Genetic therapies against HIV

Abstract

Highly active antiretroviral therapy prolongs the life of HIV-infected individuals, but it requires lifelong treatment and results in cumulative toxicities and viral-escape mutants. Gene therapy offers the promise of preventing progressive HIV infection by sustained interference with viral replication in the absence of chronic chemotherapy. Gene-targeting strategies are being developed with RNA-based agents, such as ribozymes, antisense, RNA aptamers and small interfering RNA, and protein-based agents, such as the mutant HIV Rev protein M10, fusion inhibitors and zinc-finger nucleases. Recent advances in T-cell-based strategies include gene-modified HIV-resistant T cells, lentiviral gene delivery, CD8(+) T cells, T bodies and engineered T-cell receptors. HIV-resistant hematopoietic stem cells have the potential to protect all cell types susceptible to HIV infection. The emergence of viral resistance can be addressed by therapies that use combinations of genetic agents and that inhibit both viral and host targets. Many of these strategies are being tested in ongoing and planned clinical trials.

Figure 1

HIV life cycle. (1) HIV binds to CD4 and co-receptors CCR5 and CXCR4 and is internalized. (2) Uncoating of virus. (3) Reverse transcription. (4) Integration into host chromosomal DNA. (5) Expression of early viral proteins from multiply spliced mRNAs. (6) Expression of late mRNAs encoding the structural proteins Env, Gag, Pol and integrase. (7) Packaging of unspliced genomic RNA and release of viral particles.

Figure 2

Inhibitory agents used in HIV hematopoietic cell gene therapy trials.

Figure 3

Adoptive immunotherapy strategies with gene-modified T cells and HS cells. Gene transfer approaches have tested engineered T cells and HS cells. Lymphodepletion enhances engraftment of both cell types. Other strategies under consideration include the use of common lymphoid progenitor cells (CLPs). PBMC, peripheral blood mononuclear cell.