associations of mhc ancestral haplotypes with resistance/susceptibility to aids disease development
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Disease Developmentwith Resistance/Susceptibility to AIDS Associations of MHC Ancestral Haplotypes
Teran, Juan Rodriguez-Tafur and Jean-François ZagurySebastien Bertin-Maghit, Jorge A. Ruiz-Morales, Maria E.Caillat-Zucman, Jay Rappaport, Alberto Burgos-Tiburcio, Pedro O. Flores-Villanueva, Houria Hendel, Sophie
http://www.jimmunol.org/content/170/4/19252003; 170:1925-1929; ;J Immunol
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Associations of MHC Ancestral Haplotypes with Resistance/Susceptibility to AIDS Disease Development1
Pedro O. Flores-Villanueva,2*¶ Houria Hendel,† Sophie Caillat-Zucman,‡ Jay Rappaport,§
Alberto Burgos-Tiburcio,* Sebastien Bertin-Maghit,† Jorge A. Ruiz-Morales,* Maria E. Teran,¶
Juan Rodriguez-Tafur,¶ and Jean-Francois Zagury2†§
We tested the association ofMHC ancestral haplotypes with rapid or slow progression to AIDS by comparing their frequenciesin the French genetics of resistance/susceptibility to immunodeficiency virus cohort with that reported in a control French pop-ulation. Seven ancestral haplotypes were identified in the genetics of resistance/susceptibility to immunodeficiency virus cohortwith a frequency >1%. The 8.1 (odds ratio (OR)� 3, p � 0.006), 35.1 (OR� 5.7, p � 0.001), and 44.2 (OR� 3.4, p � 0.007)ancestral haplotypes were associated with rapid progression, whereas the 35.2 (OR� 3.6,p � 0.001), 44.1 (OR� 5.4,p < 10�4),and 57.1 (OR� 5.8, p < 10�4) ancestral haplotypes were associated with slow progression to AIDS. Although the frequency ofeach ancestral haplotype is low in the population, the OR were quite higher than those previously obtained for singleHLA alleleassociations, with somep values as low as 10�4. The analysis of the recombinant fragments of these haplotypes allowed theidentification of the MHC regions in the 35.1, 35.2, and 44.2 haplotypes associated with rapid progression to AIDS and theMHCregions of the 44.1 and 57.1 haplotypes associated with slow progression to AIDS. Previous studies have identified singleHLAalleles associated with disease progression. Our results on recombinant fragments confirm the direct role ofHLA-B35 in rapidprogression. Associations withHLA-A29 and -B57 might be due to linkage disequilibrium with other causative genes within theMHC region. The Journal of Immunology, 2003, 170: 1925–1929.
D ue to the major role of the HLA locus in controlling theimmune response, associations between HLA genes andprogression to AIDS have been extensively studied (1,
2). Various cohort studies have identified associations betweenHLA genes (class I and class II) and progression to AIDS. Forexample, the HLA-B14, -B27, -B57, and -B44 were found associ-ated with slow progression to AIDS (3–6), while the HLA-A29,-DR11, -B22, and -B35 were found associated with rapid progres-sion to AIDS (3, 7–10). However, the biological explanations un-derlying these associations are not clear because of the complexityintroduced by linkage disequilibrium (LD)3 in the HLA region.
Indeed, the genes located in the HLA region (Fig. 1), a chromo-somal segment of �4000 kb on the short arm of chromosome 6,have the tendency to be inherited in a block due to LD (11). Thus,several combinations of alleles in the HLA-A, -C, -B, -DR, and-DQ loci, the central Bf, C4A, C4B, TNF-�, and TNF� loci, andgenes in between can form what are known as MHC haplotypes(11, 12). These haplotypes have been passed from generation togeneration since ancestral times and are therefore referred to asancestral haplotypes (11). To this day, �30 ancestral haplotypeshave been described (13, 14), and they received a denomination inconcordance with the HLA-B allele present in the haplotype. Forexample the ancestral haplotype 8.1 is composed of the alleles A1,Cw7, B8, BfS, C4AQ0, C4B1, DRB1*0301, and DQB1*0201 and isdenominated 8.1 after the HLA-B8 allele present in this haplotype(11). The complete description of the ancestral haplotypes inves-tigated in the present study is given in Material and Methods.
We hypothesized that the multiplicity of HLA gene variants andloci associations with slow progression or rapid progression toAIDS could be due to LD with a causative gene or causative genescontrolling these traits, and that examining the associations of an-cestral haplotypes or their recombinant fractions could be useful tomap the MHC regions that may contain such gene(s). The fact thatancestral haplotypes have been conserved in blocks during evolu-tion may otherwise suggest that they each could play a role as awhole, possibly regulated at the transcriptional level by “neigh-borhood effects” (15).
Toward this end, we have used the genetics of resistance/sus-ceptibility to immunodeficiency virus (GRIV) cohort, which iscomposed of patients with extreme patterns of progression, slowand rapid progression, and is the largest cohort of its kind in theworld. HLA genotyping for HLA-A, -B, and -C and HLA-DR andassociations with AIDS have already been described in that cohort(3). Further examination of the DQ alleles in this cohort has permitted
*Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston,MA 02115; †Centre de Recherche des Cordeliers, Universite Pierre et Marie Curie, Paris,France; ‡Laboratoire d’Immunologie, Hopital Necker, Paris, France; §Center for Neuro-virology and Cancer, Temple University, Philadelphia, PA 19122; and ¶Universidad Na-cional Mayor de San Marcos, Escuela de Medicina de San Fernando, Lima, Peru
Received for publication August 8, 2002. Accepted for publication November18, 2002.
The costs of publication of this article were defrayed in part by the payment of pagecharges. This article must therefore be hereby marked advertisement in accordancewith 18 U.S.C. Section 1734 solely to indicate this fact.1 This work was supported by a grant from Agence Nationale de Recherche sur leSIDA, by a fellowship from AIDS Cancer Vaccine Development Foundation (toJ-F.Z.), by the Bridge Award for Minority Faculty Development from Harvard Med-ical School (to P.O.F.-V.), by National Institutes of Health Grants HL29583 and R21HL72177-01, and by the Scholars in Clinical Science Program from Harvard MedicalSchool’s K30 National Institutes of Health Grant HL04095-04.2 Address correspondence and reprint requests to Dr. Jean-Francois Zagury,Centre de Recherche des Cordeliers, Universite Pierre et Marie Curie, 15 rue del’Ecole de Medecine, 75006 Paris, France. E-mail address: [email protected]; orDr. Pedro O. Flores-Villanueva, Department of Cancer Immunology and AIDS,Dana-Farber Cancer Institute, Dana Building, Room 1514, Boston, MA 02115.E-mail address: [email protected] Abbreviations used in this paper: LD, linkage disequilibrium; GRIV, genetics ofresistance/susceptibility to immunodeficiency virus; CFP, control French population;SP, slow progressor; RP, rapid progressor; OR, odds ratio; MICA, MHC class Ichain-related gene A; MICB, MHC class I chain-related gene B; KIR, killer Ig-likereceptor; SNP, single nucleotide polymorphism.
The Journal of Immunology
Copyright © 2003 by The American Association of Immunologists, Inc. 0022-1767/03/$02.00
extension of our previous studies and the analysis of ancestral haplo-types. The haplotypes have been imputed by the presence of haplo-typic allele markers, because it was not possible to strictly prove theirsegregation from family studies. The investigation presented in thisstudy allows the delineation of specific MHC regions likely to befunctionally involved in the different patterns of disease progression.
Materials and MethodsSubjects
The GRIV cohort was established in 1995 in France to generate a largecollection of DNA samples for genetic studies of candidate human poly-morphisms associated with rapid and slow progression to AIDS (3). Toavoid confounding effects associated with racial/ethnic differences in thegenetic analysis, only Caucasians of European descent were recruited fromhospital-based AIDS units throughout France. Slow progressors (SP) weredefined as asymptomatic individuals who had tested seropositive for HIV-1for �8 years with a CD4� cell count of �500/mm3 in the absence ofantiretroviral therapy. A seropositive test result for �8 years was necessaryfor inclusion in the study. Rapid progressors (RP) were defined by a CD4count of �300/mm3 in a period of time of �3 years after the last sero-negative testing. We selected for the study individuals with complete in-termediate to high resolution typings for HLA-A, -C, -B, -DRB1, and-DQB1 loci. Seventy-four RP and 198 SP to AIDS were included in thestudy.
Ancestral haplotypes frequencies for a population of 65,700 French sub-jects (control French population (CFP)) were previously published by Lon-jou et al. (16).
Genetic typings and reconstruction of the MHC ancestralhaplotypes
The methodology for HLA class I and II, and MHC class I chain-relatedgene A (MICA) DNA typings was previously described (3, 17). The an-cestral haplotypes were reconstructed by imputation of haplotypic allelemarkers as previously described (11, 12, 18) and are putative, because itwas not possible to strictly prove their segregation from family studies. Themost frequent ancestral haplotypes found in the GRIV cohort (frequency�1%), studied in the present investigation, were the following: 7.1 (HLA-A*0301, C*07, B*07, DRB1*1301, and DQB1*0603); 8.1 (HLA-A*01,C*07, B*08, DRB1*0301, and DQB1*0201); 35.1 (C*04, B*35, DRB1*11,and DQB1*0301); 35.2 (HLA-A*11, C*04, B*35, DRB1*0101, andDQB1*0501); 44.1 (HLA-A*02, C*05, B*4402, DRB1*04, and DQB1*03);44.2 (HLA-A*2902, C*16, B*4403, DRB1*07, and DQB1*0201), and 57.1(HLA-A*01, C*06, B*5701, DRB1*07, and DQB1*0303). Of note, the hap-lotype 35.1 definition does not include an HLA-A allele.
Statistical analysis
The analysis of statistical significance was done by using Pearson’s �2 andFisher’s exact tests, 2 � 2 contingency tables, and the aid of the INSTAT2.01 computer program (GraphPad, San Diego, CA).
Table I. Comparative frequencies of ancestral haplotypesa
AncestralHaplotypes
Frequency � 100 SP vs CFP RP vs CFP
SP (n � 198) RP (n � 74) CFP p value OR 95% C.I. p value O.R. 95% C.I.
7.1 2.5 0 2.4 0.90 1.1 0.4–2.6 0.33 0.3 0.02–4.48.1 6.6 10.8 3.9 0.08 1.7 1–3 0.006 3 1.4–6.235.1 0.5 5.4 1 0.73 0.5 0.07–3.6 0.001 5.7 2.1–15.535.2 3.5 1.4 �1 0.001 3.6 1.7–7.7 0.72 1.4 0.2–9.844.1 8.5 4 1.7 <0.0001 5.4 3.3–9 0.26 2.4 0.8–7.844.2 4 8.1 2.5 0.24 1.6 0.8–3.3 0.007 3.4 1.5–7.957.1 5.1 2.7 0.9 <0.0001 5.9 3.1–11.1 0.31 3.1 0.7–12.5
a Information about the frequencies of ancestral haplotypes in the French population was obtained from a previously published database of 65,700 individuals (16). Atwo-tailed Pearson’s �2 test was used to analyze the data as indicated in Materials and Methods. C.I., Confidence interval.
FIGURE 1. This figure presents thealignments of the genes in the HLAregion.
1926 MHC ANCESTRAL HAPLOTYPES AND PROGRESSION TO AIDS
ResultsThe 35.2, 44.1, and 57.1, and the 8.1, 35.1, and 44.2 ancestralhaplotypes are associated with slow and rapid progression toAIDS, respectively
To identify associations of ancestral haplotypes with slow or rapidprogression to AIDS we compared the frequencies of haplotypesfound in the GRIV cohort with the frequencies of haplotypes pre-viously published in a normal French population (16). Among theancestral haplotypes previously described (13, 14), seven had afrequency �1% in the GRIV cohort: 7.1, 8.1, 35.1, 35.2, 44.1,44.2, and 57.1 (see Material and Methods). Significant associa-tions with slow progression were obtained for the 35.2 (odds ratio(OR) � 3.6, p � 0.001), 44.1 (OR � 5.4, p � 0.0001), and 57.1(OR � 5.8, p � 0.0001) ancestral haplotypes (Table I). We alsofound an increased frequency of the 8.1 (OR � 3, p � 0.0057), ofthe 35.1 (OR � 5.7, p � 0.001), and of the 44.2 ancestral haplo-types (OR � 3.4, p � 0.007) in RP as compared with that in the
normal French population (Table I). No association was identifiedwith the 7.1 haplotype (Table I).
Because the 8.1 haplotype has previously been associated withincreased TNF-� production due to an LD with the �308 G/Asingle nucleotide polymorphism (SNP) in the TNF-� promoter(19), we have genotyped the GRIV cohort for the �308 G/A SNP.We retrieve the LD between the rare A allele of that SNP and the8.1 ancestral haplotype, which could give an explanation of theobserved association of this haplotype with rapid progressionto AIDS.
Identification of candidate regions associated with slowprogression and rapid progression to AIDS in the GRIV cohort.
To identify regions within the HLA locus associated with slow orrapid progression, we used recombinant mapping methodology(20) and compared the frequency of haplotype fragments found inSP with that in RP in the GRIV cohort (Table II).
Table II. Recombinant fragments between SPs and RPsa
a Cobigram presenting the recombinant fragments among the SP and RP populations. A one-tailed Fisher’sexact test was used to analyze the data as indicated in Materials and Methods. C.I., Confidence interval.The recombinant fragments of the ancestral haplotypes were analyzed in the SP and RP populations, as shownin color. Yellow, OR within 0.5 and 2 (no association); red, OR �2 (rapid progression); green, OR �0.5 (slowprogression). Haplotype 7.1 is not shown, because it does not exist in the RP group.
1927The Journal of Immunology
The 8.1 haplotype was fixed from the HLA-A loci to the HLA-DQB1 loci in the majority of RP to AIDS, making it impossible tomap a region specifically associated with that trait by comparisonwith SP to AIDS (Table II). The haplotype 35.1 exhibited a strik-ing association with rapid progression for all fragments within theC/DQB1 interval. The peak was obtained for the B/DQB1 intervalwith an OR value of 14.3 ( p � 0.006). For the haplotype 35.2, apeak association with rapid progression was observed for the in-terval C/B with an OR of 2.3 and a p value of 0.02. Thus, carryingthe whole 35.2 haplotype resulted in the expression of the SP phe-notype (Table I), while carrying the HLA-C/B interval of this hap-lotype resulted in the expression of the RP phenotype (Table II).For the haplotype 44.1, a nearly significant association with slowprogression is obtained for the DRB1/DQB1 interval (OR � 0.5,p � 0.06). For the haplotype 44.2, an association is observed withrapid progression to AIDS with the intervals A/B and C/B withORs close to 2.4 and p values close to 0.05 (Table II). The DRB1/DQB1 interval of the 57.1 haplotype was significantly associatedwith slow progression to AIDS (OR � 0.33, p � 0.05); however,all the fragments between C and DQB1 exhibited similar ORsclose to 0.4 and low p values such as 0.06 for the C/B interval(Table II).
The associations involving the HLA-B44 allele are of particularinterest, because it is the most prevalent allele in the Caucasianpopulation (frequency of �34%). The HLA-B gene is very close tothe MICA gene (Fig. 1), and it is known that the HLA-B*4403allele present in the 44.2 ancestral haplotype is known to be in LDwith the MICA*004 allele, while the HLA-B*4402 allele in the44.1 ancestral haplotype is in LD with the MICA*008 allele (18).The MHC class I chain-related gene B (MICB) allele MICB*01021is found in both the 44.1 and the 44.2 ancestral haplotypes (18). Apreliminary analysis of the GRIV cohort shows that, in fact, mostof the HLA-B44 carriers in our sample of RP are MICA*004, whilemost of the HLA-B44 carriers in the SP are MICA*008 (data notshown).
A recently published study showed an epistatic interaction be-tween the killer Ig-like receptor (KIR) genes and HLA-B genes,with an impact as strong as the CCR-5 �32 deletion (21). In thatstudy, an association was observed only when analyzing the KIRsin combination with their HLA ligands. It is known that theKIR2DL2 and 2DL3 receptors on NK cells bind a conservedHLA-C1 group motif (defined by S77 and N80), whereas theKIR2DL1 receptor binds the HLA-C2 group (N77 and K80). Wetried to compare the RP and SP to AIDS by sorting them in theHLA-C1 or HLA-C2 group motifs, but we could not see any dif-ference. As described by Martin et al. (21), it might be necessaryto analyze the combination of HLA and KIR gene polymorphismsto observe an association.
DiscussionAlthough the frequencies of ancestral haplotypes in all populationsare extremely low (11, 12, 16), we are reporting for the first timean association of the 35.2, 44.1, and 57.1 ancestral haplotypes, andof the 35.1 and 44.2 ancestral haplotypes with slow progressionand rapid progression to AIDS, respectively. Previous reports havealso found that the 8.1 ancestral haplotype is associated with rapidprogression to AIDS (22, 23). Of note, these associations betweenancestral haplotypes and AIDS progression withstand Bonferronicorrections. The OR in this study, comprised between 2.9 and 5.9,are globally higher than those obtained for single HLA alleles (3–10). This can be explained by two reasons: a statistical explanationbased on the small number of subjects carrying ancestral haplo-types and a biological explanation based on the importance of thecontextual arrangement of genetic elements for successful immu-
nologic control of HIV-1 infection. For instance, the single alleleHLA-B8 alone is not associated with rapid progression to AIDS(3); the HLA-B8 allele is associated with rapid progression only inthe full context of the ancestral haplotype 8.1. Our results do notexclude that ancestral haplotypes are associated with susceptibilityto infection, because they are generally higher in both the SP andRP populations than in the CFP population. It is unlikely that thereis a bias in the CFP population, because the haplotyping involved65,700 individuals (16) and the frequencies are very similar to theones from other large studies (24).
Until now, the most widely viewed explanation for HLA influ-ence is that class I and class II genes act directly by restricting theimmune response—Ag peptidic presentation—inducing selectionof HIV-1 viral escape mutants: in fact, the direct interaction be-tween HLA and the generation of escape mutants can be analyzeddirectly (25). Our approach based on the analysis of recombinantancestral haplotypes (fragments of these haplotypes) should permitfurther mapping and identification of new disease susceptibilitygenes within the HLA locus acting in concert with the classicalMHC class I and II genes (20). Our results suggest that the HLA-C/B regions of the 44.2 and 35.2 ancestral haplotypes are associ-ated with rapid progression to AIDS, and that the DRB1/DQB1regions of the 44.1 and 57.1 ancestral haplotypes are associatedwith slow progression to AIDS. For the haplotype 35.1, all inter-vals were associated with rapid progression to AIDS with a peakfor B/DQB1. It is important to emphasize that these data do notintegrate Bonferroni corrections, and only the associations of theB/DQB1 and DRB1/DQB1 fragments of the 35.1 haplotype withrapid progression to AIDS would remain significant if such cor-rections were applied. It was not possible to determine the effect ofspecific recombination events within the 8.1 ancestral haplotypebecause the haplotype was totally conserved among RP subjects;however, we found it in total LD with the previously described�308 A allele of TNF-� promoter (19).
Interestingly, among the seven ancestral haplotypes studied,four of them involve HLA gene alleles that were previously asso-ciated with disease progression (3): HLA-B35 for haplotypes B35.1and B35.2, HLA-DRB11 for the haplotype 35.1, HLA-A29 for thehaplotype B44.2, and HLAB57 for the haplotype B57.1. UnlikeHLA-B35, the ancestral haplotype B35.2 exhibited an associationwith slow progression to AIDS (Table I). However the C/B frag-ment of this ancestral hapolotype seemed to be associated withrapid progression to AIDS (Table II) and tends to confirm thedirect role of HLA-B35 allele in AIDS progression. A correctiveeffect may occur elsewhere in the haplotype, whether between theA and C gene, suggesting a possible role for HLA-E, or in theB/DQB1 region pointing out MICA/B or TNF-�. The analysis ofthe recombinant fragments of 35.1 suggests a strong associationwith rapid progression to AIDS for all the recombinant fragments,highly significant for the B/DQB1 fragment (Table II): the asso-ciation of the B35.1 haplotype appears bimodal with a peak in theOR at 14.3 linked with the combined association of the alleles B35and DR11, and two smaller ORs but very significant ( p � 0.02 andp � 0.004) at the level of the C/B and DRB1/DQB1 fragments,respectively, which correspond to the associations of B35 andDR11 with rapid progression to AIDS we previously described (3).This could suggest the tracking effect of an association for a genelocated within the B/DRB1 fragment, or a synergistic effect for thecombination of the individual alleles B35 and DR11. A recentwork has shown that the HLA-B35 allele effect was associated withthe subtypes 02, 03, and 04 of B35 (9). It is not known whether theancestral haplotypes 35.1 and 35.2 are associated with a givensubtype of B35 and that analysis will need to be performed. Ofinterest, the association with rapid progression to AIDS found on
1928 MHC ANCESTRAL HAPLOTYPES AND PROGRESSION TO AIDS
the C/B region for both the 35.1 and 35.2 haplotypes in the re-combinant analysis had an OR of 2.3, similar to the one publishedfor the B35 subtypes 02, 03, and 04 (9). The association of the 44.2haplotype with rapid progression to AIDS is similar in amplitudeto the one we previously described for A29 (3); however, the re-combinant fragment C/B of the 44.2 haplotype appears also suf-ficient to track that association. Finally, for the HLA-B57 associ-ation, the recombinant analysis of the 57.1 haplotype points to thewhole C/DQB1 region: unlike the 35.1 haplotype, the ORs aresimilar for all fragments, and all the genes in the C/DQB-1 regioncould thus be good candidates to explain the association. In thisstudy of recombinant fragments, no discrepancy is observed be-tween B and C genes, on the one hand, and DRB1 and DQB1, onthe other hand, reflecting their close proximity on chromosome 6.
In the DR/DQ region, besides the HLA DR/DQ genes them-selves, the neighboring genes known as transporter associated withAg processing and large multifunctional protease are interestingcandidate genes that are functionally involved in the Ag processingby class I molecules (26). Around the HLA B/C genes, promisingcandidates are the genes of the MICA and MICB, but the HLA-Elocus located in between the HLA-A and HLA-C is also polymor-phic (27, 28). MICA and MICB proteins are ligands of the NKcell-activating receptor NKG2D (29), while HLA-E is the ligandof the inhibitory NKG2A, -B, and -C receptors (30–32).
In conclusion, our study confirms that the molecular mecha-nisms underlying the associations between HLA genes and AIDSdisease progression are not always direct effects of HLA restrictionbut can also be indirect effects due to LD, or both. Our analysisthrough the ancestral haplotypes has brought some insight into thepossible mechanisms by pointing out class I, II, or III MHC re-gions linked to various HLA alleles susceptible to being associatedwith disease progression. The combined analysis of the TNF-�,MICA/B, HLA-E, transporter associated with Ag processing, largemultifunctional protease, and KIR/killer cell-activating receptorgene polymorphisms as well as of the viral gene sequences (25)and their interactions (21) should certainly bring a definitive an-swer to these questions.
AcknowledgmentsWe are grateful to all the patients and medical staff who have kindly col-laborated with the project.
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1929The Journal of Immunology