CCR5 receptor gene and HIV infection
PUBLISHED: April 2002
AUTHORS: Antonio Guilherme Fonseca Pacheco, (University of Pittsburgh)

  (14KB)

CCR5 GENE

The gene for CCR5 is located on chromosome 3 in the p21.3-p24  region. CCR5 is a chemokine receptor present in different cells, especially in macrophages, monocytes, and T cells, where it acts as a co-receptor for HIV-1 in these cells. Chemokines and their receptors are believed to be involved in the inflammatory response, mediating  leukocyte movement and activation.

PREVALENCE OF GENE VARIANTS

At least 23 alleles have been described for the coding region of this gene, and most of them are very rare. The most common and most studied is the 32 allele, a 32 base pair (bp) deletion that confers almost absolute protection from infection with macrophage tropic (M-tropic) viruses in homozygous individuals and provides an average 2 to 3 year delay in the progression to AIDS in those heterozygous for the deletion. The allele's prevalence varies by ethnicity, being as high as 10%-15% in Caucasians, ~2% in African Americans, and virtually absent in native Africans and East Asians (3,6). Several single nucleotide polymorphisms (SNPs) were described in the promoter region of CCR5, accounting for six different important haplotypes. Many studies showed that the 64I allele of another chemokine receptor coding gene, CCR2, is in very strong linkage disequilibrium with one allele of the promoter region of CCR5 (1), invariably in combination with CCR5+ (now named haplotype F*2). These findings led to the modern classification of 9 haplotypes for CCR5 (A, B, C, D, E, F*1, F*2, G*1, and G*2; the latter corresponding to the CCR232 allele) that actually encompass its open reading frame, the promoter region, and the CCR2 gene (3,8). Gonzales et al. have recently published world-wide distributions of these haplotypes, showing great variation in their frequencies (3).

DISEASE BURDEN

Ninety percent of the infections caused by HIV 1 involve the so-called M-tropic (or R5-tropic) strains. In addition to the CD4 receptor present in macrophages, monocytes, and T cells, these strains also need the presence of a CCR5 receptor on the cell surface to infect. The 32 bp deletion causes the resultant protein to be truncated and inactive, and individuals homozygous for the 32 allele present undetectable concentrations of the receptor, while heterozygous individuals have 20%-30% of the wild type concentrations (5,6). The result is that homozygous individuals exposed to M-tropic strains are protected from infection, while infected heterozygous individuals present a slower progression to both AIDS and death. In a cohort of 2,996 people, Marmor et al. showed only one seroconversion among 39 CCR532/ 32 participants, but this was a T-tropic strain that uses the CXCR4 receptor instead of the CCR5 receptor. In the same study, the risk ratio (RR) for seroconversion was 0.30 (95% Confidence Interval: 0.08-0.96) in the CCR532/+ group compared with the CCR5+/+ group when controlled for unprotected receptive anal sex (4). In another study that combined five different cohorts totaling 3,003 patients, Smith et al. showed that seropositive heterozygous individuals had a prolonged survival time to AIDS (Relative Hazard (RH) = 0.68, p = 0.002) and to death (RH = 0.67, p = 0.02) (7).

In a recent study by Tang et al., some features of the nine CCR5 haplotypes were studied, and the haplotype G * 2, especially the genotype A/G * 2, was more frequent in individuals highly exposed to HIV and persistently seronegative (OR = 0.54, 95% CI: 0.32-0.89) (8). Viral load during the first 42 months of infection was lower in G*2 carriers, especially among those with genotypes A/G * 2 and F *2/G*2). Progression to AIDS was also delayed for G * 2 carriers.

INTERACTIONS

Several factors interact in HIV 1 transmission since the infection depends on variables related to susceptibility, transmissibility, and host response to infection. Several other genes may play a role in the susceptibility of the cells to HIV infection. The role of gene expression of CCR5 chemokine ligands in HIV infection has been the subject of intense research, since the suppression of these ligands, secondary to CD8 + cell depletion in HIV-positive patients, has been demonstrated to lead, at least in part, to accelerated viral replication. Although there is strong evidence of potent inhibition of HIV replication in vitro, studying RANTES, MIP-1 and MIP-1ß expressions in HIV positive cohorts has shown conflicting results (2).

LABORATORY TESTS

Several different methods have been used for CCR5 genotyping, but the most common methods are DNA-PCR, followed by restriction fragment length polymorphism (RFLP) or sequencing.

POPULATION TESTING

To date, no recommendation on population testing has been issued. Since the major factor in HIV infection is exposure to the virus, protective measures against the exposure continue to be recommended as public health policy.

REFERENCES

1. Carrington, M., et al., Genetics of HIV-1 infection: chemokine receptor CCR5 polymorphism and its consequences. Hum Mol Genet, 1999. 8(10): p. 1939-45.
2. Gallo, R.C., A. Garzino-Demo, and A.L. DeVico, HIV infection and pathogenesis: what about chemokines? J Clin Immunol, 1999. 19(5): p. 293-9.
3. Gonzalez, E., et al., Global survey of genetic variation in CCR5, RANTES, and MIP-1alpha: impact on the epidemiology of the HIV-1 pandemic. Proc Natl Acad Sci U S A, 2001. 98(9): p. 5199-204.
4. Marmor, M., et al., Homozygous and heterozygous CCR5-Delta32 genotypes are associated with resistance to HIV infection. J Acquir Immune Defic Syndr, 2001. 27(5): p. 472-81.
5. McNicholl, J.M., et al., Host genes and HIV: the role of the chemokine receptor gene CCR5 and its allele. Emerg Infect Dis, 1997. 3(3): p. 261-71.
6. O'Brien, S.J. and J.P. Moore, The effect of genetic variation in chemokines and their receptors on HIV transmission and progression to AIDS. Immunol Rev, 2000. 177: p. 99-111.
7. Smith, M.W., et al., Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study. Science, 1997. 277(5328): p. 959-65.
8. Tang, J., et al., Distribution of chemokine receptor CCR2 and CCR5 genotypes and their relative contribution to human immunodeficiency virus type 1 (HIV-1) seroconversion, early HIV-1 RNA concentration in plasma, and later disease progression. J Virol. 2002 6(2):662-72.
   

WEBSITES

1. UNAIDS
2. JAMA HIV/AIDS Resource Center
3. Johns Hopkins AIDS Service
4. Centers for Disease Control and Prevention, Office of Genomics and Disease Prevention

Provides link to non-governmental sites and does not necessarily represent the views of the Centers  for Disease Control and Prevention.