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Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 1838-1842
RAPID COMMUNICATION
Chemokine and Chemokine Receptor Gene Variants and Risk of
Non-Hodgkin's Lymphoma in Human Immunodeficiency Virus-1-Infected
Individuals
By
Charles S. Rabkin,
Quan-en Yang,
James J. Goedert,
Giao Nguyen,
Hiroaki Mitsuya, and
Shizuko Sei
From the Viral Epidemiology Branch, HIV and AIDS Malignancy Branch,
and Experimental Retrovirology Section, National Cancer Institute,
Bethesda, MD; the HIV Clinical Interface Laboratory, Science
Applications International Corp-National Cancer Institute, Frederick,
MD; and the Department of Internal Medicine II, Kumamoto University
School of Medicine, Kumamoto, Japan.
 |
ABSTRACT |
Normal B-lymphocyte maturation and proliferation are regulated by
chemotactic cytokines (chemokines), and genetic polymorphisms in
chemokines and chemokine receptors modify progression of human immunodeficiency virus-1 (HIV-1) infection. Therefore, 746 HIV-1-infected persons were examined for associations of previously
described stromal cell-derived factor 1 (SDF-1) chemokine and CCR5 and
CCR2 chemokine receptor gene variants with the risk of B-cell
non-Hodgkin's lymphoma (NHL). The SDF1-3'A chemokine variant,
which is carried by 37% of whites and 11% of blacks, was associated
with approximate doubling of the NHL risk in heterozygotes and roughly
a fourfold increase in homozygotes. After a median follow-up of 11.7 years, NHL developed in 6 (19%) of 30 SDF1-3'A/3'A
homozygotes and 22 (10%) of 202 SDF1-+/3'A heterozygotes,
compared with 24 (5%) of 514 wild-type subjects. The acquired
immunodeficiency syndrome (AIDS)-protective chemokine receptor variant
CCR5- 32 was highly protective against NHL, whereas the
AIDS-protective variant CCR2-64I had no significant effect. Racial
differences in SDF1-3'A frequency may contribute to the lower
risk of HIV-1-associated NHL in blacks compared with whites. SDF-1
genotyping of HIV-1-infected patients may identify subgroups
warranting enhanced monitoring and targeted interventions to reduce the
risk of NHL.
This is a US government work. There are no restrictions on its use.
| |
INTRODUCTION |
HUMAN IMMUNODEFICIENCY virus-1
(HIV-1)-infected individuals are at greatly increased risk of
non-Hodgkin's lymphoma (NHL), which arises as a late complication in
the setting of advanced immunodeficiency.1-3 These
HIV-1-associated lymphomas are characteristically of B-cell
immunophenotype and high-grade histology (including Burkitt's and
Burkitt's-like, immunoblastic, and large-cell diffuse) and frequently
involve extranodal primary sites (especially the central nervous
system).4 Heterogeneous acquired genetic lesions are
present in varying subsets of these tumors, including activation of the
c-myc (especially in Burkitt's lymphoma), BCL-6, and ras proto-oncogenes and inactivation of the p53 tumor-suppressor
gene.5 Episomal Epstein-Barr virus DNA is often detectable,
especially in primary central nervous system tumors.6
The pathogenesis of HIV-1-related B-cell lymphoma is poorly
understood, but may be related to HIV-induced immune dysregulation. HIV-1-infected individuals maintain a state of chronic B-cell hyperactivation and hyperproliferation, which may be a consequence of
disruption of the normal steady-state cytokine network and/or direct
stimulation by binding of HIV.7,8 Lymphomagenesis may be a
multistage process progressing from this polyclonal B-cell proliferation to oligoclonal expansion of antigen-selected clones and
subsequent outgrowth of a monoclonal tumor.9
Chemokines are cytokines that are produced and act locally in tissues
to attract and stimulate lymphocytes at sites of infection and
inflammation.10 A candidate chemokine mediating B-cell
hyperproliferation in HIV-1 infection is stromal cell-derived factor 1 (SDF-1), a member of the CXC family of polypeptide chemokines. SDF-1 is
a potent mitogen and chemoattractant for B cells and B-cell precursors, which is constitutively expressed by bone marrow stromal cells and in
other tissues.11,12 SDF-1 is a natural ligand of the G-protein-coupled seven transmembrane receptor, CXC-chemokine receptor
4 (CXCR4),13-16 and downmodulates CXCR4 surface expression on T-lymphocyte cell lines.17 CXCR4 also functions as a
coreceptor for T-cell-tropic HIV-1 isolates,13,14,18 and
SDF-1 blocks cellular entry of T-cell-tropic HIV-1 in
vitro.13,14
The SDF1 gene is polymorphic, and a variant with a G-to-A transition at
position 801 of the 3' untranslated region of the SDF-1 gene
transcript (designated SDF1-3'UTR-801G-A, and abbreviated as
SDF1-3'A) has an allele frequency of 21% in whites and 6% in blacks in the United States.19 SDF1-3'A/3'A
homozygotes have been variably reported to have slower19 or
faster20,21 progression of HIV-1 infection to acquired
immunodeficiency syndrome (AIDS) and death. Polymorphisms in two
chemokine receptor genes, CCR5 and CCR2, have been reported to be
protective against HIV-1. A 32-bp deletion in the coding region of the
CCR5 gene, termed CCR5- 32, and a valine to isoleucine substitution
at position 64 in the transmembrane domain of CCR2, termed CCR2-64I,
are each protective in heterozygotes against progression to
AIDS.22-25 CCR5-32 homozygotes are also strongly
protected against HIV-1 infection, but an effect of CCR2-64I on risk of
infection has not been demonstrated.22-25 Because
interactions between chemokines and chemokine receptors may be
important regulators of B-cell activation and proliferation, we
examined the associations of previously described SDF-1, CCR5, and CCR2
genetic polymorphisms with the risk of NHL in 3 HIV-1-infected cohorts.
| |
MATERIALS AND METHODS |
Research subjects came from three National Cancer Institute (NCI)
cohort studies of HIV-1-infected patients. One-hundred forty-six were
HIV-1-infected children receiving care from the HIV and AIDS Malignancy Branch (formerly a part of the Pediatric Branch), NCI, of
which 129 (88%) were infected neonatally.26 One hundred
twenty were HIV-1-infected male homosexuals and 480 were
HIV-1-infected hemophilia patients in two cohorts observed by the
Viral Epidemiology Branch, NCI.27,28 Median age at HIV-1
seroconversion was 33.2 years for the homosexual cohort and 20.2 years
for the hemophilia cohort. Additionally, 24 HIV-1-uninfected patients
with NHL observed in other NCI studies were included. All studies were
approved by institutional review boards of NCI and at collaborating
institutions, and written informed consent was obtained from each
subject (or his or her guardian).
Dates of HIV-1-seroconversion were estimated as previously described
for each cohort.26-28 Incident cases of NHL and other AIDS-defining clinical conditions were ascertained at follow-up visits
and from clinical records. Lymphoma cases were categorized by primary
site (as central nervous system v systemic) and, for systemic
tumors, by histologic subtype (as Burkitt's and Burkitt-like v
all other). Diagnoses of NHL made at other institutions were verified
at the NCI by examination of biopsy specimens (when available) and by
review of pathology reports. Data through February 1998 for the
pediatric cohort (median follow-up, 8.6 years) and through December
1997 for the homosexual (8.7 years) and hemophilia (12.6 years) cohorts
were used in this analysis.
SDF1-3'A genotyping was performed on peripheral blood mononuclear
cell DNA by a polymerase chain reaction (PCR)-restriction fragment
length polymorphism (RFLP) assay, as previously
described.19 CCR5-32 genotyping was performed by
single-strand conformation polymorphism (SSCP) analysis, as previously
described.23 CCR2-64I genotyping was performed by SSCP and
PCR-RFLP, as previously described.22 c-myc
translocations in circulating peripheral blood mononuclear cells were
detected by nested PCR, as previously described.29
Odds ratios were computed from the prevalence of variant genotypes in
subjects with and without NHL or other AIDS-defining clinical
conditions; odds ratios for NHL subtypes were computed from the odds in
subjects with a given subtype versus the odds in subjects without NHL.
P values and 95% confidence intervals (CI) on odds ratios were
calculated by Fisher's exact test, using Epi-Info version 5.0 (Centers
for Disease Control and Prevention, Atlanta, GA) and STATA version 5.0 (STATA Press, College Station, TX) software packages. Cox proportional
hazard regression modelling was performed to examine the effect of
SDF1-3'A on incidence of NHL after HIV-1 infection, using the
PHREG procedure in PC-SAS version 6.12 (SAS Institute, Cary, NC)
statistical software. Covariates in these models included race
(categorized as white, black, and other), age at seroconversion
(categorized in approximate tertiles as <12, 12 to 29, and >29
years), and CCR5-32 and CCR2-64I polymorphisms (categorized as
present [homozygous or heterozygous] and absent). Initial models
included separate terms for homozygous and heterozygous SDF1-3'A
genotypes; gene dose-effect was then estimated using a single term for
the number of allelic copies (0, 1, or 2) of SDF1-3'A.
| |
RESULTS |
SDF1-3'A carriers were at increased risk of NHL, and homozygotes
had a higher risk than heterozygotes. After a median follow-up of 11.7 years, 6 (19%) of 30 SDF1-3'A/3'A subjects and 22 (10%) of 202 SDF1-+/3'A subjects developed lymphoma, compared with 24 (5%) of 514 wild-type subjects (P < .01 for both
comparisons). The increased risk was particularly pronounced for
Burkitt's and Burkitt-like tumors (5 of 6 cases occurred in
SDF1-3'A carriers), although other high-grade systemic tumors and
primary brain lymphomas were also increased
(Table 1). SDF1-3'A was not
significantly associated with risk of Kaposi's sarcoma in male
homosexuals, based on 23 genotyped cases. SDF1-3'A homozygotes
had a slightly decreased frequency of opportunistic infection (ie,
AIDS-indicator clinical conditions other than NHL and Kaposi's
sarcoma), but the numbers were small and not statistically significant.
Because of the striking association with HIV-1-associated Burkitt's
lymphoma, an additional 20 HIV-1-negative Caucasians with Burkitt's/Burkitt-like lymphoma were evaluated for SDF1 genotype. Five
(25%) were SDF1-3'A carriers (all heterozygous) and 15 (75%) were wild-type. Four HIV-1-uninfected Caucasians with NHL of other histologies were also tested; all 4 were wild-type for SDF1.
CCR5-32 appeared to be protective against HIV-1-associated
lymphoma, with 2 (2%) of 98 CCR5-32 carriers developing NHL, compared with 49 (8%) of 619 wild-type subjects (P = .03;
Table 2). Conversely, the protective effect
of CCR2-64I against AIDS appeared to be restricted to an effect on
opportunistic infection, because 7 (6%) of 120 CCR2-64I carriers
developed NHL, compared with 22 (5%) of 466 wild-type subjects (Table
2).
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Table 2.
Associations of CCR5-32 and CCR2-64I With NHL and
Other AIDS Indicator Conditions in HIV-1-Infected Patients
|
|
Thirteen (12%) of 110 subjects in the homosexual cohort were
previously reported to have detectable c-myc translocations in circulating peripheral blood mononuclear cells.29 The
frequency of these translocations in subjects with chemokine and
chemokine receptor polymorphisms was similar to that of the overall
cohort. In those with sufficient DNA for the current analysis, 4 (11%) of 36 SDF1-3'A carriers, 1 (6%) of 16 CCR5-32 carriers, and 4 (18%) of 22 CCR2-64I carriers had circulating c-myc detected
on one or more occasions.
To further investigate the relationship of SDF1-3'A with
HIV-1-associated-NHL, lymphoma-free survival was graphed separately for the three cohorts. The cohorts differed in overall risk of NHL,
which occurred in 15 (10%) of 146 HIV-1-infected children and 16 (13%) of 120 HIV-1-infected male homosexuals (P = .5), compared with only 21 (4%) of 480 HIV-1-infected hemophilia patients (P = .01 and P = .001 v pediatric and
homosexual cohorts, respectively). However, cumulative incidence of NHL
was consistently higher in SDF1-3'A carriers (heterozygous plus
homozygous) compared with homozygous wild-type for all three cohorts
(Fig 1).
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| Fig 1.
Cumulative incidence of NHL in carriers (heterozygous
plus homozygous) of SDF1-3'A (solid lines) compared with
homozygous wild-type (dashed lines). Vertical ticks represent censoring
times of subjects without NHL. (Top panel) HIV-1-infected children (N
= 146). (Middle panel) HIV-1-infected male homosexuals (N = 120).
(Bottom panel) HIV-1-infected hemophilia patients (N = 480).
|
|
Cox proportional hazards analysis was used to estimate the relative
hazards of AIDS-lymphoma associated with heterozygous and homozygous
SDF1-3'A (all models were stratified by cohort to account for
variation in lymphoma risk). Compared with the wild-type,
SDF1-3'A was associated with approximate doubling of the NHL
hazard in heterozygotes and roughly a fourfold increase in homozygotes
(Table 3). Adjustment for race, age at
seroconversion, and CCR5-32 and CCR2-64I polymorphisms did not
appreciably alter the estimates. The adjusted relative hazard of NHL
per copy of the SDF1-3'A allele was 2.0 (95% CI, 1.3 to 3.1).
| |
DISCUSSION |
In this study, SDF1-3'A carriers in all three cohorts had an
increased absolute risk of NHL, which cannot be explained by an
influence (either favorable or unfavorable) on other AIDS outcomes. The
intermediate risk of SDF1-3'A heterozygotes indicates that the
variant allele is codominant in its effect on the incidence of
HIV-1-associated NHL. As compared with the other two cohorts, the
lower NHL risk of the hemophilia patients, half of whom became infected
in childhood, corresponds to the slower course of HIV-1 disease in
children (excluding those neonatally infected) compared with
adults.28
Although the numbers were small, the chemokine receptor polymorphisms
tended to have mutually exclusive effects on the risks for either
HIV-1-associated lymphoma or other AIDS outcomes. CCR2-64I appeared
protective against opportunistic infection but not NHL, whereas
CCR5-32 appeared strongly protective against NHL but not
opportunistic infection.
In the HIV-1-infected subjects, SDF1-3'A was particularly
associated with Burkitt's and Burkitt-like lymphoma, histologic subtypes that uniformly have a c-myc activating chromosomal
translocation. However, SDF1-3'A was not associated with
detection of c-myc translocations in HIV-1-infected subjects
without lymphoma. The association of Burkitt's lymphoma with
SDF1-3'A contrasts with that tumor's phenotypic resemblance to
germinal center lymphocytes (reviewed by Magrath and
Bhatia30), because germinal center B cells may be
unresponsive to SDF1.31 SDF1-3'A was not associated
with increased risk of Burkitt's and Burkitt-like lymphomas in the
absence of HIV-1 infection, suggesting that this polymorphism may be
phenotypically silent unless triggered by HIV-1.
Based on the adjusted relative hazards from the Cox proportional
hazards model and the reported allele frequencies of SDF1-3'A, the etiologic fraction32 of HIV-1-associated-NHL (ie,
proportion of cases in the population attributable to SDF1-3'A)
may be estimated as 36% for whites and 10% for blacks.
Correspondingly, among reported US AIDS cases, NHL is approximately one
half as common among blacks than in whites (relative risks of 0.31, 0.61, and 0.39 for Burkitt's, primary brain, and immunoblastic
lymphoma, respectively).1 Thus, differences in
SDF1-3'A allele frequency may partially explain racial
differences in incidence of HIV-1-associated NHL.
SDF1-3'A differs from the wild-type in an untranslated region of
the structural gene transcript. The physiologic effect of this
variation is not known, but may be associated with overexpression of
SDF-1 protein, which in turn stimulates B-lymphocyte proliferation. HIV-1 infection may be a necessary cofactor for increased SDF1 protein
production or for a B-cell proliferative response. Alternatively, HIV-1-induced immunodysregulation may be required for such B-cell stimulation to lead to lymphomagenesis. Paradoxically, increased levels
of SDF-1 may protect T lymphocytes against HIV-1 infection but
predispose B lymphocytes to malignant transformation.
The marked protection against NHL by the CCR-5-32 mutation would not
be predicted from known physiologic functions of the CCR5 chemokine
receptor. Conceivably, the protective effect may be due to enhanced
control of replication of HIV or some tumorigenic coinfection (eg, the
Epstein-Barr virus).
The greatly increased risk of HIV-1-associated NHL in SDF1-3'A
carriers suggests clinical utility of SDF-1 genotyping. HIV-1-infected patients with the SDF1-3'A gene variant may warrant enhanced
monitoring for earlier detection and treatment of NHL. Such patients
have a potentially modifiable risk factor for HIV-1-associated NHL that should be a target for development of preventive interventions.
Chemokine and chemokine receptor manipulations could serve as novel
approaches for ameliorating the effects of HIV-1 on the immune system.
The paradoxical effects of these genetic polymorphisms on the risks of
lymphoma and opportunistic infections represents an additional
challenge in designing chemokine-related therapies for HIV-1 infection.
| |
ACKNOWLEDGMENT |
The authors thank Kishor Bhatia, Paul Levine, and Konrad Huppi for
providing DNA samples from Burkitt's lymphoma patients; Robert Wittes,
Brigitta Mueller, Anne Marie Boler, and Melissa Adde for helpful
discussions; the collaborators and study managers for the Washington
and New York Men's Research Study and the Multicenter Hemophilia
Cohort Study for providing clinical data; Frances Yellin for performing
statistical analyses; and Ian Magrath for providing critical advice.
| |
FOOTNOTES |
Submitted September 14, 1998; accepted December 28, 1998.
Supported in part by National Cancer Institute Contracts No.
NO1-CP-40501 and NO1-CP-33002 with Research Triangle Institute.
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.
This is a US government work. There are no restrictions on its use.
Address reprint requests to Charles S. Rabkin, MD, Viral Epidemiology
Branch, National Cancer Institute, MSC 7248, Bethesda, MD 20892.
| |
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TOP
ABSTRACT
INTRODUCTION