Novel cell and gene therapies for HIV

Abstract

Highly active antiretroviral therapy dramatically improves survival in HIV-infected patients. However, persistence of HIV in reservoirs has necessitated lifelong treatment that can be complicated by cumulative toxicities, incomplete immune restoration, and the emergence of drug-resistant escape mutants. Cell and gene therapies offer the promise of preventing progressive HIV infection by interfering with HIV replication in the absence of chronic antiviral therapy. Individuals homozygous for a deletion in the CCR5 gene (CCR5Δ32) are largely resistant to infection from R5-topic HIV-1 strains, which are most commonly transmitted. A recent report that an HIV-infected patient with relapsed acute myelogenous leukemia was effectively cured from HIV infection after transplantation of hematopoietic stem/progenitor cells (HSC) from a CCR5Δ32 homozygous donor has generated renewed interest in developing treatment strategies that target viral reservoirs and generate HIV resistance in a patient's own cells. Although the development of cell-based and gene transfer therapies has been slow, progress in a number of areas is evident. Advances in the fields of gene-targeting strategies, T-cell-based approaches, and HSCs have been encouraging, and a series of ongoing and planned trials to establish proof of concept for strategies that could lead to successful cell and gene therapies for HIV are under way. The eventual goal of these studies is to eliminate latent viral reservoirs and the need for lifelong antiretroviral therapy.

Figure 1.

Zinc finger nucleases. (A) ZFNs bind CCR5 target sequence (underlined), and create a five-base-pair double-stranded staggered cut. (B) The double-stranded break is repaired by the error-prone nonhomologous end-joining (NHEJ) repair pathway. (C) The NHEJ results in a variety of insertions or deletions that disrupt the open reading frame (ORF). In the case of the CCR5 ZFNs, the most common repair leads to a 5-pb duplication (boxed). This insertion introduces two adjacent stop codons in the ORF that result in premature termination. (Figure adapted from Cannon and June 2011; reprinted, with permission, from the author.)

Figure 2.

First clinical application of CCR5 ZFNs (protocol NCT00842634; see text).