CCR5 Background

CCR5 – C-C motif chemokine receptor 5: C-C chemokine receptor type 5 (CCR5) is found on the surface of white blood cells. The CCR5 protein is part of the beta chemokine receptor family of integral membrane proteins. It is a G-protein-coupled receptor. It functions as a receptor for inflammatory CC chemokines and as a result, transduces a signal increasing the intracellular calcium ion level1,2

CCR5 & HIV-1: It is most commonly known for its role as a coreceptor of human immunodeficiency virus-1 (HIV-1). HIV-1 uses chemokine receptors such as CCR5 as coreceptors to enter immune cells due to their location on the surface of the host cell’s, which provide HIV a method of entry. HIV-1 envelope glycoprotein structure facilitates viral entry into the host cells3–5. The envelope protein mimics a chemokine giving HIV-1 the capability to bind to chemokine receptors. Knowledge of the mechanism by which HIV-1 interacts with CCR5 to cause infection has led scientists to attempt to develop therapeutic interventions to block CCR5 function. This class of HIV drugs is known as CCR5 receptor antagonists and interfere with the interaction between the envelope of HIV-1 and CCR5. These drugs are experimental and only one, Maraviroc, has been approved by the FDA for clinical use. 

CCR5 Evolution and Conservation: CCR5 is identified in 98 different species. Compiling the sequences as shown below we can identify multiple conserved sites on the protein.

CCR5-D32 (CCR5-Delta 32): Some individuals have an inherited variant in CCR5 known as Delta 32. Within CCR5 this is the most common variant throughout the world. The variant CCR5-D32 has an allele frequency of >10% in those from European descent but is present throughout all populations at lower frequencies. Overall, around 0.38% of individuals carry two copies of CCR5-D32, known as homozygous individuals, with those of European descent elevated to 0.91%.

CCR5-D32 is a 32-base-pair deletion in the DNA that results in shifting the code for reading RNA to protein codons. This shift results in p.Ser185IlefsTer32. This variant starts at amino acid 185, a serine (Ser), changing that position to isoleucine (Ile) followed by 31 amino acids that are not like CCR5 normal sequence. After that stretch there is a stop codon that terminates the protein. This loss of function variant results in a protein no longer able to be made, having three of seven transmembrane domains removed. Thus, there is no receptor for HIV-1 to infect white blood cells. Homozygosity for the Delta 32 variant has been found to result in immunity to the HIV-1 infection. Heterozygosity has been associated with resistance to HIV-1 infection and a slow progression of the disease to AIDS. Heterozygosity has always been associated with improved viral response to antiretroviral treatment. Although the Delta 32 variant can be beneficial to the host in the case of HIV-and related infections, it can be disadvantageous in others such as tick-borne encephalitis and West Nile virus6,7. This is because CCR5 interacts with different classes of pathogens by different mechanisms due to the complexity of the immune system’s response to infection. Research has speculated that the variant affects post-infection inflammatory process, which can injure tissues leading to further pathology and increasing lethality of infection, although much debate currently exists around this hypothesis.

Human CRISPR: In November 2018, He Jiankui announced that he had edited several human embryos using CRISPR-Cas9. The embryos were created during a clinical experiment in which the mom was HIV-1 negative, but the dad HIV-1 positive. He claimed that the goal of the experiment was to alter CCR5 using CRISPR-Cas9 technology to make offspring less susceptible to HIV-1 infection, mimicking the Delta 32 variant. These embryos resulted in a pregnancy leading to the birth of twin girls, Lulu and Nana. The process did not result in mutations identical to the delta 32 variant, and neither of the girls had identical copies of the CCR5 gene.

Ethics:  He’s experiment edited the genome of babies and has resulted in mutations in germline cells that can be passed to any of the girl’s future offspring. This means that any negative effects of the editing can now be passed on, propagating mutations not identical to the naturally occurring CCR5-D32 variant. These variants may have been unsuccessful in rendering CCR5 nonfunctional or may result in unpredicted side effects. It has already been shown that individuals with the CCR5-D32 variant are more susceptible to certain types of infections and have a more extreme secondary immune response as a result. Lulu and Nana may or not have these effects, and they may have additional side effects as the result of editing.

Ordering 3D Models

5 x 2.8 x 2 inch model

1 x 0.6 x 0.4 inch model

References:

1.             Lee B, Sharron M, Blanpain C, Doranz BJ, Vakili J, Setoh P, Berg E, Liu G, Guy HR, Durell SR, Parmentier M, Chang CN, Price K, Tsang M, Doms RW. Epitope mapping of CCR5 reveals multiple conformational states and distinct but overlapping structures involved in chemokine and coreceptor function. J Biol Chem. 1999 Apr 2;274(14):9617–9626. PMID: 10092648

2.             Oppermann M. Chemokine receptor CCR5: insights into structure, function, and regulation. Cell Signal. 2004 Nov;16(11):1201–1210. PMID: 15337520

3.             Hütter G, Nowak D, Mossner M, Ganepola S, Müssig A, Allers K, Schneider T, Hofmann J, Kücherer C, Blau O, Blau IW, Hofmann WK, Thiel E. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009 Feb 12;360(7):692–698. PMID: 19213682

4.             Huang Y, Paxton WA, Wolinsky SM, Neumann AU, Zhang L, He T, Kang S, Ceradini D, Jin Z, Yazdanbakhsh K, Kunstman K, Erickson D, Dragon E, Landau NR, Phair J, Ho DD, Koup RA. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat Med. 1996 Nov;2(11):1240–1243. PMID: 8898752

5.             He J, Chen Y, Farzan M, Choe H, Ohagen A, Gartner S, Busciglio J, Yang X, Hofmann W, Newman W, Mackay CR, Sodroski J, Gabuzda D. CCR3 and CCR5 are co-receptors for HIV-1 infection of microglia. Nature. 1997 Feb 13;385(6617):645–649. PMID: 9024664

6.             Glass WG, McDermott DH, Lim JK, Lekhong S, Yu SF, Frank WA, Pape J, Cheshier RC, Murphy PM. CCR5 deficiency increases risk of symptomatic West Nile virus infection. J Exp Med. 2006 Jan 23;203(1):35–40. PMCID: PMC2118086

7.             Glass WG, Lim JK, Cholera R, Pletnev AG, Gao J-L, Murphy PM. Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection. J Exp Med. 2005 Oct 17;202(8):1087–1098. PMCID: PMC2213214