1. Associations of MHC Ancestral Haplotypes
with Resistance/Susceptibility to AIDS
Disease Development
This information is current as
of October 8, 2013.
Pedro O. Flores-Villanueva, 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-François Zagury
J Immunol 2003; 170:1925-1929; ;
http://www.jimmunol.org/content/170/4/1925
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References

2. The Journal of Immunology
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 of MHC ancestral haplotypes with rapid or slow progression to AIDS by comparing their frequencies
in the French genetics of resistance/susceptibility to immunodeficiency virus cohort with that reported in a control French population. Seven ancestral haplotypes were identified in the genetics of resistance/susceptibility to immunodeficiency virus cohort
with a frequency >1%. The 8.1 (odds ratio (OR) ‫ ,3 ؍‬p ‫( 1.53 ,)600.0 ؍‬OR ‫ ,7.5 ؍‬p ‫ ,)100.0 ؍‬and 44.2 (OR ‫ ,4.3 ؍‬p ‫)700.0 ؍‬
ancestral haplotypes were associated with rapid progression, whereas the 35.2 (OR ‫ ,6.3 ؍‬p ‫( 1.44 ,)100.0 ؍‬OR ‫ ,4.5 ؍‬p < 10؊4),
and 57.1 (OR ‫ ,8.5 ؍‬p < 10؊4) ancestral haplotypes were associated with slow progression to AIDS. Although the frequency of
each ancestral haplotype is low in the population, the OR were quite higher than those previously obtained for single HLA allele
associations, with some p values as low as 10؊4. The analysis of the recombinant fragments of these haplotypes allowed the
identification of the MHC regions in the 35.1, 35.2, and 44.2 haplotypes associated with rapid progression to AIDS and the MHC
regions of the 44.1 and 57.1 haplotypes associated with slow progression to AIDS. Previous studies have identified single HLA
alleles associated with disease progression. Our results on recombinant fragments confirm the direct role of HLA-B35 in rapid
progression. Associations with HLA-A29 and -B57 might be due to linkage disequilibrium with other causative genes within the
MHC region. The Journal of Immunology, 2003, 170: 1925–1929.
D
ue to the major role of the HLA locus in controlling the
immune response, associations between HLA genes and
progression to AIDS have been extensively studied (1,
2). Various cohort studies have identified associations between
HLA genes (class I and class II) and progression to AIDS. For
example, the HLA-B14, -B27, -B57, and -B44 were found associated with slow progression to AIDS (3– 6), while the HLA-A29,
-DR11, -B22, and -B35 were found associated with rapid progression to AIDS (3, 7–10). However, the biological explanations underlying these associations are not clear because of the complexity
introduced by linkage disequilibrium (LD)3 in the HLA region.
*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 Neuroˆ
virology and Cancer, Temple University, Philadelphia, PA 19122; and ¶Universidad Nacional Mayor de San Marcos, Escuela de Medicina de San Fernando, Lima, Peru
Received for publication August 8, 2002. Accepted for publication November
18, 2002.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance
with 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 le
SIDA, by a fellowship from AIDS Cancer Vaccine Development Foundation (to
J-F.Z.), by the Bridge Award for Minority Faculty Development from Harvard Medical School (to P.O.F.-V.), by National Institutes of Health Grants HL29583 and R21
HL72177-01, and by the Scholars in Clinical Science Program from Harvard Medical
School’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 de
´
l’Ecole de Medecine, 75006 Paris, France. E-mail address: jfz@ccr.jussieu.fr; or
´
Dr. Pedro O. Flores-Villanueva, Department of Cancer Immunology and AIDS,
Dana-Farber Cancer Institute, Dana Building, Room 1514, Boston, MA 02115.
E-mail address: pedro_flores-villanueva@dfci.harvard.edu
3
Abbreviations used in this paper: LD, linkage disequilibrium; GRIV, genetics of
resistance/susceptibility to immunodeficiency virus; CFP, control French population;
SP, slow progressor; RP, rapid progressor; OR, odds ratio; MICA, MHC class I
chain-related gene A; MICB, MHC class I chain-related gene B; KIR, killer Ig-like
receptor; SNP, single nucleotide polymorphism.
Copyright © 2003 by The American Association of Immunologists, Inc.
Indeed, the genes located in the HLA region (Fig. 1), a chromosomal segment of ϳ4000 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, and
genes in between can form what are known as MHC haplotypes
(11, 12). These haplotypes have been passed from generation to
generation since ancestral times and are therefore referred to as
ancestral haplotypes (11). To this day, Ͼ30 ancestral haplotypes
have been described (13, 14), and they received a denomination in
concordance with the HLA-B allele present in the haplotype. For
example the ancestral haplotype 8.1 is composed of the alleles A1,
Cw7, B8, BfS, C4AQ0, C4B1, DRB1*0301, and DQB1*0201 and is
denominated 8.1 after the HLA-B8 allele present in this haplotype
(11). The complete description of the ancestral haplotypes investigated in the present study is given in Material and Methods.
We hypothesized that the multiplicity of HLA gene variants and
loci associations with slow progression or rapid progression to
AIDS could be due to LD with a causative gene or causative genes
controlling these traits, and that examining the associations of ancestral haplotypes or their recombinant fractions could be useful to
map the MHC regions that may contain such gene(s). The fact that
ancestral haplotypes have been conserved in blocks during evolution may otherwise suggest that they each could play a role as a
whole, possibly regulated at the transcriptional level by “neighborhood effects” (15).
Toward this end, we have used the genetics of resistance/susceptibility to immunodeficiency virus (GRIV) cohort, which is
composed of patients with extreme patterns of progression, slow
and rapid progression, and is the largest cohort of its kind in the
world. HLA genotyping for HLA-A, -B, and -C and HLA-DR and
associations with AIDS have already been described in that cohort
(3). Further examination of the DQ alleles in this cohort has permitted
0022-1767/03/$02.00

3. 1926
MHC ANCESTRAL HAPLOTYPES AND PROGRESSION TO AIDS
FIGURE 1. This figure presents the
alignments of the genes in the HLA
region.
extension of our previous studies and the analysis of ancestral haplotypes. The haplotypes have been imputed by the presence of haplotypic allele markers, because it was not possible to strictly prove their
segregation from family studies. The investigation presented in this
study allows the delineation of specific MHC regions likely to be
functionally involved in the different patterns of disease progression.
Materials and Methods
Subjects
The GRIV cohort was established in 1995 in France to generate a large
collection of DNA samples for genetic studies of candidate human polymorphisms associated with rapid and slow progression to AIDS (3). To
avoid confounding effects associated with racial/ethnic differences in the
genetic analysis, only Caucasians of European descent were recruited from
hospital-based AIDS units throughout France. Slow progressors (SP) were
defined as asymptomatic individuals who had tested seropositive for HIV-1
for Ն8 years with a CD4ϩ cell count of Ͼ500/mm3 in the absence of
antiretroviral therapy. A seropositive test result for Ͼ8 years was necessary
for inclusion in the study. Rapid progressors (RP) were defined by a CD4
count of Ͻ300/mm3 in a period of time of Ͻ3 years after the last seronegative testing. We selected for the study individuals with complete intermediate to high resolution typings for HLA-A, -C, -B, -DRB1, and
-DQB1 loci. Seventy-four RP and 198 SP to AIDS were included in the
study.
Ancestral haplotypes frequencies for a population of 65,700 French subjects (control French population (CFP)) were previously published by Lonjou et al. (16).
Genetic typings and reconstruction of the MHC ancestral
haplotypes
The methodology for HLA class I and II, and MHC class I chain-related
gene A (MICA) DNA typings was previously described (3, 17). The ancestral haplotypes were reconstructed by imputation of haplotypic allele
markers as previously described (11, 12, 18) and are putative, because it
was not possible to strictly prove their segregation from family studies. The
most frequent ancestral haplotypes found in the GRIV cohort (frequency
Ͼ1%), studied in the present investigation, were the following: 7.1 (HLAA*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, and
DQB1*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 haplotype 35.1 definition does not include an HLA-A allele.
Statistical analysis
The analysis of statistical significance was done by using Pearson’s ␹2 and
Fisher’s exact tests, 2 ϫ 2 contingency tables, and the aid of the INSTAT
2.01 computer program (GraphPad, San Diego, CA).
Table I. Comparative frequencies of ancestral haplotypesa
Frequency ϫ 100
Ancestral
Haplotypes
7.1
8.1
35.1
35.2
44.1
44.2
57.1
SP vs CFP
RP vs CFP
SP (n ϭ 198)
RP (n ϭ 74)
CFP
p value
OR
95% C.I.
p value
O.R.
95% C.I.
2.5
6.6
0.5
3.5
8.5
4
5.1
0
10.8
5.4
1.4
4
8.1
2.7
2.4
3.9
1
Ͻ1
1.7
2.5
0.9
0.90
0.08
0.73
0.001
<0.0001
0.24
<0.0001
1.1
1.7
0.5
3.6
5.4
1.6
5.9
0.4–2.6
1–3
0.07–3.6
1.7–7.7
3.3–9
0.8–3.3
3.1–11.1
0.33
0.006
0.001
0.72
0.26
0.007
0.31
0.3
3
5.7
1.4
2.4
3.4
3.1
0.02–4.4
1.4–6.2
2.1–15.5
0.2–9.8
0.8–7.8
1.5–7.9
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). A
two-tailed Pearson’s ␹2 test was used to analyze the data as indicated in Materials and Methods. C.I., Confidence interval.

4. The Journal of Immunology
1927
a
Table II. Recombinant fragments between SPs and RPs
a
Cobigram presenting the recombinant fragments among the SP and RP populations. A one-tailed Fisher’s
exact 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 shown
in color. Yellow, OR within 0.5 and 2 (no association); red, OR Ͼ2 (rapid progression); green, OR Ͻ0.5 (slow
progression). Haplotype 7.1 is not shown, because it does not exist in the RP group.
Results
The 35.2, 44.1, and 57.1, and the 8.1, 35.1, and 44.2 ancestral
haplotypes are associated with slow and rapid progression to
AIDS, respectively
To identify associations of ancestral haplotypes with slow or rapid
progression to AIDS we compared the frequencies of haplotypes
found in the GRIV cohort with the frequencies of haplotypes previously published in a normal French population (16). Among the
ancestral haplotypes previously described (13, 14), seven had a
frequency Ͼ1% in the GRIV cohort: 7.1, 8.1, 35.1, 35.2, 44.1,
44.2, and 57.1 (see Material and Methods). Significant associations with slow progression were obtained for the 35.2 (odds ratio
(OR) ϭ 3.6, p ϭ 0.001), 44.1 (OR ϭ 5.4, p Ͻ 0.0001), and 57.1
(OR ϭ 5.8, p Ͻ 0.0001) ancestral haplotypes (Table I). We also
found an increased frequency of the 8.1 (OR ϭ 3, p ϭ 0.0057), of
the 35.1 (OR ϭ 5.7, p ϭ 0.001), and of the 44.2 ancestral haplotypes (OR ϭ 3.4, p ϭ 0.007) in RP as compared with that in the
normal French population (Table I). No association was identified
with the 7.1 haplotype (Table I).
Because the 8.1 haplotype has previously been associated with
increased TNF-␣ production due to an LD with the Ϫ308 G/A
single nucleotide polymorphism (SNP) in the TNF-␣ promoter
(19), we have genotyped the GRIV cohort for the Ϫ308 G/A SNP.
We retrieve the LD between the rare A allele of that SNP and the
8.1 ancestral haplotype, which could give an explanation of the
observed association of this haplotype with rapid progression
to AIDS.
Identification of candidate regions associated with slow
progression and rapid progression to AIDS in the GRIV cohort.
To identify regions within the HLA locus associated with slow or
rapid progression, we used recombinant mapping methodology
(20) and compared the frequency of haplotype fragments found in
SP with that in RP in the GRIV cohort (Table II).

5. 1928
MHC ANCESTRAL HAPLOTYPES AND PROGRESSION TO AIDS
The 8.1 haplotype was fixed from the HLA-A loci to the HLADQB1 loci in the majority of RP to AIDS, making it impossible to
map a region specifically associated with that trait by comparison
with SP to AIDS (Table II). The haplotype 35.1 exhibited a striking association with rapid progression for all fragments within the
C/DQB1 interval. The peak was obtained for the B/DQB1 interval
with an OR value of 14.3 ( p ϭ 0.006). For the haplotype 35.2, a
peak association with rapid progression was observed for the interval C/B with an OR of 2.3 and a p value of 0.02. Thus, carrying
the whole 35.2 haplotype resulted in the expression of the SP phenotype (Table I), while carrying the HLA-C/B interval of this haplotype resulted in the expression of the RP phenotype (Table II).
For the haplotype 44.1, a nearly significant association with slow
progression is obtained for the DRB1/DQB1 interval (OR ϭ 0.5,
p ϭ 0.06). For the haplotype 44.2, an association is observed with
rapid progression to AIDS with the intervals A/B and C/B with
ORs close to 2.4 and p values close to 0.05 (Table II). The DRB1/
DQB1 interval of the 57.1 haplotype was significantly associated
with slow progression to AIDS (OR ϭ 0.33, p ϭ 0.05); however,
all the fragments between C and DQB1 exhibited similar ORs
close 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 particular
interest, because it is the most prevalent allele in the Caucasian
population (frequency of ϳ34%). The HLA-B gene is very close to
the MICA gene (Fig. 1), and it is known that the HLA-B*4403
allele present in the 44.2 ancestral haplotype is known to be in LD
with the MICA*004 allele, while the HLA-B*4402 allele in the
44.1 ancestral haplotype is in LD with the MICA*008 allele (18).
The MHC class I chain-related gene B (MICB) allele MICB*01021
is found in both the 44.1 and the 44.2 ancestral haplotypes (18). A
preliminary analysis of the GRIV cohort shows that, in fact, most
of the HLA-B44 carriers in our sample of RP are MICA*004, while
most of the HLA-B44 carriers in the SP are MICA*008 (data not
shown).
A recently published study showed an epistatic interaction between the killer Ig-like receptor (KIR) genes and HLA-B genes,
with an impact as strong as the CCR-5 ⌬32 deletion (21). In that
study, an association was observed only when analyzing the KIRs
in combination with their HLA ligands. It is known that the
KIR2DL2 and 2DL3 receptors on NK cells bind a conserved
HLA-C1 group motif (defined by S77 and N80), whereas the
KIR2DL1 receptor binds the HLA-C2 group (N77 and K80). We
tried to compare the RP and SP to AIDS by sorting them in the
HLA-C1 or HLA-C2 group motifs, but we could not see any difference. As described by Martin et al. (21), it might be necessary
to analyze the combination of HLA and KIR gene polymorphisms
to observe an association.
Discussion
Although the frequencies of ancestral haplotypes in all populations
are extremely low (11, 12, 16), we are reporting for the first time
an association of the 35.2, 44.1, and 57.1 ancestral haplotypes, and
of the 35.1 and 44.2 ancestral haplotypes with slow progression
and rapid progression to AIDS, respectively. Previous reports have
also found that the 8.1 ancestral haplotype is associated with rapid
progression to AIDS (22, 23). Of note, these associations between
ancestral haplotypes and AIDS progression withstand Bonferroni
corrections. 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 explanation
based on the small number of subjects carrying ancestral haplotypes and a biological explanation based on the importance of the
contextual arrangement of genetic elements for successful immu-
nologic control of HIV-1 infection. For instance, the single allele
HLA-B8 alone is not associated with rapid progression to AIDS
(3); the HLA-B8 allele is associated with rapid progression only in
the full context of the ancestral haplotype 8.1. Our results do not
exclude that ancestral haplotypes are associated with susceptibility
to infection, because they are generally higher in both the SP and
RP populations than in the CFP population. It is unlikely that there
is a bias in the CFP population, because the haplotyping involved
65,700 individuals (16) and the frequencies are very similar to the
ones from other large studies (24).
Until now, the most widely viewed explanation for HLA influence is that class I and class II genes act directly by restricting the
immune response—Ag peptidic presentation—inducing selection
of HIV-1 viral escape mutants: in fact, the direct interaction between HLA and the generation of escape mutants can be analyzed
directly (25). Our approach based on the analysis of recombinant
ancestral haplotypes (fragments of these haplotypes) should permit
further mapping and identification of new disease susceptibility
genes within the HLA locus acting in concert with the classical
MHC class I and II genes (20). Our results suggest that the HLAC/B regions of the 44.2 and 35.2 ancestral haplotypes are associated with rapid progression to AIDS, and that the DRB1/DQB1
regions of the 44.1 and 57.1 ancestral haplotypes are associated
with slow progression to AIDS. For the haplotype 35.1, all intervals were associated with rapid progression to AIDS with a peak
for B/DQB1. It is important to emphasize that these data do not
integrate Bonferroni corrections, and only the associations of the
B/DQB1 and DRB1/DQB1 fragments of the 35.1 haplotype with
rapid progression to AIDS would remain significant if such corrections were applied. It was not possible to determine the effect of
specific recombination events within the 8.1 ancestral haplotype
because the haplotype was totally conserved among RP subjects;
however, we found it in total LD with the previously described
Ϫ308 A allele of TNF-␣ promoter (19).
Interestingly, among the seven ancestral haplotypes studied,
four of them involve HLA gene alleles that were previously associated with disease progression (3): HLA-B35 for haplotypes B35.1
and B35.2, HLA-DRB11 for the haplotype 35.1, HLA-A29 for the
haplotype B44.2, and HLAB57 for the haplotype B57.1. Unlike
HLA-B35, the ancestral haplotype B35.2 exhibited an association
with slow progression to AIDS (Table I). However the C/B fragment of this ancestral hapolotype seemed to be associated with
rapid progression to AIDS (Table II) and tends to confirm the
direct role of HLA-B35 allele in AIDS progression. A corrective
effect may occur elsewhere in the haplotype, whether between the
A and C gene, suggesting a possible role for HLA-E, or in the
B/DQB1 region pointing out MICA/B or TNF-␣. The analysis of
the recombinant fragments of 35.1 suggests a strong association
with rapid progression to AIDS for all the recombinant fragments,
highly significant for the B/DQB1 fragment (Table II): the association of the B35.1 haplotype appears bimodal with a peak in the
OR at 14.3 linked with the combined association of the alleles B35
and DR11, and two smaller ORs but very significant ( p ϭ 0.02 and
p ϭ 0.004) at the level of the C/B and DRB1/DQB1 fragments,
respectively, which correspond to the associations of B35 and
DR11 with rapid progression to AIDS we previously described (3).
This could suggest the tracking effect of an association for a gene
located within the B/DRB1 fragment, or a synergistic effect for the
combination of the individual alleles B35 and DR11. A recent
work has shown that the HLA-B35 allele effect was associated with
the subtypes 02, 03, and 04 of B35 (9). It is not known whether the
ancestral haplotypes 35.1 and 35.2 are associated with a given
subtype of B35 and that analysis will need to be performed. Of
interest, the association with rapid progression to AIDS found on

6. The Journal of Immunology
the C/B region for both the 35.1 and 35.2 haplotypes in the recombinant analysis had an OR of 2.3, similar to the one published
for the B35 subtypes 02, 03, and 04 (9). The association of the 44.2
haplotype with rapid progression to AIDS is similar in amplitude
to the one we previously described for A29 (3); however, the recombinant fragment C/B of the 44.2 haplotype appears also sufficient to track that association. Finally, for the HLA-B57 association, the recombinant analysis of the 57.1 haplotype points to the
whole C/DQB1 region: unlike the 35.1 haplotype, the ORs are
similar for all fragments, and all the genes in the C/DQB-1 region
could thus be good candidates to explain the association. In this
study of recombinant fragments, no discrepancy is observed between B and C genes, on the one hand, and DRB1 and DQB1, on
the other hand, reflecting their close proximity on chromosome 6.
In the DR/DQ region, besides the HLA DR/DQ genes themselves, the neighboring genes known as transporter associated with
Ag processing and large multifunctional protease are interesting
candidate genes that are functionally involved in the Ag processing
by class I molecules (26). Around the HLA B/C genes, promising
candidates are the genes of the MICA and MICB, but the HLA-E
locus located in between the HLA-A and HLA-C is also polymorphic (27, 28). MICA and MICB proteins are ligands of the NK
cell-activating receptor NKG2D (29), while HLA-E is the ligand
of the inhibitory NKG2A, -B, and -C receptors (30 –32).
In conclusion, our study confirms that the molecular mechanisms underlying the associations between HLA genes and AIDS
disease progression are not always direct effects of HLA restriction
but can also be indirect effects due to LD, or both. Our analysis
through the ancestral haplotypes has brought some insight into the
possible mechanisms by pointing out class I, II, or III MHC regions linked to various HLA alleles susceptible to being associated
with disease progression. The combined analysis of the TNF-␣,
MICA/B, HLA-E, transporter associated with Ag processing, large
multifunctional protease, and KIR/killer cell-activating receptor
gene polymorphisms as well as of the viral gene sequences (25)
and their interactions (21) should certainly bring a definitive answer to these questions.
1929
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Acknowledgments
We are grateful to all the patients and medical staff who have kindly collaborated with the project.
23.
24.
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