Current progress and challenges in HIV gene therapy

Abstract

HIV-1 causes AIDS, a syndrome that affects millions of people globally. Existing HAART is efficient in slowing down disease progression but cannot eradicate the virus. Furthermore the severity of the side effects and the emergence of drug-resistant mutants call for better therapy. Gene therapy serves as an attractive alternative as it reconstitutes the immune system with HIV-resistant cells and could thereby provide a potential cure. The feasibility of this approach was first demonstrated with the 'Berlin patient', who was functionally cured from HIV/AIDS with undetectable HIV-1 viral load after transplantation of bone marrow harboring a naturally occurring CCR5 mutation that blocks viral entry. Here, we give an overview of the current status of HIV gene therapy and remaining challenges and obstacles.

Figure 1. The HIV-1 life cycle

DNA is shown in blue while RNA is shown in pink. (A) Adsorption. The HIV-1 gp120 on the surface of the virion binds to the CD4 receptor on helper T cells, macrophages and dendritic cells, and either the α-chemokine receptor CXCR4 (T cell-tropic) or the β-chemokine receptor CCR5 coreceptor (macrophage-tropic). (B) Fusion. (C) Uncoating. (D) Reverse transcription of the viral RNA genome into cDNA. (E) Formation of the pre-integration complex. (F) Nuclear import of pre-integration complex. (G) Integration of viral cDNA into the host genome to form the provirus. (H) Transcription of the proviral DNA. Although the HIV promoter embedded in the 5′ long terminal repeats is functional and able to recruit the host’s transcription machinery, the elongation efficiency is very low, resulting in production of short and early-terminated transcripts. Additionally, most of the mRNA transcripts are spliced multiple times at this stage by the cellular machinery, and as a result, mRNAs encoding Tat and Rev proteins are produced. (I) Translation of Tat and Rev. (J) Import of Tat and Rev into the nucleus. The HIV Tat enhances transcription elongation by interacting with the transactivation response element in the 5′ end of HIV transcripts to increase the number of full-length transcripts. (K) Rev facilitates the export of full-length HIV-1 RNA genome for packaging. (L) Rev exports unspliced and singly spliced HIV-1 transcripts to the cytoplasm by interacting with the Rev-response element for the translation of late gene products, including Gag and Gag–Pol (which later cleaves into viral enzymes, including protease and reverse transcriptase), Env, and accessory proteins Vpu, Vpr and Vif. (M) Assembly. The assembly of a new HIV virion takes place at the plasma membrane of the host cell, involving two copies of the viral RNA genome and the Gag and Gag–Pol polyproteins. The proper selection of the viral genome for packaging depends on interaction of the packaging signal, the ψ locus, on the RNA, with the nucleocapsid domain of the Gag polyprotein. (N) Budding. (O) Maturation. The viral protease cleaves the HIV polyproteins into functional protein and enzyme components during maturation to form fully infectious virions. Vif: Viral infectivity factor; Vpr: Viral protein R; Vpu: Viral protein U.