Challenges and Opportunities of Using Adoptive T-Cell Therapy as Part of an HIV Cure Strategy

Abstract

HIV-infected individuals successfully controlling viral replication via antiretroviral therapy often have a compromised HIV-specific T-cell immune response due to the lack of CD4 T-cell help, viral escape, T-cell exhaustion, and reduction in numbers due to the withdrawal of cognate antigen. A successful HIV cure strategy will likely involve a durable and potent police force that can effectively recognize and eliminate remaining virus that may emerge decades after an individual undergoes an HIV cure regimen. T cells are ideally suited to serve in this role, but given the state of the HIV-specific T-cell response, it is unclear how to best restore HIV-specific T-cell activity prior initiation of a HIV cure strategy. Here, we review several strategies of generating HIV-specific T cells ex vivo that are currently being tested in the clinic and discuss how infused T cells can be part of an HIV cure strategy.

Keywords: T-cell exhaustion; T-cell receptor; antiretroviral therapy; chimeric antigen receptor; ex vivo T-cell expansion; human-immunodeficiency-virus; latency reversing agent.

Figure 1.

Cartoon depicting current adoptive T-cell therapies for human immunodeficiency virus (HIV) infection. Top (purple): Natural T cells from HIV-infected or seronegative individuals are stimulated ex vivo with HIV peptide pool targeting conserved regions of HIV. The expanded cell product can be infused as a preventative vaccine or as part of an HIV cure strategy. Bottom right (yellow): T cells are gene-engineered to express HIV-specific T-cell receptors (TCRs) that effectively controls HIV replication. Most major histocompatibility complex (MHC) class I restricted TCRs would have to be affinity enhanced in order to function in CD4 T cells. This strategy would only be effective in individuals harboring the correct MHC allele and, presumably, several populations of unique HIV-specific TCR-expressing T cells would need to be infused to prevent viral escape. Bottom left (green): T cells are gene-engineered to express a chimeric antigen receptor (CAR) that provides HLA-independent targeting HIV_Env. Shown here is a CAR that uses CD4 or single chain antibody (scFv) to bind HIV_ENV. Each of these approaches can work in CD4 and CD8 T cells and can be linked to costimulatory domains to further enhance the potency, expansion, and survival of these CAR T-cell products in vivo.