Table 1.

Approaches to HIV-Specific Adoptive T-Cell Therapy

Approach	Ex Vivo Expanded HIV-Specific T Cells	HIV-Specific TCR Redirected T-Cell Therapy	HIV-Specific CAR Redirected T-Cell Therapy
Genome editing	No genome editing	Site-specific TCR/CAR integrate via dsDNA break and homology-directed repair using AAV donor template
		Retroviral/lentiviral transduction with vector containing TCR/CAR To date, no serious adverse events reported due to genotoxicity caused by engineering T cells
Cell expansion	Multipeptide stimulation via autologous APCs	Polyclonal T-cell stimulation using artificial APCs or anti-CD3/CD28 antibody-coated beads
Antigen recognition	Ex vivo expanded HIV-specific T cells react to a variety of distinct HIV-derived epitopes Responses are restricted to the individual’s HLA haplotype	TCR transgenic T cells recognize a single epitope comprising 8–11 amino acids derived from a conserved region in the HIV genome	CARs recognize infected cells independent of HLA/peptide presentation Antigen recognition moiety of the CAR (CD4- or scFv-based) targets HIVENV expressed on the cell surface
HIV escape	Constrains virus escape by restoring broad T-cell responses Latent HIV may harbor preexisting mutations that render infected cells insensitive to therapy	Target conserved region in the genome where mutations likely impair viral fitness Infusion of T cells with multiple specificities will further constrain virus escape Affinity-enhanced TCRs may limit virus escape but could result in off-target toxicity	Escape from CD4-based CAR likely imposes a fitness loss as mutations that abrogate CD4 binding will compromise viral entry scFv-based CARs will likely select for resistant virus much like the infusion of neutralizing antibodies CAR T cells expressing unique HIV-specific scFvs will likely be required to prevent escape
HIV accessory proteins	HIVNEF and HIVVPU prevent the surface expression of HLA molecules Reduction in peptide-HLA complexes on infected cell surface impairs TCR T-cell recognition and killing		CAR T cells recognize infected cells independent of HLA and are not affected by HIV-induced HLA downregulation
Function and exhaustion	Failure to control HIV after ART cessation will impair TCR T-cell function due to persistent exposure to viral antigen Collapse of CD4 T-cell help from depletion of HIV-specific CD4 T cells will further impair the function of infused TCR T cells		Integration of costimulatory domains (ie, 4-1BB) augments CAR T-cell function and susceptibility to exhaustion CD4- and scFv-based CAR T cells are susceptible to infection but can become resistant (ie, by genetic disruption of HIV coreceptor CCR5)

Abbreviations: AAV, adeno-associated virus; APC, antigen presenting cell; ART, antiretroviral therapy; CAR, chimeric antigen receptor; dsDNA, double-stranded DNA; HIV, human immunodeficiency virus; scFv, single-chain variable fragment; TCR, T-cell receptor.