RANTES (regulated upon activation, normal T cell expressed and secreted) is a CC chemokine that chemoattracts leukocytes. RANTES and the related chemokines, macrophage inflammatory protein (MIP)-1α and MIP-1β, these are the major HIV suppressive factors produced by CD8+T cells [1,2]. This fact facilitated the identification of the RANTES, MIP-1α and MIP-1β receptor, CCR5, as the major cellular entry co-factor with CD4 for primary and macrophage-tropic HIV isolates [3–7], extending the earlier discovery of a T cell line-tropic HIV-specific co-receptor, the chemokine receptor CXCR4 .
RANTES acts by blocking binding of the HIV envelope glycoprotein gp120 to CCR5 and by reducing surface levels of CCR5 . However, signalling induced by RANTES may paradoxically increase CXCR4 tropic HIV replication and may facilitate the spread of HIV from cell to cell [10,11].
Both CCR5 and RANTES expression levels vary among individuals, and this may affect the risk of HIV transmission and progression [12,13]. The basis for this variation includes genetic polymorphism. With respect to CCR5, three genetic polymorphisms have been identified, two in the promoter (59029-G/A, 59356-C/T) and one in the open reading frame (CCR5Δ32), which are associated with altered disease outcome in cohorts exposed to HIV [14–21].
Two other polymorphisms, designated CCR2-64I, which affects the open reading frame of the minor HIV co-receptor CCR2, and SDF1-3′A, which affects the 3′ untranslated region of the CXCR4 ligand SDF-1, have been associated with a reduced rate of HIV disease progression [22–26]. However, their mechanisms of action have not been defined.
With respect to RANTES, CD4+T cells from highly exposed-uninfected individuals produce increased amounts compared with random blood donor controls [27,28], whereas immortalized CD4+T cells from AIDS patients produce much less RANTES than those from long-term non-progressors [29,30]. However, a recent study  measured RANTES in serum samples and found that higher levels of RANTES were associated with faster progression.
At the genetic level, a variant RANTES promoter haplotype named ‘−403A, −28G’ has been associated with a decreased rate of CD4+T cell decline among HIV-infected Japanese individuals with hemophilia, and exhibited increased promoter activity when tested by promoter assay in U937 or Jurkat cells [32,33]. Here we provide evidence extending the effect of the −403A RANTES promoter polymorphism on HIV progression to Caucasians and homosexual men, and also present the first evidence that this polymorphism is a risk factor for HIV transmission.
Materials and methods
Participants in the study were anonymous blood donors from the Warren Grant Magnuson Clinical Center at the National Institutes of Health and the American Red Cross, anonymous blood donors from West Africa collected for onchocerciasis epidemiology research , and participants in the Multicenter AIDS Cohort Study (MACS) studied under an approved protocol [34,35]. Blood donors in all cohorts were classified into self-described racial groups. Genomic DNA was purified from peripheral whole blood or purified peripheral blood mononuclear cells as previously described . All samples that yielded polymerase chain reaction product were genotyped by the method described below and used in the presented data. More than 95% of all samples were informative at both polymorphic sites.
The MACS study began in 1984–1985 and now includes over 5000 men who have had biannual follow-up at four centers in the USA. The exposed-uninfected cohort (n = 123) used in this paper is the same as in our previous publication describing the effects of CCR5Δ32 on HIV transmission . It includes all available MACS participants in the highest 10% of risk for HIV infection, as defined by the number of anal receptive intercourse partners in the 2.5 years before their second MACS visit (n = 95) . An additional 28 men were included who were not in the highest 10% of exposure risk but who are believed to have had an abortive infection with HIV . These individuals are exposed uninfected because they have remained seronegative and asymptomatic despite a transient ability to culture HIV.
Other MACS participants included in this study were HIV-positive (n = 672). Of these, 506 were seroconverters, defined as individuals who were HIV-1 seronegative at the time of enrolment in the study who subsequently seroconverted. However, only individuals with less than 9 months’ elapsed time between testing HIV negative and positive were included in the seroconverter group progression analysis (n = 404) to ensure a uniform study population and to be consistent with our previous publications on HIV progression [14,21]. The time of infection was chosen as the midpoint between the date of the first HIV seropositive visit and the date of the last negative HIV-1 blood sample. When analysing progression effects, a cut-off date of 1 January 1996 was used to avoid possible confounding effects of highly active antiretroviral therapy. The remaining 266 HIV-positive subjects under study did not meet the seroconverter definition for the progression analysis (i.e. they entered the study seropositive or had more than 9 months’ time elapsed between their last HIV seronegative and first HIV seropositive dates). The demographic characteristics for the exposed-uninfected and HIV-positive cohorts were similar (median age 34.2 and 31.2 years and 89.4 and 87.5% Caucasian, respectively). The CD4 cell count decline was analysed using linear regression to calculate the CD4 cell count slope from the date of the third seropositive visit until the participant initiated potent antiretroviral therapy. Because at least two CD4 cell counts during this period were needed to calculate the slope, this eliminated 45 of the 404 seroconverters from the analysis.
In this paper the RANTES gene sequence is enumerated according to Nomiyama et al.  (accession number AF088219). Using single-strand conformation polymorphism and genomic DNA, we recently identified two dimorphic single nucleotide polymorphisms (SNP) at sites 28 and 403 base pairs (bp) 5′ of the transcription start point, as defined by Nelson et al. , by screening a 944 bp region of the RANTES promoter region from 40 individuals. Samples that exhibited variation in banding patterns were then sequenced using the dye terminator cycle sequencing kit (Applied Biosystems, Foster City, CA, USA) and the novel alleles −403A and −28G were deposited in the European Molecular Biology Laboratory, accession numbers AJ007391and AJ007462 [40,41]. Genotyping of all samples was by polymerase chain reaction restriction fragment length polymorphism as previously described [40,41].
The differences in compound genotypic and haplotypic frequencies for the RANTES promoter were examined for significance using the Pearson chi-square test. HIV progression was analysed using Kaplan–Meier estimates of time to CD4+T lymphocyte counts of less than 200 cells/μl or a CD4 percentage of less than 14, AIDS-1993 (as determined by the US Centers for Disease Control), Clinical AIDS (criterion exactly the same as AIDS-1993 except that the CD4+T cell criterion is eliminated), and death. The determination of the significance of survival curves was based on Cox proportional hazards models. The effects on CD4 cell count decline were analysed using a Wilcoxon rank sum test.
We and others have previously identified RANTES promoter alleles that form compound genotypes [32,40,41]. Here we first analysed the distribution of the RANTES compound genotypes in different racial and clinical groups (Table 1). The two SNP are in complete linkage disequilibrium such that only three haplotypes are seen rather than the four that are theoretically possible. In particular, all individuals with a genotype of G/G at the −403 position also had a C/C at the −28 position, and all those with a G/G at the −28 position also had an A/A at the −403 position. Therefore, in agreement with Liu et al. , we did not observe any individuals with a −403G, −28G haplotype. This is probably due to a lack of cross-over events because of the close physical proximity of the two polymorphisms and the way that these two SNP have arisen in human evolution. An alternative but less likely explanation could be that the −403G, −28G haplotype markedly diminishes reproductive fitness.
Haplotype −403G, −28C was observed at high frequency in all racial groups tested (47–81%). Haplotype –403A, −28C was found at somewhat lower frequency and with much greater variability among racial groups, e.g. a two to threefold difference between Caucasian and Black individuals. Haplotype –403A, −28G was almost never observed in Black and Hispanic individuals and was relatively uncommon in Caucasians (4%) (Table 1). Allelic and genotypic frequencies of the −28 and −403 polymorphisms were in Hardy–Weinberg equilibrium within each racial group of random donors.
We next analysed the two most common compound genotype frequencies in exposed-uninfected and HIV-positive subjects from the MACS (Table 2). These were designated G1 (−403G/G, −28C/C) and G4 (−403G/A, −28C/C) and were found in 67 and 23% of Caucasian random blood donors, respectively. Because G1 and G4 together represented over 90% of the MACS participants, the remaining compound genotypes were too rare to make significant comparisons, and could be considered to have a negligible result on the analysis and were therefore excluded. We previously reported that the homozygous CCR5Δ32 genotype was enriched among exposed-uninfected individuals relative to random blood donors (5 versus 1%), and was absent among HIV-positive individuals . We now found that the RANTES G4 compound genotype was more common in MACS seroconverter versus exposed-uninfected participants (30.0 versus 21.1%). Conversely, the G1 compound genotype was more common in exposed-uninfected versus HIV-positive MACS participants (72.4 versus 59.9%;Table 2). The reciprocal skewing of these genotypic frequencies was statistically significant [odds ratio (OR) 1.72, P = 0.016]. Because CCR5Δ32 homozygosity is known to diminish the probability of HIV transmission, and CCR5Δ32 heterozygotes are known to have diminished levels of CCR5 on the cell surface, we reasoned that any effects of RANTES promoter polymorphism on transmission might be more evident if we excluded from consideration all individuals that had a CCR5Δ32 allele (~ 20% of the sample) . As shown in Table 2, this caused a small increase in the difference in frequency for both genotype groups in seroconverter versus exposed-uninfected groups (G4: 31.4% in HIV-positive versus 19.1% in exposed-uninfected; and G1: 75.3% in exposed-uninfected versus 58.1% in HIV-positive; OR 2.13, P = 0.005).
Because of the variation in allele frequencies in different racial groups, we next limited the analysis to Caucasian individuals who lacked CCR5Δ32. Despite the lower numbers of individuals available for comparison, the difference in genotype frequencies persisted in seroconverter versus exposed-uninfected comparisons and remained significant (G4: 29.8% in HIV-positive versus 17.7% in exposed-uninfected; and G1: 78.5% in exposed-uninfected versus 62.5% in HIV-positive, OR 2.11, P = 0.011). Racial bias in the comparison groups could thus not explain the results. Differences in haplotype frequencies in HIV-positive versus exposed-uninfected groups followed the same pattern and magnitude as for the compound genotype analysis (Table 2). When the exposed-uninfected group studied was limited to the 95 MACS participants in the top 10% of risk, excluding the 28 abortively HIV-infected individuals, the results still showed an approximately twofold difference in risk of initial infection according to RANTES promoter genotype (OR 1.94;P = 0.047).
In Caucasian random blood donors who lacked CCR5Δ32, frequencies for each of these two compound genotypes were intermediate between those of the exposed-uninfected and HIV-positive groups. This is consistent with a selective pressure acting to enrich the −403G, −28C haplotype in exposed-uninfected populations while depleting it in HIV-positive populations, and vice versa for the −403A, −28C haplotype. Collectively, these data strongly suggest that the −403A allele is a dominant risk factor for HIV transmission.
Finally, we tested the effects of RANTES promoter polymorphism on HIV progression using all eligible seroconverters from the MACS cohort. These individuals have a very precisely defined date of infection because they entered the study HIV seronegative, were tested every 6 months, and were subsequently observed to be HIV seropositive. Therefore, these individuals are an ideal cohort to study the effects of a genotype on progression rate. MACS seroconverters possessing a G4 compound genotype progressed more slowly to AIDS-1993 than those with the G1 compound genotype. Although the difference did not reach statistical significance [median time to AIDS 1993: 7.1 versus 5.6 years; relative hazard (RH) 0.79;P = 0.078], it was similar in magnitude to the effect of CCR5Δ32. When seroconverters possessing a CCR5Δ32 allele were removed from the analysis, the difference reached statistical significance (median time to AIDS-1993 7.6 versus 5.4 years; RH 0.65, P = 0.007) (Fig. 1). A significant difference in outcome was also observed when the endpoint of CD4 T lymphocyte counts of less than 200 cells/μl or a CD4 cell count percentage of less than 14 was used. MACS seroconverters lacking CCR5Δ32 and possessing a G4 compound genotype thus progressed significantly more slowly to this endpoint than those with the G1 compound genotype (median time to endpoint 10.3 versus 6.1 years; RH 0.55, P = 0.001). When clinical AIDS (similar to the Centers for Disease Control AIDS-1987 definition) was used as an endpoint with the seroconverters lacking CCR5Δ32, the difference was smaller and did not reach significance but exhibited the same trend (median time to clinical AIDS 9.4 versus 8.0 years, RH 0.78, P = 0.17). Time to death was not significantly different between the two groups (RH 0.92, P = 0.68). When the multivariate analysis was carried out controlling for CCR2-V64I the RH and P values were similar to the uncensored analysis. MACS seroconverters possessing a G4 compound genotype thus still progressed significantly more slowly to AIDS-1993 than those with the G1 compound genotype (median time to AIDS-1993 7.2 versus 5.4 years; RH 0.63, P = 0.006).
Our results show that RANTES promoter polymorphism −403G/A is a risk factor for HIV transmission and progression, and provide the first genetic evidence in support of the hypothesis that variation in the HIV co-receptor ligands can modulate the risk of HIV transmission. Because RANTES can block the HIV co-receptor activity of CCR5 in vitro, it is reasonable to postulate that the effects of RANTES promoter polymorphism are mediated directly, through modulation of RANTES transcription and protein production. The eightfold increase of promoter activity reported by Nickel et al.  for the −403A construct versus the −403G construct after transfection of the CD4+T cell line Jurkat, would be compatible with previous observations that slower HIV progressing populations have CD4 cells that secrete more RANTES, and our current finding that −403A individuals progress more slowly to AIDS [29,30,33]. The presumed mechanism would be the differential blockade of HIV access to CCR5 through increased RANTES, resulting in slowed HIV replication. If this is the mechanism of action, it would also lend support to the idea that RANTES or RANTES analogue treatment of HIV patients could have beneficial effects, despite worries about stimulating the replication of CXCR4 using viruses . Alternatively, it is important to consider the possibility that RANTES polymorphism could influence disease progression by immune mechanisms related to CD4+T cell depletion, rather than through viral replication per se.
Not only may the effects of a genetic risk factor in disease vary in penetrance, depending on both environmental and host factors, it may also conceivably have opposite effects on different aspects of pathogenesis. Therefore, in our study, we found that, compared with the −403A allele, the −403G allele was associated with decreased susceptibility to HIV transmission but an increased rate of HIV progression in HIV-positive individuals. Understanding the mechanism may provide important clues for the safety and applicability of future therapeutic or preventative interventions involving chemokine analogues.
Our association of the −403A allele with an increased risk of transmission is also somewhat surprising given the previous in-vitro finding that CD4 cells from exposed-uninfected individuals secrete more CC chemokines when exposed to HIV antigens [27,28]. This may reflect differential expression of relevant transcription factors in epithelial or mesothelial cells versus T cells and macrophages. The same genetic background may thus support different levels of RANTES production at different sites in different cells and at different times. Alternatively, it is possible that increased RANTES at the mucosal surface or in submucosal areas may actually facilitate viral replication or HIV transfer from cell to cell through CCR5 or other RANTES receptor signalling, by enhancing cellular inflammation, or by other indirect effects. This would be consistent with a study in which RANTES treatment enhanced the transfer of HIV from human umbilical vein endothelial cells to T cells in co-culture , suggesting that RANTES, like other pro-inflammatory cytokines, could stimulate the spread of HIV across tissue barriers.
It is also possible that an apparent association with disease outcome is actually caused by linkage of the −403A allele to other polymorphic sites. The RANTES gene is on chromosome 17 clustered with many other CC chemokine genes; however, all other chemokine system polymorphisms known to be associated with altered HIV outcome are located on other chromosomes, ruling out linkage at least to these polymorphisms as a mechanistic explanation . Our results suggest a potential mechanism to explain HIV resistance in a portion of the 95% of MACS exposed-uninfected individuals who are not CCR5Δ32 homozygotes . However, it is important to realize that any protection of a certain genotype is relative and not absolute. Even among CCR5Δ32 homozygotes, who have no functional CCR5, a growing number of HIV-infected individuals have been identified [42,43].
As mentioned in the Introduction, Liu et al.  have reported both polymorphisms studied here and found an association of the RANTES −403A, −28G haplotype with slower CD4 cell count decline in a Japanese cohort. Our study had only 17 seroconverters with the −403A, −28G haplotype, and thus may have been underpowered to see a small or modest effect of this haplotype on the HIV progression rate. However, in agreement with Liu et al. , we did see a reduction in the rate of decline of CD4+T cells in the few individuals who possessed a −403A, −28G-containing haplotype versus all others that could be analysed, although it did not quite reach statistical significance (n = 15, median of −37.28 versus −66.76/year, P = 0.08). This suggests that the −28G allele may also have effects on HIV progression. In contrast to our results, risk of HIV transmission did not significantly differ between individuals with G1 and G4 RANTES genotypes in the Japanese hemophiliacs studied by Liu, et al. These authors did not study the relationship of these specific genotypes with HIV disease progression rate.
There are two important differences between our study and that of Liu et al.  that must be considered in interpreting the different results regarding transmission: first, Liu et al.  studied primarily Japanese individuals with hemophilia, whereas we focused on Caucasian men who have sex with men; and second, their HIV-uninfected group included only 50 individuals with possible exposure to HIV, whereas ours included 123 individuals with high exposure. Despite the differences, it is important to note that both studies support the idea that RANTES promoter polymorphism modulates risk in HIV disease. Differences in risk based on race, the type of exposure, and cohort composition and definition have also been reported previously for the CCR5Δ32, SDF1-3′ A and CCR2-64I polymorphisms [17–26].
It is interesting to note the much higher frequency of the −403A allele in Black African than in Caucasian and Asian individuals. This suggests that there may exist or may have existed a strong selective pressure in favor of this allele. This may have involved differential susceptibility to ancestral plagues. A compelling and related example of this is the Duffy antigen receptor for chemokines, which causes genetic resistance to infection by the malaria-causing protozoan Plasmodium vivax through polymorphism in the promoter [44–46].
Our results support a role for RANTES in the modulation of risk of both HIV infection and disease progression. However, future work will be needed to test directly whether the promoter variants we have studied differentially affect RANTES protein levels in appropriate biological contexts. Our results further highlight the utility of a candidate gene approach focused on other CCR5 ligands and related molecules for further analysis of differential outcome in HIV disease.
The authors would like to thank all the patients who have volunteered to participate in the MACS prospective epidemiological study. Epidemiological data in this manuscript were collected by the Multicenter AIDS Cohort Study (MACS) with centers (principal investigators) at The Johns Hopkins School of Public Health (Joseph Margolick, Alvaro Muñoz); Howard Brown Health Center and Northwestern University Medical School (John Phair); University of California, Los Angeles (Roger Detels, Janis V. Giorgi); and University of Pittsburgh (Charles Rinaldo). The authors also wish to thank the Onchocerciasis Control Program of the World Health Organization in Burkina Faso for the use of their data. Sponsorship: The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute: UO1-AI-35042, 5-M01-RR-00052 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041.
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