Importantly, gene protection not only protects the gene-modified cells themselves, but also appears to lead to an improvement in overall immune function, including function of non-gene-modified cells. With this in mind, we are evaluating the ability of a therapeutic vaccine targeting conserved elements of the viral proteome (CE vaccine) to facilitate generation and then function of gene-protected T cells. As both CCR5 disruption and vaccination strategies are currently in clinical trials, the translational potential of this combinatorial approach is clear.