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Effect of TNF-α genetic variants and CCR5Δ32 on the vulnerability to HIV-1 infection and disease progression in Caucasian Spaniards
- Sergi Veloso1, 2, 3,
- Montserrat Olona1, 2, 3,
- Felipe García4,
- Pere Domingo5, 6,
- Carlos Alonso-Villaverde2, 3, 7,
- Montserrat Broch2, 3, 8,
- Joaquim Peraire1, 2, 3,
- Consuelo Viladés1, 2, 3,
- Montserrat Plana4,
- Enric Pedrol9,
- Miguel López-Dupla1, 2, 3,
- Carmen Aguilar1, 2, 3, 8,
- Mar Gutiérrez5,
- Agathe Leon4,
- Mariona Tasias9,
- Josep Ma Gatell4, 10,
- Cristóbal Richart1, 2, 3, 8 and
- Francesc Vidal1, 2, 3Email author
© Veloso et al; licensee BioMed Central Ltd. 2010
Received: 21 July 2009
Accepted: 26 April 2010
Published: 26 April 2010
Tumor necrosis factor alpha (TNF-α) is thought to be involved in the various immunogenetic events that influence HIV-1 infection.
We aimed to determine whether carriage of the TNF-α-238G>A, -308G>A and -863 C>A gene promoter single nucleotide polymorphisms (SNP) and the CCR5Δ32 variant allele influence the risk of HIV-1 infection and disease progression in Caucasian Spaniards. The study group consisted of 423 individuals. Of these, 239 were uninfected (36 heavily exposed but uninfected [EU] and 203 healthy controls [HC]) and 184 were HIV-1-infected (109 typical progressors [TP] and 75 long-term nonprogressors [LTNP] of over 16 years' duration). TNF-α SNP and the CCR5Δ32 allele were assessed using PCR-RFLP and automatic sequencing analysis methods on white blood cell DNA. Genotype and allele frequencies were compared using the χ 2 test and the Fisher exact test. Haplotypes were compared by logistic regression analysis.
The distribution of TNF-α-238G>A, -308G>A and -863 C>A genetic variants was non-significantly different in HIV-1-infected patients compared with uninfected individuals: -238G>A, p = 0.7 and p = 0.3; -308G>A, p = 0.05 and p = 0.07; -863 C>A, p = 0.7 and p = 0.4, for genotype and allele comparisons, respectively. Haplotype analyses, however, indicated that carriers of the haplotype H3 were significantly more common among uninfected subjects (p = 0.04). Among the infected patients, the distribution of the three TNF-α genetic variants assessed was non-significantly different between TP and LTNP: -238G>A, p = 0.35 and p = 0.7; -308G>A, p = 0.7 and p = 0.6: -863 C>A, p = 0.2 and p = 0.2, for genotype and allele comparisons, respectively. Haplotype analyses also indicated non-significant associations. Subanalyses in the LTNP subset indicated that the TNF-α-238A variant allele was significantly overrepresented in patients who spontaneously controlled plasma viremia compared with those who had a detectable plasma viral load (genotype comparisons, p = 0.02; allele comparisons, p = 0.03). The CCR5Δ32 distribution was non-significantly different in HIV-1-infected patients with respect to the uninfected population (p = 0.15 and p = 0.2 for genotype and allele comparisons, respectively) and in LTNP vs TP (p = 0.4 and p = 0.5 for genotype and allele comparisons, respectively).
In our cohort of Caucasian Spaniards, TNF-α genetic variants could be involved in the vulnerability to HIV-1 infection. TNF-α genetic variants were unrelated to disease progression in infected subjects. The -238G>A SNP may modulate the control of viremia in LTNP. Carriage of the CCR5Δ32 variant allele had no effect on the risk of infection and disease progression.
TNF-α is a pleiotropic cytokine that acts as an immune and inflammatory mediator. It is synthesized mainly by macrophages and T-cells and most of its actions take place by binding to two cell receptors: TNF-α R1 and R2 . Investigations suggest that TNF-α is involved in the pathogenesis of HIV-1 infection since it is overproduced by infected individuals [2–4].
Like many other proinflammatory cytokines, the production of TNF-α is at least partially genetically determined [5, 6]. Several functional single nucleotide polymorphisms (SNP) have been identified within the TNF-α gene cluster [5–8], the most widely studied of which are a G>A transition at position -238, a G>A transition at position -308, and a C>A transition at position -863 . Several cohort studies have assessed the influence of TNF-α SNP on the immunogenetics of HIV-1 infection. The information available on how TNF-α genetic variants affect vulnerability to infection is inconsistent [10–14]: some studies have found no effect [11, 13, 14] while others have found a strong association [10, 12]. Case-control studies have assessed the influence of TNF-α genetic variants on HIV-1 disease progression in infected patients [10–12, 14–17]. While some of these studies have reported an association with progression [10–12, 16, 17], others have failed to find such an association [14, 15]. A minority of untreated HIV-1-infected patients show an uncommon clinical form of infection characterized by a non-progressive disease and, sometimes, by self-limited viremia over the years. These patients are known as long-term nonprogressors (LTNP)  and elite controllers , respectively. Little data is available on the influence of TNF-α SNP on these uncommon clinical forms of HIV-1 infection [11, 16].
In this study we have assessed the influence of TNF-α SNP on the vulnerability to HIV-1 infection and, in infected patients, on disease progression. For this purpose we analysed a cohort that we have already used for several immunogenetic studies on HIV-1 infection which contains a subset of repeatedly exposed but uninfected individuals and a carefully collected cohort of extreme long-term nonprogressors [20, 21]. Given its modulating role in HIV-1-infection and disease progression reported elsewhere , the CCR5Δ32 allele was also assessed.
Design and setting
This was a multicenter cross-sectional population association study. All subjects were recruited from a prospectively collected cohort of almost 6000 HIV-1-infected patients treated at the HIV outpatients' clinics of the participating hospitals, which are located in an epidemiological setting in which intravenous drug use is one of the main causes of HIV-1-infection.
Demographic and clinical characteristics of the population analysed
(n = 203)
(n = 36)
(n = 109)
(n = 75)
(mean ± SD)
44.2 ± 9.9
46.7 ± 9.2
41.8 ± 8.9
41.6 ± 7.1
Duration of HIV-1 infection
(mean ± SD)
6.2 ± 2.7
18.2 ± 1.6
Time span between documented infection and the onset of antiretroviral treatment
(mean ± SD)
4.8 ± 1.3
Plasma HIV-1 RNA (copies/ml)
(median and range)
CD4+ T-cell count (cells/μl)
(median and range)
< 0.0001 ##,****
Exposure to HIV-1
DNA and plasma samples
Blood samples with ethylene diamine tetra-acetic acid were obtained from an antecubital vein. Five mL of whole blood was used to determine the CD4+ T-cell count, and 500 μl was used to isolate DNA with a MagNa Pure LC Instrument (Roche Diagnostics, Basel, Switzerland). Plasma for determining HIV-1 viral load was obtained by centrifugation at 3500 g for 15 minutes at 4C°.
This was diagnosed using an enzymoimmunoanalysis and confirmed by a Western-Blot test.
Plasma HIV-1 viral load
This was determined by the HIV Cobas Ampliprep CAP-CTMHIV-1 using the COBAS AMPLICOR system (Roche Diagnostics, Basel, Switzerland). The cutoff for undetectable viral load was 50 copies/μl.
Assessment of blood CD4+ T-cell count
Samples were analyzed in a flow cytometer FAC Scan (Becton Dickinson Immunocytometry Systems, San José, CA, USA). The data acquired were analyzed using the Multiset program.
-238 TNF-αgenotype (rs 361525)
This polymorphism consists of a G→ A substitution at position -238 in the proximal promoter of the TNF-α gene. The primers used in PCR were: forward primer 5' AGAAGACCCCCCTCGGAACC3', modified in 3' for RFLP analysis with Msp I restriction endonuclease, and reverse primer 5' ATCTGGAGGAAGCGGTAGTG 3'. A fragment of 152 bp was amplified at a final volume of 50 μL, with 3 mM of MgCl2, 0.2 mM dNTPs, 0.2 μM of each primer and 1 unit of Taq polymerase. DNA was amplified for 35 cycles: 95° for 30 seconds, 55° for 30 seconds and 72° for 30 seconds. PCR products were digested with MspI and revealed a fragment of 152 bp for the A allele and two fragments of 133 and 19 bp for the G allele.
-308 TNF-αgenotype (rs 1800629)
This polymorphism consists of a G→ A substitution at position -308 in the proximal promoter of the TNF-α gene. The primers used in the PCR were 5'AGGCAATAGGTTTTGAGGGCCAT3' and 5'TCCTCCCTGCTCCGATTCCG3'. Amplification was performed at a final volume of 50 μl containing 3 mM MgCl2, 0.5 mM of each nucleotide (Boehringer Mannheim™, Manheim, Germany), 0.2 μl of each oligonucleotide and 1 U of Taq polymerase (Gibco BRL). DNA was amplified for 35 cycles with denaturation at 94°C for 1 minute (min), annealing at 60°C for 1 min and extension at 72°C for 1 min. The first cycle was at 94°C for 3 min, at 60°C for 1 min and at 72°C for 1 min, followed by the 35 cycles and, finally, a cycle at 94°C for 1 min, at 60°C for 1 min and at 72°C for 5 min. The PCR products were digested at 37°C with NcoI for 24 hours, subjected to 2.5% agarose gel electrophoresis at 80 V and stained with ethidium bromide. The 107 bp band corresponded to the A allele and the set of 87 bp and 20 bp bands corresponded to the G allele.
-863 TNF-αgenotype (rs 1800630)
This polymorphism consists of a C→ A substitution at position -863 in the proximal promoter of the TNF-α gene. The primers used in the PCR were 5'GGCTCTGAGGAATGGGTTAC3' and 5'CTACATGGCCCTGTCTTCGTTACG3'. Amplification was performed at a final volume of 25 μl containing 1 mM MgCl2, 0.2 mM of each nucleotide (Boehringer Mannheim™, Manheim, Germany), 1.2 μl of each oligonucleotide and 0.5 U of Taq polymerase (Gibco BRL). DNA was amplified for 35 cycles with denaturation at 94°C for 30 seconds, annealing at 62.3°C for 1 min and extension at 72°C for 2 min. The first cycle was at 94°C for 3 min, followed by the 35 cycles and, finally, an extension at 72°C for 5 min. The amplified product was digested with Bsa AI restriction enzyme (New England Biolabs) at 37°C for 24 hours, electrophoresed on 2.5% agarose gel at 80 V and stained with ethidium bromide. The 126 pb band corresponded to the C wild-type allele and the set of 103 bp and 23 pb bands corresponded to the variant A allele.
The PCR primers used were 5'GCTCTCTCCCAGGAATCATC3' and antisense 5'TTCCCGAGTAGCAGATGACC3' with annealing at 60°C. The Genbank accession number was AF031237.1. The PCR products were visualized on 2.5% agarose gel. The wild-type CCR5 gene led to a 174 bp fragment and the CCR5Δ32 variant resulted in a 142 bp fragment.
Descriptive data were expressed as the mean ± SD or median (range) for non-parametric distributions. The differences in levels between groups in continuous variables were compared using Student's t test, the Mann-Whitney U test, or ANOVA when necessary. To evaluate the association between HIV-1 TP and the different categories of uninfected subjects for the different genotypes, the odds ratio (OR) and 95% confidence interval (95%CI) were calculated. The Hardy-Weinberg equilibrium was assessed by the chi-square goodness-of-fit test. Genotype distribution and allele frequencies in the different groups were compared by the χ2 test or Fisher's exact test when necessary. To evaluate the association of TNF-α genetic variants and CCR5Δ32 with the risk of HIV-1 infection, the differences in the distribution between HIV-1-infected, HC and EU were assessed. To evaluate the association of TNF-α genetic variants and CCR5Δ32 with disease progression in infected subjects, we compared HIV-1-infected TP vs HIV-1-infected LTNP. In the latter subset, we also compared LTNP-DVL and LTNP-EC. Analyses were performed using the SPSS/PC+ statistical package (v. 12.0 for Windows; Chicago, Illinois, USA). Haplotype frequencies were estimated by the maximum-likelihood method. Haplotype frequencies were estimated by the PAC-likelihood method , which takes into account the similarity of haplotypes and the fact that linkage disequilibrium decays with distance. The distributions of the different haplotypes between groups were compared by logistic regression analysis. The commonest haplotype (which we arbitrarily called haplotype H1) was taken as a reference. Haplotype analyses were performed using the PHASEv2.1 software [29, 30]. A p value < 0.05 was considered significant.
Four hundred and twenty-three individuals were studied: 239 uninfected (203 healthy controls [HC] and 36 EU) and 184 HIV-1-infected. Of the infected individuals, most of whom had acquired HIV-1 through intravenous drug use, 109 were TP and 75 were LTNP. Of the LTNP, 20 were elite controllers. The age, gender and risk factors of acquiring HIV-1 infection in the TP and LTNP were not significantly different. Most TP (>90%) were receiving highly active antiretroviral therapy. Table 1 shows selected characteristics of the population studied. As expected, the duration of HIV-1 infection was significantly greater in LTNP than in TP. CD4+ T-cell counts were also greater and viral loads were lower.
Tables 2 and 3 show the genotype distribution and allele frequencies of the TNF-α-238G>A, -308G>A and -863 C>A gene promoter SNP and the CCR5Δ32 allele for the control group and the different patient categories. The genotype distribution in control subjects, EU, HIV-1-infected, HIV-1 TP and HIV-1 LTNP fits the expected Hardy-Weinberg equilibrium for each TNF-α SNP.
TNF-α and CCR5Δ32 genotype and allele frequencies in HC, EU and HIV-1-infected for assessment of associations with the risk of HIV-1 infection.
Genotype and allele frequencies
(n = 203)
(n = 36)
(n = 184)
Variant allele A
Variant allele A
Variant allele A
TNF-α and CCR5Δ32 genotype and allele frequencies in the different subsets of HIV-1-infected patients for assessment of associations with disease progression.
(n = 109)
(n = 75)
(n = 55)
(n = 20)
Variant allele A
Variant allele A
Variant allele A
Variant allele Δ32
TNF-α haplotypes and risk of HIV-1-infection.
n (estimated frequencies in %)
(n = 373)
(n = 189)1
(n = 184)
0.95 - 2.30
1.04 - 2.64
0.52 - 2.04
0.23 - 9.47
TNF-α haplotypes and disease progression in HIV-1-infected patients.
n (estimated frequencies in %)
(n = 184)
(n = 109)
(n = 75)
0.92 - 3.64
0.60 - 2.41
0.68 - 4.95
There were no significant differences in the prevalence of the CCR5Δ32 genetic variant allele among the different categories of patients assessed (Tables 2 and 3). CCR5Δ32 homozygosity was not detected.
In this cohort of Caucasian Spaniards, we found that TNF-α gene polymorphism may be involved in vulnerability to HIV-1 infection. In infected patients, none of the TNF-α genetic variants assessed influences disease progression, but the TNF-α-238G>A SNP may modulate viremia control in LTNP. Carriage of the CCR5Δ32 variant allele does not influence the risk of infection or disease progression.
To explain the variable interindividual vulnerability to HIV-1 infection, we sought a genetically-driven host susceptibility. Several candidate genes were checked, one of which was TNF-α because of its robust role in initial response to infection influences both innate and acquired immunity [1, 3, 31, 32]. Our data indicate that none of the individual polymorphisms assessed influence vulnerability to HIV-1 infection, but haplotype analyses suggest that the combination of some genetic variants within the TNF-α gene may modulate the risk of infection. These results agree with some reports that showed an association between TNF-α SNP and the risk of infection [10, 12]; other investigations, however, observed no significant associations [11, 13–15]. The discrepancy between our findings and those reported previously may be because of the low number of patients assessed in some studies , which often provides unstable data , or because the different ethnicities of the people assessed in others [13, 14] may have led to genuine population differences .
Other reports have investigated the involvement of TNF-α genetic variants in a variety of immunogenetic events that affect HIV-1 disease progression. Some studies have related the risk of progression [10–12, 16, 17] and/or of developing a diversity of AIDS-related events [35–41] with carriage of some TNF-α genetic variants while others, like ours, have failed to find any significant association [14, 15]. In this respect, our study suggests that there are no significant associations between TNF-α genetic variants and disease progression. To assess this issue we used a cohort of TP as controls and a subset of LTNP of over 16 years' duration as cases. This extreme LTNP phenotype was expressly chosen to prevent groups from superposing. Of particular note, however, was that within the LTNP group we showed a significant association between carriage of the TNF-α-238A variant allele and the spontaneous "elite controller" phenotype. This replicates what was reported in an early study  but, since this finding is supported by a very small number of patients it should be further replicated in larger series of this uncommon subset of HIV-1-infected patients.
For CCR5Δ32, we found that there is no signal for non progression. This is in agreement with CCR5Δ32 having a primary effect against rapid progression as pointed out by the GRIV study [42, 43]. We acknowledge, however, that in order to see the effect of CCR5Δ32, the use of a larger cohort and/or a Kaplan-Meier plot of patients' evolution since seroconversion under various endpoints could have been useful.
Our study has some limitations. First, the cross sectional nature of the design provides associations, not causality. Second, the comparison of the LTNP with the TP subsets is rather limited since it involves long-term non progression and not simple progression, and additional analyses with Kaplan-Meier curves (with various endpoints such as death or AIDS 1993 criteria) could lead to different results. Finally, some of the subsets assessed were small, particularly the exposed uninfected and elite controllers. This means that our analyses of these subsets may be too underpowered to detect other significant associations.
In summary, in a cohort of Caucasian Spaniards, polymorphism within the TNF-α gene may be associated with vulnerability to HIV-1 infection. In infected patients, none of the TNF-α genetic variants assessed influences disease progression but the TNF-α-238G>A SNP may modulate the elite controller status. The CCR5Δ32 variant allele influences neither the risk of infection nor disease progression.
This study has been partially financed by grants from the Fondo de Investigacion Sanitaria (07/0976, 08/1032); SAF 2008-02278; Fondos Europeos para el Desarrollo Regional (FEDER); Fundación para la Investigación y Prevención del Sida en España (FIPSE 06/36572 and 06/30610); Grups Reconeguts AGAUR (2009 SGR 959 and 2009 SGR 1061); Red de Investigación en Sida, Instituto de Salud Carlos III (RIS; RD06/006/0000, RD06/006/0022 and RD06/006/1004). Montserrat Plana was supported by contract FIS 03/00072 from the Fundació Privada Clínic per a la Recerca Biomèdica in collaboration with the Spanish Health Department. Pilar Hernandez helped us in the statistical analyses. John Bates kindly improved the English text. The constructive comments and criticisms of the three reviewers helped us to improve the manuscript and are greatly appreciated.
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