C-C chemokine receptor type five (CCR5): An emerging target for the control of HIV infection

Abstract

When HIV was initially discovered as the causative agent of AIDS, many expected to find a vaccine within a few years. This has however proven to be elusive; it has been approximately 30 years since HIV was first discovered, and a suitable vaccine is still not in effect. In 2009, a paper published by Hutter et al. reported on a bone marrow transplant performed on an HIV positive individual using stem cells that were derived from a donor who was homozygous for a mutation in the CCR5 gene known as CCR5 delta-32 (Δ32) (Hütter et al., 2009). The HIV positive individual became HIV negative and remained free of viral detection after transplantation despite having halted anti-retroviral (ARV) treatment. This review will focus on CCR5 as a key component in HIV immunity and will discuss the role of CCR5 in the control of HIV infection.

Keywords: CCR5; HIV; Therapeutics; Δ32.

Fig. 1

A. Structure of a mature HIV virion. B. Structure of the HIV genome.

Fig. 2

Diagram illustrating HIV replication. (A) The virus glycoprotein receptors bind to host cell CD4 and a co-receptor CCR5. (B) Fusion of the virus with the host cell membrane results in viral uncoating and the release of the viral nucleocapsid into the cytoplasm. (C) The enzyme reverse transcriptase converts the single stranded RNA into double stranded DNA. (D) The viral DNA is transported to the host nucleus where it is integrated into the host's DNA. (E) Viral DNA is transcribed and translated using host cell machinery and then cleaved by viral protease into functional viral proteins. (F) Viral RNA and proteins assemble at the cell surface and bud off the cellular membrane.

Fig. 3

CCR5 protein structure. Protein structure of CCR5 indicating regions of importance with the dotted line showing disulfide linkage, the boxed S and P indicating sulfate and phosphate moieties and the three zig zag lines showing palmitoylation of C moieties. The DRYLAVVH sequence is highlighted in blue. Image adapted from Blanpain and Parmentier, 2000.

Fig. 4

Structure of the CCR5 gene.

Fig. 5

Diagram of the differences between wild-type CCR5 and ∆32. Illustration of the region involving the ∆32 mutation with the upper section showing the translation of the wild type CCR5 protein while the lower section demonstrates the translation of the mutant protein. The red highlighted region in the wild type sequence refers to the region deleted in ∆32. The red highlighted region in the mutant protein sequence refers to the novel amino acids inserted followed by the stop codon.