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Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 936-941
Combined Genotypes of CCR5, CCR2, SDF1, and HLA Genes Can Predict
the Long-Term Nonprogressor Status in Human Immunodeficiency
Virus-1-Infected Individuals
By
Magdalena Magierowska,
Ioannis Theodorou,
Patrice Debré,
Françoise Sanson,
Brigitte Autran,
Yves Rivière,
Dominique Charron,
French ALT,
IMMUNOCO Study Groups, and
Dominique Costagliola
From the Laboratoire d'Immunologie Cellulaire et Tissulaire, UMR
CNRS 7627, Hôpital Pitié-Salpêtrière, Paris;
URA CNRS 1157, Institut Pasteur, Paris; Laboratoire d'Immunologie,
Hôpital Saint-Louis, Paris; and INSERM SC4, IFR Saint-Antoine de
recherche en Santé, Paris, France.
 |
ABSTRACT |
Human immunodeficiency virus (HIV)-1-infected long-term
nonprogressors (LT-NP) represent less than 5% of HIV-1-infected
patients. In this work, we tried to understand whether combined
genotypes of CCR5- 32, CCR2-64I, SDF1-3'A and HLA alleles can
predict the LT-NP status. Among the chemokine receptor genotypes, only
the frequency of the CCR5-32 allele was significantly higher in
LT-NP compared with the group of standard progressors. The predominant HLA alleles in LT-NP were HLA-A3, HLA-B14, HLA-B17, HLA-B27, HLA-DR6, and HLA-DR7. A combination of both HLA and chemokine receptor genotypes
integrated in a multivariate logistic regression model showed that if a
subject is heterozygous for CCR5-32 and homozygous for SDF1 wild
type, his odds of being LT-NP are increased by 16-fold, by 47-fold when
a HLA-B27 allele is present with HLA-DR6 absent, and by 47-fold also if
at least three of the following alleles are present: HLA-A3, HLA-B14,
HLA-B17, HLA-DR7. This model allowed a correct classification of 70%
of LT-NPs and 81% of progressors, suggesting that the host's genetic
background plays an important role in the evolution of HIV-1. The
chemokine receptor and chemokine genes along with the HLA genotype can
serve as predictors of HIV-1 outcome for classification of
HIV-1-infected subjects as LT-NPs or progressors.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
IN HUMAN immunodeficiency virus (HIV)-1
disease, a small fraction (<5%) of infected individuals remains
asymptomatic and clinically healthy for long periods.1
These individuals usually have a lower viral load and higher and
relatively stable peripheral blood CD4+ cell counts
compared with the normal/rapid progressors.2 It is still
unclear whether these subjects represent a distinct group, sharing a
common biological phenomenon for such a resistance to progression or if
they are only casual and extremely rare exceptions to the general rule.
Some investigators proposed that the HIV-1 disease-free progression
might be genetically controlled.3 The first candidates were
the major histocompatibility complex genes (MHC-HLA in humans).
Combination of HLA class I (HLA-A1, HLA-A2, HLA-B14, HLA-B17, HLA-B27)
and class II antigens (HLA-DR5 and HLA-DR6) have been correlated with
low rates of disease progression.4-7 In contrast, the
presence of HLA-B35, HLA-DR1, HLA-DR3, HLA-DQ1 antigens was
significantly associated with a bad prognosis and a rapid progression
to acquired immunodeficiency syndrome (AIDS).8-11
More recently, several groups showed that the polymorphic genes of the
chemokine receptor family and particularly the CCR5 and CCR2 genes,
which were identified as coreceptors for HIV-1 entry into the
cell,12-16 also influence disease-free survival of
HIV-1-infected patients. A truncated form of CCR5 (a  32-bp, observed in white individuals only17) and a mutated form of the CCR2 (64I) were more frequently found in individuals whose progression to AIDS was postponed compared with rapid
progressors.18-21 Two recent reports showed that, in
whites, the CCR2 and CCR5 mutant alleles are in strong linkage
disequilibrium.19,22
Despite important studies, it is still controversial whether the
CCR532 allele protects from progression to AIDS. In seroconverters, for which long-term data were available, the CCR532 heterozygotes were shown to develop the AIDS-defining illness significantly later
than patients without the 32bp.18 On the other hand, other investigators reported only a slightly different disease course
with a lower proportion of AIDS-free individuals during the first 4 to
6 years after seroconversion and a higher proportion of AIDS-free
individuals after 10 years.23 Our group found that the
protective effect of the 32 deletion was detectable during the first
7 years of infection.24
Other genetic factors, namely an SDF1 chemokine gene variant
SDF1-3'A, which is the ligand for the CXCR4 chemokine receptor, conferred a recessive protective effect in long-term nonprogressors (LT-NP).25
In this report, we studied chemokine receptors (CCR2, CCR5), chemokine
(SDF1), and HLA class I and II genotypes in LT-NP and attempted to find
out whether any particular pattern of host genetics could be implicated
in the LT-NP phenotype. Data presented in this report show for
the first time that the combined host genetic background strongly
influences the evolution of HIV-1 disease. The CCR5/CCR2/SDF1 and HLA
loci appeared to influence independently disease progression. Mutated
variants of CCR5, CCR2, and SDF1 genes along with the HLA genotype can
serve as predictors of HIV-1 infection outcome and allowed the correct
classification of 70% of HIV-1-infected subjects as LT-NP
and 81% as progressors.
| |
MATERIALS AND METHODS |
Studied cohorts.
Subjects from two different French cohorts were included in our study:
a cohort of LT-NP (French ALT) and a cohort of standard progressors (IMMUNOCO). From the two cohorts, only subjects of white
origin were taken into account for statistical analysis: 70 from French
ALT and 83 from IMMUNOCO. A total of 153 subjects were analyzed. The
main characteristics of individuals are presented in Table 1. The
evolution of the immune and virologic status of both cohorts has been
described elswhere (ALT: Hadida et al; Candotti et al, XI International
Conference on AIDS 1996, V Conference on Retroviruses and Opportunistic
Infections 1998 and manuscript in preparation; IMMUNOCO: Autran et al,
XI International Conference on AIDS 1996 and manuscript in preparation).
Genotyping assay.
The presence of the CCR532 allele was determined using a polymerase
chain reaction (PCR)-based assay as already described.17 The CCR2-64I allele was detected by PCR-restriction fragment length polymorphism (RFLP) assay. The 380-bp fragment from the
NH2-terminal domain of the gene was amplified using
5'-GGATTGAACAAGGACGCATTTCCCC-3' and
5'-TTGCACATTGCATTCCCAAAGACCC-3' as forward and reverse
primers, respectively. PCR was run for 40 cycles at 63°C annealing
temperature. Digestion with Fok I restriction endonuclease
yielded 215-bp and 165-bp fragments only when an ATC triplet coding for
isoleucine (64I) was present. The SDF1-3'A allele was detected by
PCR-RFLP as described by Winkler et al.25 HLA class I
(HLA-A, HLA-B) typing was performed by standard serological methods and
class II (HLA-DRB1) by generic molecular typing.
Statistical analysis.
We performed a case-control analysis with cases defined as subjects
included in the ALT cohort and controls as subjects included in the
IMMUNOCO cohort. Cases and controls were compared for baseline characteristics using the  2 test for categorical
variables (sex, transmission) and the nonparametric Mann-Whitney test
for continuous variables (age at first positive test, time since first
positive test, CD4 counts and CD8 counts). These data are presented in
Table 1. For the comparison of genotypes between case and control
subjects, we considered only those HLA alleles present in at least 10%
of all subjects (cases + controls). Alleles were compared between the
two groups and only those alleles with a comparison 2
P value less than .20 were retained for further analysis. This is nearly equivalent to the limits chosen by Kaslow et al5 in their recent report. Similar analysis was performed to assess the
role of CCR2, CCR5, and SDF1 genotype and that of different potential
confounding factors. Age and transmission group (homo/bisexual men,
heterosexuals, intravenous [IV] drug users, others) were considered
as potential confounding factors because they are associated in the
literature with disease progression. Age was considered as a continuous
variable. We also studied linkage disequilibrium between CCR5 and CCR2,
as well as HLA genes. A multivariate stepwise logistic regression was
used to assess the roles of HLA genotypes, CCR2, CCR5, and SDF1
genotypes and potential confounding factors. All 2 × 2 interactions were tested and when interaction was detected, combined
variables were used in further analysis. Only genotypes and confounding
factors selected as significant in the multivariate analysis were
further considered. As described by Kaslow et al,5 we also
constructed a summary HLA score by counting the number of HLA genotypes
that were found associated with long-term nonprogression. To assess the
goodness of fit of the final model, the distribution of the
standardized residuals was compared with a normal distribution. The
robustness of our model was explored by performing an estimation of the
logistic model parameters 50 times on a random sample of 80% of the
subjects. The frequency of significantly positive variables included in
the model was evaluated and the odds-ratio values were compared.
| |
RESULTS AND DISCUSSION |
In this study, we performed a comparative analysis of subjects included
in two French cohorts of LT-NP (ALT) and of progressors (IMMUNOCO),
taking into account the contribution to the slow progression of the
HIV-1 infection, of confounding factors, and genetic components such as
the CCR5, CCR2, and SDF1 genes and the HLA class I and II alleles. The
confounding factors (sex, age, and transmission group) were similar
between the two cohorts (Table 1).
We screened for three frequent modifications in chemokine receptors:
CCR5-32, CCR2-64I, and a chemokine gene SDF1-3'A. When taking
into account the genetic background of HIV-1-infected subjects, we
observed a higher frequency of the CCR5-32 allele in LT-NP with 37%
of heterozygotes compared with the 14% found in progressors (Table 2), confirming earlier published
studies.20,26 This finding is not very surprising because
the CCR5-32 allele was already suggested as protective against rapid
progression in HIV-1 disease.18,20,23,24,26 We did not find
any homozygous individual for this mutated allele in any of the two
groups. The two other mutated alleles, CCR2-64I and SDF1-3'A,
occurred at similar frequencies in both LT-NP and progressors and few
homozygous individuals were found for either mutation. To avoid samples
too small for a meaningful statistical analysis, two groups were
created with one group of individuals bearing at least one mutation,
and in the other, group wild-type individuals (Table 2). After
regrouping, we observed 23% of CCR2 wild/mut genotypes
among LT-NP and 16% among progressors (P = .258). Similarly,
36% of LT-NP had at least one mutant SDF1 allele versus 44% in
progressors (P = .335). A detailed description of the different
genotypes comprising CCR2, CCR5, and SDF1 genes is presented in
Table 3. We did not find a clear linkage
disequilibrium between the CCR2 and CCR5 genes (2 × 2 analysis,
P = .074). This finding is not necessarily in
contradiction with the report by Smith et al,19 because the
design of both studies was slightly different (ours a case/control
study v a cohort study by these investigators) or could also be
explained by a lack of power in our study. As with Smith et al, we did
not find any CCR2 mut/mut individual bearing also the 32
modification of the CCR5 gene. It is worth noting that only two LT-NP
subjects were found SDF1 mut/mut compared with four progressors at
variance to the results reported by Winkler et al25 (Table
2). This difference may be due to the following reasons: (1) our study
was based on the precisely characterized group of LT-NPs compared with
the control group of normal progressors, while Winkler analyzed the
slow/nonprogressors category issued from the cohort of seroprevalent
subjects without giving any clear definition of this group; (2) Winkler
et al stated that although SDF1-3'A/3'A protection was more
apparent in later stages of HIV-1 infection, the principal effect may
involve a strong protection against rapid progression to AIDS. Because
we did not study the rapid progressors, it is not surprising that in
our particular group of LT-NP subjects, we did not find the same
results as Winkler et al.
However, it seems more likely that several other mechanisms predispose
an individual to a rapid or a slow evolution of the HIV-1 disease. Many
investigators propose, following studies on independent samples, that
HLA genes may also play a part in delaying the AIDS symptoms, as they
are strongly implicated in the control of the cellular response to pathogens.
In both cohorts, we measured the frequency of HLA alleles (class I and
II). We report in Table 2 only those markers found in more than 10%
and less than 90% of the individuals, for which the P value
was lower than .20. The predominant HLA alleles found were HLA-A3,
HLA-B14, HLA-B17, HLA-B27, HLA-DR6, and HLA-DR7 in LT-NP subjects and
HLA-B12 in progressors (Table 2).
We then looked for possible genetic links between these markers.
Statistically significant associations were found in all subjects of
both cohorts for the following allelic couples: HLA-B5/HLA-DR6, HLA-B12/HLA-DR7, HLA-B17/HLA-B12, and HLA-B17/HLA-DR7. Next, we proceeded with a multivariate analysis and, as a result, retained only
six single alleles as being significantly more frequent in the LT-NP
group: HLA-A3, HLA-B14, HLA-B17, HLA-B27, HLA-DR6, and HLA-DR7, for
which the P value was lower than .05. The HLA-B12 allele was
not retained after this analysis. These alleles have been already
proposed by others as associated with an increased probability for
AIDS-free infection.4-6
All data were collated to build a genetic model, predictive for
long-term nonprogression of HIV-1 disease. We then looked for
interactions between the different genes and their impact when LT-NP
and progressors were compared. Interactions were evident between the
CCR2/CCR5/SDF1 genes and between HLA-B27 and HLA-DR6, respectively. We
constructed combined variables (Table 4).
The first one comprised the CCR2, CCR5, and SDF-1 genes. The
combination CCR2 wild/mut, CCR5 wild/wild, and SDF1 wild/wild was
associated with an odds-ratio of being LT-NP of 4.6 (P = .036).
The most frequently observed combination in nonprogressors was the CCR2 wild/wild or wild/mut, CCR5 wild/mut, and SDF1 wild/wild (P = .0002). The odds-ratio of being LT-NP was estimated as 25.8 for a
subject bearing this composite genotype compared with a subject with
only wild-type genotype (Table 4). In other words, in
HIV-1-infected subjects with this gene combination, the odds of
meeting the criteria of LT-NP increase by 26-fold. Apparently, the CCR5
mutated allele dominates over the two other genes during restriction to
AIDS. Although we did not find any protective effect by SDF1 mut/mut allele itself as Winkler et al,25 the role of this gene in
AIDS avoidance seems to be important, as its wild-type allele is
strongly associated with the 32 deletion of CCR5 in our combined
genotype. As was reported for CCR2 and CCR5 genes,19 SDF1
might also be in linkage disequilibrium with an as yet unidentified
marker, which could influence the LT-NP status.
The second combined variable investigated was the combination of
HLA-B27 present and HLA-DR6 allele absent, which was found much more
frequently in the LT-NP than in progressors, with an odds-ratio
estimated as 81 as compared with a subject without HLA-B27 or HLA-DR6.
The third combined variable was built out of the four following
alleles: HLA-A3, HLA-B14, HLA-B17, and HLA-DR7 because no interaction
was found between them. We simply assessed how many of these alleles
were present in a given subject and attributed an HLA score of: 0 when
no allele was present, 1 when one or two alleles were present, and 2 when three or four alleles were present. As shown in Table 4, LT-NPs
were more likely to present either one or two markers (70% v
54%) or three or four markers (10% v 1%) compared with
progressors. We found that this HLA score was an independent predictor
of long-term nonprogression. For an individual with one or two of the
above HLA markers, the odds-ratio of being LT-NP was estimated as 4.4 as compared with an individual with none of these four alleles. For an
individual with at least three HLA markers, the odds-ratio of being
LT-NP was estimated as 49.5.
When assessing goodness of fit of our model, no departure from
normality was observed when checking the distribution of the standardized residual. Similarly, the three variables included in the
final model were found significant in 50 of 50 parameter estimations
performed on 50 independent random samples including 80% of the
subjects, showing the robustness of the analysis. Of course, our model
deserves to be confirmed on another independent set of subjects. When
all analyzed genetic factors were integrated in the logistic model,
70% of LT-NP and 81% of progressors were correctly classified,
suggesting that the host's genetic background plays an important role
in the evolution of HIV disease.
We showed for the first time that LT-NP share a particular genotype for
both HLA and chemokine receptor loci, which independently influence the
outcome of their disease. The most important point seems to be that the
chemokine and chemokine receptor genes act in a particular combination
with the most significant effect observed with the CCR5-32 and SDF1
wild-type alleles. We are still far from a definitive understanding of
the LT-NP phenomenon. However, in our opinion, a complex screening of
the genetic background of HIV-1-infected subjects would increase the
predictive ratio of disease evolution. The lesson we will learn from
these subjects could modify the follow-up and the differential
administration of treatment to those with progressive disease and
serve, besides viral load and CD4 cells counts, as a decision-making
tool for management of HIV-1-infected patients.
| |
APPENDIX |
The French ALT Study Group is composed of the presenting authors
together with H. Agut, V. Calvez, D. Candotti, C. Taureau, and J-M
Huraux, Laboratoire de Virologie, Hôpital
Pitié-Salpêtrière, Paris; A. Goubar and L. Marrero,
INSERM SC4, Hôpital Saint-Antoine, Paris; F. Hadida and O. Bonduelle, Laboratoire d'Immunologie Cellulaire et Tissulaire, UMR
CNRS 7627, Paris; N. Ngo-Giang-Huong and C. Rouzioux, Laboratoire de
Virologie, Hôpital Necker-Enfants-Malades, Paris; J-P Clauvel and
J-M Bouley, Sevice d'Immuno-Hématologie, Hôpital
Saint-Louis, Paris; D. Sicard and S. Chaput, Médecine Interne,
Hôpital Cochin, Paris; R. Vigne, INSERM U372, Campus de Luminy,
Marseille, France.
The IMMUNOCO Study Group is composed of the following persons: B. Autran, Laboratoire d'Immunologie Cellulaire et Tissulaire, UMR CNRS
7627, Paris; J-M Bouley, Sevice d'Immuno-Hématologie, Hôpital Saint-Louis, Paris; Elisabeth Gomard, Direction
Générale au Service des Programmes, INSERM, Paris; Yves
Rivière, URA CNRS 1157, Institut Pasteur, Paris; C. Katlama,
Service des Maladies Infectieuses, Hôpital
Pitié-Salpêtrière, Paris.
| |
ACKNOWLEDGMENT |
The authors thank Dr Stephen J. O'Brien for sharing SDF1-3'A
data before publication and Marie-Hélène Sumyuen for
critically reading the manuscript.
| |
FOOTNOTES |
Submitted May 14, 1998; accepted September 22, 1998.
M.M. is a fellow of SIDACTION. D.C. was supported by a grant from the
Agence Nationale de la Recherche sur le SIDA.
See Appendix for a list of members of the French ALT and IMMUNOCO Study Groups.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Patrice Debré, MD, PhD,
Laboratoire d'Immunologie Cellulaire et Tissulaire, CNRS 7627, CERVI,
Hôpital Pitié-Salpêtrière, 83, Bd de
l'Hôpital 75651 Paris Cedex 13, France; e-mail:
patrice.debre{at}psl.ap-hop-paris.fr.
| |
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Top
Abstract
Introduction