|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 4 (August 15), 1998:
pp. 1317-1323
Aberrant and Unstable Expression of Immunoglobulin Genes in
Persons Infected With Human Immunodeficiency Virus
By
Alberto Bessudo,
Laura Rassenti,
Diane Havlir,
Douglas Richman,
Ellen Feigal, and
Thomas J. Kipps
From the Divisions of Hematology/Oncology and Infectious Diseases,
Department of Medicine, University of California, San Diego, La Jolla,
CA; and the National Cancer Institute, Bethesda, MD.
 |
ABSTRACT |
We examined the IgM VH gene subgroup use-distribution in
serial blood samples of 37 human immunodeficiency virus (HIV)-infected patients and a group of HIV-seronegative healthy adults. The IgM VH gene repertoires of healthy adults were relatively
similar to one another and were stable over time. In contrast,
individuals infected with HIV had IgM VH gene repertoires
that were significantly more heterogeneous and unstable. Persons at
early stages of HIV infection generally had abnormal expression levels
of Ig VH3 genes and frequently displayed marked
fluctuations in the relative expression levels of this VH
gene subgroup over time. In contrast, persons with established acquired
immunodeficiency syndrome (AIDS) had a significantly lower incidence of
abnormalities in Ig VH3 expression levels, although
continued to display abnormalities and instability in the expression
levels of the smaller Ig VH gene subgroups. Moreover, the
skewing and/or fluctuations in the expressed-IgM VH
gene repertoire appeared greatest for persons at earlier stages of HIV
infection. These studies show that persons infected with HIV have
aberrant and unstable expression of immunoglobulin genes suggestive of
a high degree humoral immune dysregulation and ongoing humoral immune
responses to HIV-associated antigens and superantigens.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
PATIENTS INFECTED WITH human
immunodeficiency virus (HIV) are at increased risk for B-cell
lymphoproliferative disease and B-cell lymphoma.1,2 Various
mechanisms are hypothesized to account for this. These include direct
infection of B cells with viruses, such as Epstein-Barr virus (EBV);
chronic antigenic stimulation due to HIV or opportunistic infections;
immune dysregulation secondary to attrition of CD4 T cells or other
immune-accessory cells; or antigen-induced B-cell activation and
depletion.3-6
Recent studies have provided evidence that antigen may play a role in
acquired immunodeficiency syndrome (AIDS)-associated B-cell
lymphomagenesis. Certain Ig heavy chain variable region genes
(VH genes) that have a higher-relative intrinsic capacity to incur nonconservative mutations in the complementarity-determining regions (CDR) appear to be expressed most frequently by AIDS-associated B-cell lymphomas.7 Furthermore, the Ig VH genes
expressed by such lymphomas have somatic mutations similar to those
expressed by B cells engaged in secondary immune responses to
antigen.7-9 This is striking, considering the profound
immune deficiency of the patients who develop such lymphomas, limiting
their capacity to mount such secondary immune responses. As such, the B
cells that subsequently develop into B-cell lymphoma may have
originated at stages of the HIV infection that are earlier than that of
end-stage AIDS when most lymphomas become clinically apparent.
Previous studies have noted alterations in the B-cell compartment in
patients infected with HIV, which may precede the development of B-cell
lymphoma. Indeed, persons infected with HIV have been found to have a
skewed Ig VH repertoire depleted of IgM+,
IgM/IgD+, and IgG+ B cells that express Ig
encoded by VH genes of the VH3
subgroup.10,11 This subgroup is one of seven human Ig
VH gene subgroups, each subgroup containing VH
genes that share more than 80% nucleic acid sequence
homology.12 In part because this VH gene
subgroup has the largest number of functional VH genes in
the human haploid genome,13,14 VH3 genes
ordinarily are used by approximately 45% to 60% of the blood B cells
of normal adults.15,16 As such, depletion of B cells
expressing Ig VH3 genes reflects a major alteration in the
B-cell compartment.
The relative depletion of B cells that express Ig VH3 could
be secondary to loss of B cells that express Ig VH3 genes
and/or a relative expansion of B cells that express Ig
VH genes of other VH gene subgroups. However,
in view of recent findings that B cells are generated continuously
throughout life,17 it appears unlikely that there would be
a fixed depletion of B cells expressing Ig VH3 genes unless
HIV-infected patients also acquire defects in B-cell lymphopoiesis.
However, detailed analyses of the relative expression of all the
VH gene subgroups in patients infected with HIV are
lacking. Also lacking are data on whether such clonal imbalances occur
early during the course of HIV infection and progress over time. To
examine this, we analyzed the relative expression of Ig VH
gene subgroups by blood B cells of adults infected with HIV and
age-matched seronegative controls.
| |
MATERIAL AND METHODS |
Patient material.
We obtained blood specimens from HIV-infected persons and aged-matched
controls who were not infected with HIV. The donors were divided into
five different groups. Group I consisted of nine HIV-positive patients
who did not satisfy diagnostic criteria for AIDS and who each had
greater than 500 CD4+ T cells per mm3 of blood.
Three blood samples were obtained at 6-month intervals. Groups II and
III consisted of 14 patients with AIDS who had less than 200 CD4+ T cells per mm3 of blood. Nine of these
patients (Group III) developed AIDS-associated Lymphoma (AAL) at a
later date. In each case we examined two to five serial blood specimens
every 3 to 6 months. Group IV consisted of 14 patients with AIDS who
were sampled at the time of diagnosis of AAL. Finally, Group V
consisted of six age-matched control donors who were not infected with
HIV. Two to six blood samples were obtained from each at 2- to 4-month
intervals. In addition, one blood sample was obtained from each of 22 additional normal adults who were not infected with HIV.
RNA isolation, and cDNA synthesis.
We isolated RNA from 5 × 106 to 1 × 107 cryopreserved blood lymphocytes using RNAzol B
(Cinna/biotex, Friendswood, TX). The cDNA was synthesized from 5 µg
total RNA using an oligo-dT primer and Superscript II reverse
transcriptase (Life Technologies, Grand Island NY). Reverse
transcription was performed for one hour at 42°C. Afterwards the
mixture was heated to 70°C for 15 minutes. The sample was treated
with 0.3 mol/L NaOH for 30 minutes to hydrolyze residual RNA.
Analysis of IgM VH gene use.
The distribution of IgM VH gene transcripts in blood B
cells was tested using a reverse transcriptase polymerase chain
reaction (RT-PCR)/ enzyme-linked immunosorbent assay (ELISA), a
technique that uses anchored RT-PCR to amplify all Cµ
transcripts independent of Ig VH gene use. This technique
has been verified to allow for sensitive and accurate measurement of
the relative VH gene subgroup use by IgM-expressing B
cells.18-20 Briefly, the cDNA was poly dG-tailed with dGTP
and terminal deoxytransferase (Boehringer Mannheim, Indianapolis, IN).
One-fourth of the sample was subjected to primary anchored PCR
amplification using an antisense oligonucleotide primer specific for
the constant region of human IgM (Cµ ) (5 -AATTCTCACAGGAGACGA-3) and a 9:1 mixture of two anchor
sense-strand primers (5-ATTACGGCGGCCGCGGATCC-3, and
5-ATTACGGCGGCCGC-GGATCCCCCCCCCCCCCC-3). The PCR
products were purified using the QIAquik purification columns (Qiagen,
Chatsworth, CA) and one-third of this product was used as a template
for a nested PCR. This second PCR reaction was the same as the primary
anchored PCR except a 5 biotinylated Cµ-antisense
primer was used that was upstream of the initial Cµ
primer. The nested PCR product was purified and distributed onto ELISA
wells that had been precoated with streptavidin (Sigma, St. Louis, MO).
The double-stranded DNA bound to the plate was denatured using 0.1mol/L
NaOH. After washing, antisense strands of specific Ig VH
gene cDNA are detected using digoxigenenin-labeled sense-strand
oligonucleotides corresponding to specific leader or framework
sequences of each of the major Ig VH gene subgroups except
Ig VH7. This subgroup is detected by the Ig VH1
leader-sequence oligonucleotide probes and generally accounts for less
than 1% of the normal adult repertoire.18,19,21 A
peroxidase-conjugated antidigoxigenin antibody was used to detect the
bound probe. The wells were subsequently washed and then incubated with
tetramethylbenzidine (TMB) and peroxidase (Kirkegaard and Perry
Laboratories, Gaithersburg, MD). The reaction was stopped with 1 mol/L
O-phosphoric acid (Fisher Scientific, Pittsburgh, PA) and the optical
densities (OD) were measured at 450 nm using an ELISA microplate reader
(Molecular Devices, Menlo Park, CA).
Statistical Analysis.
We considered the relative level of a particular Ig VH gene
subgroup to be "abnormal" when it was higher or lower than two standard deviations (SD) from the mean observed in the control population. We compared the incidence of Ig VH gene
repertoire skewing among two groups of individuals using the Bonferroni
t test and chi-square test.
| |
RESULTS |
The normal adult Ig VH gene subgroup repertoire.
Using the RT-PCR/ELISA technique, we examined the IgM VH
gene subgroups used by blood B cells of 28 unrelated adults who were not infected with HIV. We found that the relative expression levels of
the Ig VH gene subgroups varied relatively little between
these individuals. The Ig VH3 gene subgroup accounted for
55% ± 7% (SD) of all the expressed IgM VH genes,
ranging from 43% to 68%. The next largest was the VH4
gene subgroup, which accounted for 26% ± 5% of the repertoire,
ranging from 13% to 36%. The next largest detected subgroup was Ig
VH1, which accounted for 13% ± 5% of the repertoire,
with proportions ranging from 4% to 21%. The smaller VH
gene subgroups of VH2, VH5, and
VH6, each accounted for 1% ± 1%, 3% ± 2%, or
1% ± 2% of the IgM VH gene repertoire, respectively. These values are similar to those reported for the relative levels of
Ig VH gene subgroups used by individual adults using other techniques.22,23
From these data, we defined a normal adult repertoire as having
proportions of each Ig VH gene subgroup within two standard deviations of the mean for each respective subgroup. Accordingly, the
"normal" range for the proportions of Ig VH1 was 3%
to 22%, VH2 was 0% to 4%, VH3 was 40% to
69%, VH4 was 15% to 37%, VH5 was 0% to 8%,
and VH6 was 0% to 6%. We defined a repertoire as being
"abnormal" when the expression level of one or more Ig
VH gene subgroups was outside the normal range. Using these
definitions, we noted that only 2 of the 28 persons (7%) had
"abnormal" levels of Ig VH gene subgroups. One had a
VH4 subgroup level that was 3% below the lower limit for
VH4, whereas the other had an expression level of the Ig
VH5 subgroup that was 2% above the "normal" range for VH5.
The Ig VH gene subgroup repertoire of adults infected
with HIV.
We also analyzed Ig VH gene subgroups used by blood B cells
of 37 HIV-infected persons who were at various stages of disease. We
segregated these patients into four groups. Group I consisted of nine
HIV-infected persons without AIDS who each had more than 500 CD4+ T-cells per mm3 of blood. Groups II and
III consisted of 14 patients with AIDS who had less than 200 CD4+ T cells per mm3 of blood. Nine of these
patients (Group III) developed AIDS-associated Lymphoma (AAL) at a
later date. Group IV consisted of 14 AIDS patients who had blood
sampled when they were found to have AAL.
We found that 29 of the 37 persons infected with HIV (78%) had an
"abnormal" repertoire (Table 1). One
hundred percent (9 of 9) of the persons in Group I, 100% (5 of 5) of
those in Group II, 56% (5 of 9) of those in Group III, and 79% (11 of
14) of those in Group IV, had "abnormal" levels of one or more of
the Ig VH gene subgroups (Table 1). Moreover, most had
abnormalities in more than one subgroup and had Ig VH gene
subgroup levels that differed significantly from those of the normal
control group (P < .01, Bonferroni t test).
Furthermore, the proportions of each group of HIV-infected persons that
had abnormal repertoires were significantly higher than that of the
control group (P < .001, X2 analysis).
The VH gene subgroups that were most affected appeared to
vary between the different groups of HIV-infected persons. For example, Group I had a significantly higher proportion of persons with abnormal
VH3 gene levels than did any other group (P < .05, Bonferroni t test). Eight of the nine persons in this
group (89%) had abnormal levels of Ig VH3. Five of these
(HO, HP, HQ, HR, and HW; Table 1, shaded values) had levels of Ig
VH3 that were below the normal range for Ig
VH3, whereas the remaining three (HT, HU, and HV; Table 1)
had values that exceeded the normal range. In contrast, only two of the
five (40%) in Group II (HA, HB; Table 1), one of nine (11%) in Group
III (HG; Table 1) and 5 of 14 (36%) in Group IV (H3, H5, H6, H19, and
LV; Table 1) had abnormal levels of VH3.
With one exception (HW; Table 1), the decrease or increase in the
levels of Ig VH3 noted in patients of Group I were
associated with reciprocal changes in the levels of the Ig
VH4 gene subgroup. This resulted in markedly abnormal
expression levels of VH4. For the one exception, the
abnormally low level of Ig VH3 instead was associated with
an abnormally high level of the Ig VH1 subgroup (HW; Table
1). In contrast, all persons in Groups II , III and IV who had abnormal
levels of VH3 did not have reciprocal changes in the levels
of Ig VH4, except one (H6; Table 1). Instead, the low
levels of Ig VH3 observed in persons of Groups II and III were associated with abnormally high levels of Ig VH1 (eg,
HA, HB, HG; Table 1).
Stability of the Ig VH gene subgroup repertoire
over time.
To examine the stability of the Ig VH gene subgroup
distribution over time, we collected six blood samples from each of six members of the control group at 3- to 6-month intervals
(Fig 1). One control subject had Ig
VH gene subgroups levels that always were within the
defined "normal" range. Four of the six had a single Ig
VH gene subgroup level that was a few percentage points above or below the "normal" range on one or two occasions.
Finally, one control subject had an elevated level of VH2
(at 5%) on two occasions, an elevated proportion of VH6
(at 9%) on another occasion, and a low level of VH3 (at
32%) associated with a high level of VH4 (at 52%) on one
occasion (see lines connecting the diamonds in the graphs of the far
right column, labeled "Control," Fig 1). We calculated the mean
and standard deviation of each Ig VH gene subgroup in the
serial samples for each individual (Fig 2). We found that these standard deviations of the means over time for each
person ranged from 3% to 9% for Ig VH1, 4% to 12% for Ig VH3, and 3% to 13% for Ig VH4, among the
six members of the control group.
View larger version (44K):
[in this window]
[in a new window]
| Fig 1.
Expressed IgM VH gene distribution in serial
blood samples of HIV infected patients. Each graph depicts the percent
expression of Ig VH gene subgroups 1 through 6, over time
in: (I) persons infected with HIV infection and CD4+
T-cell count of more than 500 cells per mm3 blood; (II)
patients with AIDS and a CD4+ T-cell count of less than
200 cells per mm3 blood; (III) patients with AIDS, as
described in Group II that developed lymphoma at a later date; and
Controls, healthy HIV-seronegative adults. One symbol is used for the
same subject within a given group.
|
|
View larger version (23K):
[in this window]
[in a new window]
| Fig 2.
Variation in the proportions of the major Ig
VH gene subgroups in HIV-infected persons and control
subjects over time. The graphs depict the data collected on persons in
Group I (top left), Group II (top right), Group III (bottom left), or
HIV-seronegative controls (bottom right), as indicated at the top of
each graph. The standard deviations (SD) about the mean levels of
VH1, VH3, or VH4 over time for each
subject are indicated by the symbols. The percent SD about the mean Ig
VH gene subgroup levels are indicated on the far right
axis. Lines connect the symbols that correspond to the SD of the mean
levels for the same person. Each symbol corresponds to the same symbol
and subject as in Fig 1.
|
|
In parallel, we analyzed two to five serial blood samples that were
collected at 3- to 6-month intervals from each of the HIV-infected
persons in Groups I , II , and III (Fig 1). Overall, we found
fluctuations of the expressed Ig VH gene distribution that
were higher than the one observed in normal controls. In detail, four
of the eight repetitively examined persons of Group I (HO, HQ, HR, and
HP; Table 1) had extreme reciprocal variations in the levels of Ig
VH3 and Ig VH4 subgroups over time (Fig 1), with standard deviations about the means over time ranging from 24% to
32% for Ig VH3, and 20% to 37% for Ig VH4
(Fig 2). Two of these four subjects also had fluctuations in the Ig
VH5 and Ig VH6 subgroups that reciprocated the
changes observed in Ig VH3 (open squares and diamonds in
the column labeled "I"; Fig 1). Finally, one person in Group I
experienced increases in the proportions of Ig VH1 and Ig
VH5 that were associated with decreases in relative
proportion of Ig VH3 over time (HW; Table 1 and Fig 1). On
the other hand, three persons in Group I had VH gene
subgroup distributions that did not vary over time, despite having
abnormally high levels of Ig VH3 and low levels of Ig
VH4 (HT, HU, HV; Table 1 and Fig 2). Whatever the pattern,
however, the subjects of Group I generally had "abnormal" levels
of Ig VH3. Only one individual (HP; Table 1) who was found
initially to have abnormal expression of Ig VH3 genes had a
normal Ig VH3 level on more than one occasion (Fig 1; open
diamonds, Column I).
In contrast, the subjects in Groups II and III had relatively normal
levels of Ig VH3 on successive testing. Those who initially had "abnormal" levels of Ig VH3 (HA, HB, and HG;
Table 1) were found to have "normal" Ig VH3 levels at
later time points (Fig 1). Also, the high levels of Ig VH1
that initially were observed in these subjects dropped to normal levels
(Fig 1). Except for one member of Group II who had an abnormally low Ig
VH3 level of 36% on one occasion (HE; Table 1), the other
members of these groups (namely HC, HD, HF, HH, HI, HJ, HK, HM,
and HN; Table 1) had Ig VH3 levels within the normal range
at all time points tested (Fig 1). Collectively, the proportion of
subjects in Groups II and III who had normal Ig VH3 levels
at each time point was significantly higher than that noted for those
in Group I at any time point (P < .05, Student's t
test).
Instead, the subjects in Groups II more typically had abnormalities in
the levels of some of the smaller Ig VH gene subgroups. In
particular, four of the five members of this group (HB, HC, HD, and HE;
Table 1) had marked fluctuations in the levels of Ig VH5,
with levels of more than 10% on at least one occasion (Fig 1). Two of
these (HC and HE; Table 1) at one point had levels of Ig
VH6 in excess of 10% (Fig 1). Finally, three subjects in this group (HC, HD, and HE; Table 1) also had levels of Ig
VH2 in excess of 8% on at least one occasion. Such
abnormalities were not observed in the samples obtained from members of
Group III. Nevertheless, the subjects in either Group II or III tended
to have standard deviations about the means over time for the larger Ig
VH gene subgroups that were higher than that of the control group (Fig 2).
| |
DISCUSSION |
We examined the relative expression of Ig VH gene subgroups
in serial blood samples of persons infected with HIV and seronegative healthy adults. The blood B cells of seronegative donors had Ig VH gene subgroup repertoires that were similar to those
previously reported for normal adults.14,15,18,19,23,24
Furthermore, upon testing six seronegative donors at 3- to 6-month
intervals, we noted that the Ig VH subgroup expression
levels for each normal subject were relatively constant over time.
These observations are consistent with those made in a previous study
on pairs of adult monozygotic twins, eight of which were concordant or
discordant for rheumatoid arthritis (RA).19 Each pair had
more similar IgM VH gene repertoires than did unrelated subjects, regardless of whether they were discordant for RA.
Collectively, these studies suggest that genetic factors have a
predominant influence on the distribution of Ig VH gene
subgroups expressed by IgM+ blood B cells.
However, the IgM+ blood B cells of persons infected with
HIV expressed VH gene subgroup repertoires that were
strikingly aberrant and generally unstable. Twenty-nine of the 37 persons tested (78%) had "abnormal" repertoires, generally
involving two or more Ig VH gene subgroups (Table 1).
Moreover, 24 (65%) had levels of one or more Ig VH gene
subgroups that differed by more than three standard deviations from the
mean observed among seronegative adults (Table 1). The incidence of
abnormal subgroup distributions among HIV-infected persons was
significantly higher than that noted among the control group (P < .001, X2 analysis). In addition, persons
infected with HIV generally had large fluctuations in the proportionate
expression of several Ig VH gene subgroups over time (Fig
2).
Prior studies noted that persons infected with HIV can have skewed Ig
VH repertoires depleted of IgM+,
IgM/IgD+, and IgG+ B cells that express Ig
VH genes of the VH3
subgroup.10,11,25 However, these studies did not examine
the proportions of the Ig VH gene subgroups relative to
that of all the other VH gene subgroups, or examine the
same patient on more than one occasion. In light of the current study,
it seems likely that the relative deficiency noted in the expression of
Ig VH3 genes by persons infected with HIV may not have been
a stable phenotype. Moreover, cases with overexpression of Ig
VH3 genes relative to that of the other subgroups may have
been missed. Finally, the results of our study indicate that
alterations in the relative expression levels of this subgroup most
typically occur in persons at the early stages of HIV-infection,
contrary to speculation that persons infected with HIV may develop
progressive depletion of VH3-expressing B cells over
time.11
Conceivably, B-cell superantigens may account for the abnormal levels
of Ig VH gene subgroups observed in patients infected with
HIV.26,27 B-cell superantigens are substances that bind the
immunoglobulin encoded by most Ig VH genes of a given
subgroup.28-30 Moreover, most Ig that react with a
superantigen, such as Staphylococcal protein A, are encoded by
Ig VH genes homologous to their germline counterparts,31 indicating that somatic mutation and
selection are not required to develop Ig with superantigen binding
activity. Such antigens can induce expansion or depletion of all B
cells that express surface Ig encoded by a specific Ig VH
gene subgroup. This is in contrast to conventional antigens that
generally induce specific antibodies encoded by any one of several
different Ig VH subgroups.
HIV gp120 binds to a conserved immunoglobulin motif unique to
immunoglobulins encoded by Ig VH genes of the
VH3 subgroup.32 Berberian et al25
reported a threefold elevation of such B cells in some HIV-seropositive
adults relative to that of seronegative control subjects. However, they
noted that the number of VH3-expressing B cells were
markedly reduced in patients with AIDS, as were the levels of serum
anti-gp120 antibodies bearing a VH3-encoded crossreactive idiotype. As such, gp120 may function as a superantigen that can induce
expansion or deletion of B cells expressing antibodies encoded by
VH3 genes.
However, in the current study we found large fluctuations in Ig
VH gene subgroups other than VH3 that could not
be explained by alterations in the levels of Ig VH3 alone.
For example, isolated expansions or contractions in the population of B
cells that express Ig encoded by VH3 genes should not
affect the proportion of the second largest Ig VH gene
subgroup, VH4, relative to that of Ig VH1, or
to that of the other Ig VH subgroups. However, we found that the proportions of these smaller Ig VH groups relative
to one another also fluctuated over time. As such, patients infected with HIV do not have abnormalities restricted to B cells expressing Ig
VH3 genes, particularly patients at advanced stages of
infection.
This does not exclude the possibility that aberrant use of Ig
VH genes in HIV-infected individuals reflects an ongoing
immune response to HIV or an interaction between HIV-associated
glycoproteins and B-cell surface Ig. During the early stages of HIV
infection, individuals often develop an antibody response against HIV
glycoproteins that diminishes as the CD4+ T-cell counts
fall.33 Furthermore, Ig VH genes isolated from AIDS-associated lymphoproliferations or AIDS-associated lymphoma have
evidence for somatic mutations suggestive of having been selected in an
antigen-driven immune response(s).7,34,35 In addition, the
instability in the expression of the various Ig VH gene
subgroups may reflect changes occurring in the antigenic-epitopes of
the virus in any one person over time. It is estimated that HIV
undergoes over 180 generations per year,36 allowing for the
emergence of a large number of different HIV mutants soon after
infection.37,38 Mutations generally occur in the genes encoding the envelop glycoproteins that alter the tropism and biologic
properties of the virus over time.39-42 Such alterations may account for the differences observed in the proportionate use of Ig
VH genes in patients with high CD4+ T-cell
counts (Group I ) versus those used by Groups II and III who had
established AIDS.
The mutability and altered tropism of the HIV glycoproteins that occur
during the course of infection for any one individual can provide for a
complex and dynamic relationship between the virus and its host. B
cells may express functional chemokine receptors that recently have
been identified as being important coreceptors for
HIV.43-45 This raises the possibility that HIV may interact with B cells directly via surface Ig and such receptors to induce the
B-cell pathophysiology that is observed in patients infected with HIV.
In any case, the results of our study is consistent with the notion
that B cells of persons infected with HIV are undergoing rapid
turnover, with successive waves of stimulation, expansion, and/or depletion. Such turnover may allow for chance
acquisition of somatic changes that can lead to the malignant
transformation of a responding B-cell clone. Further study on the
mechanism(s) underlying the dynamics within the B-cell compartment of
persons infected with HIV may show the factor(s) accounting for the
high rate of lymphomas that occur in patients with AIDS.
| |
FOOTNOTES |
Submitted January 27, 1998;
accepted April 8, 1998.
This project was funded by NIH Grants No. RO1 CA 65408-03 (T.J.K.),
AI27670, and AI 36214 (Center for AIDS Research), and the Research
Center for AIDS and HIV Infection of the San Diego Veterans Affairs
Medical Center.
Address correspondence to Thomas J. Kipps, MD, PhD,
Divisions of Hematology/Oncology and Infectious Diseases, Department of Medicine, University of California, San Diego, CA 92093-0663.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
REFERENCES |
1.
Serraino D,
Salamina G,
Franceschi S,
Dubois D,
La Vecchia C,
Brunet JB,
Ancelle-Park RA:
The epidemiology of AIDS-associated non-Hodgkin's lymphoma in the World Health Organization European Region.
Br J Cancer
66:912,
1992[Medline]
[Order article via Infotrieve]
2.
Kaplan LD,
Abrams DI,
Feigal E,
McGrath M,
Kahn J,
Neville P,
Ziegler J,
Volberding PA:
AIDS-associated non-Hodgkin's lymphoma in San Francisco.
JAMA
261:719,
1989[Abstract]
3.
Cremer KJ,
Spring SB,
Gruber J:
Role of human immunodeficiency virus type 1 and other viruses in malignancies associated with acquired immunodeficiency disease syndrome.
J Natl Cancer Inst
82:1016,
1990[Free Full Text]
4.
Astrin SM,
Laurence J:
Human immunodeficiency virus activates c-myc and Epstein-Barr virus in human B lymphocytes.
Ann N Y Acad Sci
651:422,
1992[Abstract]
5.
Karp JE,
Broder S:
The pathogenesis of AIDS lymphomas: A foundation for addressing the challenges of therapy and prevention.
Leuk Lymphoma
8:167,
1992[Medline]
[Order article via Infotrieve]
6.
Liebman HA:
The acquired immunodeficiency syndrome (AIDS)
, in Beutler E,
Lichtman MA,
Coller BS,
Kipps TJ
(eds):
Williams Hematology
New York, NY, McGraw-Hill
, 1995
, p 975
7.
Bessudo A,
Cherepakhin V,
Johnson TA,
Rassenti LZ,
Feigal E,
Kipps TJ:
Favored use of immunoglobulin Vh4 genes in AIDS-associated B-cell lymphoma.
Blood
88:252,
1996[Abstract/Free Full Text]
8.
Przybylski GK,
Goldman J,
Ng VL,
McGrath MS,
Herndier BG,
Schenkein DP,
Monroe JG,
Silberstein LE:
Evidence for early B-cell activation preceding the development of Epstein-Barr virus-negative acquired immunodeficiency syndrome-related lymphoma.
Blood
88:4620,
1996[Abstract/Free Full Text]
9.
Eclache V,
Magnac C,
Pritsch O,
Delecluse HJ,
Davi F,
Raphael M,
Dighiero G:
Complete nucleotide sequence of Ig V genes in three cases of Burkitt lymphoma associated with AIDS.
Leuk Lymphoma
20:281,
1996[Medline]
[Order article via Infotrieve]
10.
Berberian L,
Valles-Ayoub Y,
Sun N,
Martinez-Maza O,
Braun J:
A VH clonal deficit in human immunodeficiency virus-positive individuals reflects a B-cell maturational arrest [published erratum appears in Blood 1991 Oct 1;78(7):1899].
Blood
78:175,
1991[Abstract/Free Full Text]
11.
David D,
Demaison C,
Bani L,
Zouali M,
Theze J:
Selective variations in vivo of VH3 and VH1 gene family expression in peripheral B cell IgM, IgD and IgG during HIV infection.
Eur J Immunol
25:1524,
1995[Medline]
[Order article via Infotrieve]
12.
Tomlinson IM,
Walter G,
Marks JD,
Llewelyn MB,
Winter G:
The repertoire of human germline VH sequences reveals about fifty groups of VH segments with different hypervariable loops.
J Mol Biol
227:776,
1992[Medline]
[Order article via Infotrieve]
13.
Walter MA,
Surti U,
Hofker MH,
Cox DW:
The physical organization of the human immunoglobulin heavy chain gene complex.
EMBO J
9:3303,
1990[Medline]
[Order article via Infotrieve]
14.
Pascual V,
Capra JD:
Human immunoglobulin heavy-chain variable region genes: organization, polymorphism, and expression.
Adv Immunol
49:1,
1991[Medline]
[Order article via Infotrieve]
15.
Guigou V,
Cuisinier AM,
Tonnelle C,
Moinier D,
Fougereau M,
Fumoux F:
Human immunoglobulin VH and VK repertoire revealed by in situ hybridization.
Mol Immunol
27:935,
1990[Medline]
[Order article via Infotrieve]
16.
Cook GP,
Tomlinson IM:
The human immunoglobulin VH repertoire.
Immunol Today
16:237,
1995[Medline]
[Order article via Infotrieve]
17.
Nunez C,
Nishimoto N,
Gartland GL,
Billips LG,
Burrows PD,
Kubagawa H,
Cooper MD:
B cells are generated throughout life in humans.
J Immunol
156:866,
1996[Abstract]
18.
Rassenti LZ,
Kohsaka H,
Kipps TJ:
Analysis of immunoglobulin VH gene repertoire by an anchored PCR-ELISA.
Ann N Y Acad Sci
764:463,
1995[Abstract]
19.
Kohsaka H,
Carson DA,
Rassenti LZ,
Ollier WE,
Chen PP,
Kipps TJ,
Miyasaka N:
The human immunoglobulin V(H) gene repertoire is genetically controlled and unaltered by chronic autoimmune stimulation.
J Clin Invest
98:2794,
1996[Medline]
[Order article via Infotrieve]
20.
Rassenti LZ,
Kipps TJ:
Lack of Allelic Exclusion in B cell chronic lymphocytic leukemia.
J Exp Med
185:1435,
1997[Abstract/Free Full Text]
21.
Mortari F,
Newton JA,
Wang JY,
Schroeder HWJ:
The human cord blood antibody repertoire. Frequent usage of the VH7 gene family.
Eur J Immunol
22:241,
1992[Medline]
[Order article via Infotrieve]
22. (abstr)
Stewart AK,
Rubinstein DB,
Huang C,
Stollar BD,
Schwartz RS:
Highly restricted VH gene use in peripheral blood B cells.
Blood
80:252a,
1992
23.
Huang C,
Stewart AK,
Schwartz RS,
Stollar BD:
Immunoglobulin heavy chain gene expression in peripheral blood B lymphocytes.
J Clin Invest
89:1331,
1992
24.
Huang C,
Stollar BD:
A majority of Ig H chain cDNA of normal human adult blood lymphocytes resembles cDNA for fetal Ig and natural autoantibodies.
J Immunol
151:5290,
1993[Abstract]
25.
Berberian L,
Shukla J,
Jefferis R,
Braun J:
Effects of HIV infection on VH3 (D12 idiotope) B cells in vivo.
J Acquir Immune Defic Syndr
7:641,
1994
26.
Goodglick L,
Braun J:
Revenge of the microbes. Superantigens of the T and B cell lineage.
Am J Pathol
144:623,
1994[Medline]
[Order article via Infotrieve]
27.
Domiati-Saad R,
Lipsky PE:
B cell superantigens: Potential modifiers of the normal human B cell repertoire.
Int Rev Immunol
14:309,
1997[Medline]
[Order article via Infotrieve]
28.
Suda T,
Nagata S:
Purification and characterization of the Fas-ligand that induces apoptosis.
J Exp Med
179:873,
1994[Abstract/Free Full Text]
29.
Roben PW,
Salem AN,
Silverman GJ:
VH3 family antibodies bind domain D of staphylococcal protein A.
J Immunol
154:6437,
1995[Abstract]
30.
Domiati-Saad R,
Attrep JF,
Brezinschek HP,
Cherrie AH,
Karp DR,
Lipsky PE:
Staphylococcal enterotoxin D functions as a human B cell superantigen by rescuing VH4-expressing B cells from apoptosis.
J Immunol
156:3608,
1996[Abstract]
31.
Hakoda M,
Hayashimoto S,
Yamanaka H,
Terai C,
Kamatani N,
Kashiwazaki S:
Molecular basis for the interaction between human IgM and staphylococcal protein A.
Clin Immunol Immunopathol
72:394,
1994[Medline]
[Order article via Infotrieve]
32.
Berberian L,
Goodglick L,
Kipps TJ,
Braun J:
Immunoglobulin VH3 gene products: Natural ligands for HIV gp120.
Science
261:1588,
1993[Abstract/Free Full Text]
33.
Shirai A,
Cosentino M,
Leitman-Klinman SF,
Klinman DM:
Human immunodeficiency virus infection induces both polyclonal and virus-specific B cell activation.
J Clin Invest
89:561,
1992
34.
Ng VL,
Hurt MH,
Fein CL,
Khayam-Bashi F,
Marsh J,
Nunes WM,
McPhaul LW,
Feigal E,
Nelson P,
Herndier BG:
IgMs produced by two acquired immune deficiency syndrome lymphoma cell lines: Ig binding specificity and VH-gene putative somatic mutation analysis.
Blood
83:1067,
1994[Abstract/Free Full Text]
35.
Ng VL,
Hurt MH,
Herndier BG,
Fry KE,
McGrath MS:
VH gene use by HIV type 1-associated lymphoproliferations.
AIDS Res Hum Retroviruses
13:135,
1997[Medline]
[Order article via Infotrieve]
36. (suppl 3)
Coffin JM:
HIV viral dynamics.
AIDS
10:S75,
1996
37.
Coffin JM:
HIV pathogenesis. Lines drawn in epitope wars [news; comment].
Nature
375:534,
1995[Medline]
[Order article via Infotrieve]
38.
Pennisi E,
Cohen J:
Eradicating HIV from a patient: Not just a dream? [news].
Science
272:1884,
1996[Free Full Text]
39.
Schuitemaker H,
Koot M,
Kootstra NA,
Dercksen MW,
de Goede RE,
van Steenwijk RP,
Lange JM,
Schattenkerk JK,
Miedema F,
Tersmette M:
Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population.
J Virol
66:1354,
1992[Abstract/Free Full Text]
40.
Connor RI,
Mohri H,
Cao Y,
Ho DD:
Increased viral burden and cytopathicity correlate temporally with CD4+ T-lymphocyte decline and clinical progression in human immunodeficiency virus type 1-infected individuals.
J Virol
67:1772,
1993[Abstract/Free Full Text]
41.
Richman DD,
Bozzette SA:
The impact of the syncytium-inducing phenotype of human immunodeficiency virus on disease progression.
J Infect Dis
169:968,
1994[Medline]
[Order article via Infotrieve]
42.
Connor RI,
Sheridan KE,
Ceradini D,
Choe S,
Landau NR:
Change in coreceptor use coreceptor use correlates with disease progression in HIV-1-infected individuals.
J Exp Med
185:621,
1997[Abstract/Free Full Text]
43.
O'Brien WA,
Koyanagi Y,
Namazie A,
Zhao JQ,
Diagne A,
Idler K,
Zack JA,
Chen IS:
HIV-1 tropism for mononuclear phagocytes can be determined by regions of gp120 outside the CD4-binding domain.
Nature
348:69,
1990[Medline]
[Order article via Infotrieve]
44.
Choe H,
Farzan M,
Sun Y,
Sullivan N,
Rollins B,
Ponath PD,
Wu L,
Mackay CR,
LaRosa G,
Newman W,
Gerard N,
Gerard C,
Sodroski J:
The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates.
Cell
85:1135,
1996[Medline]
[Order article via Infotrieve]
45.
D'Souza MP,
Harden VA:
Chemokines and HIV-1 second receptors. Confluence of two fields generates optimism in AIDS research.
Nat Med
2:1293,
1996[Medline]
[Order article via Infotrieve]
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
M. ZOUALI
Exploitation of Host Signaling Pathways by B Cell Superantigens--Potential Strategies for Developing Targeted Therapies in Systemic Autoimmunity
Ann. N.Y. Acad. Sci.,
January 1, 2007;
1095(1):
342 - 354.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Subramaniam, N. French, and L.-a. Pirofski
Cryptococcus neoformans-Reactive and Total Immunoglobulin Profiles of Human Immunodeficiency Virus-Infected and Uninfected Ugandans
Clin. Vaccine Immunol.,
October 1, 2005;
12(10):
1168 - 1176.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. W. Maitta, K. Datta, Q. Chang, R. X. Luo, B. Witover, K. Subramaniam, and L.-a. Pirofski
Protective and Nonprotective Human Immunoglobulin M Monoclonal Antibodies to Cryptococcus neoformans Glucuronoxylomannan Manifest Different Specificities and Gene Use Profiles
Infect. Immun.,
August 1, 2004;
72(8):
4810 - 4818.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Viau, N. S. Longo, P. E. Lipsky, L. Bjorck, and M. Zouali
Specific In Vivo Deletion of B-Cell Subpopulations Expressing Human Immunoglobulins by the B-Cell Superantigen Protein L
Infect. Immun.,
June 1, 2004;
72(6):
3515 - 3523.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. H. Chan, K. G. Hadlock, S. K. H. Foung, and S. Levy
VH1-69 gene is preferentially used by hepatitis C virus-associated B cell lymphomas and by normal B cells responding to the E2 viral antigen
Blood,
February | |
Abstract
Introduction
Abstract