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Previous Article | Next Article 
Clinical and Diagnostic Laboratory Immunology, November 1999, p. 783-786, Vol. 6, No. 6
1071-412X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Antibody to Human Endogenous Retrovirus Peptide in
Urine of Human Immunodeficiency Virus Type 1-Positive
Patients
Roy W.
Stevens,1
Aldona L.
Baltch,2,*
Raymond
P.
Smith,2
Bruce J.
McCreedy,3,
Phyllis B.
Michelsen,2
Lawrence H.
Bopp,2 and
Howard B.
Urnovitz4,
Biomedical Resource
Group1 and Stratton VA Medical Center
and Albany Medical College,2 Albany, New York;
Laboratory Corporation of America, Research Triangle Park,
North Carolina3; and Calypte
Biomedical Corporation, Berkeley, California4
Received 1 March 1999/Returned for modification 3 May 1999/Accepted 23 July 1999
 |
ABSTRACT |
Human endogenous retrovirus (HERV)-like sequences are normal
inherited elements that constitute several hundredths of the human
genome. The expression of genes located within these elements can occur
as a consequence of several different events, including persistent
inflammation or genotoxic events. Antibodies to endogenous retroviral
gene products have been found in a number of infectious, chronic, and
malignant diseases, suggesting a role in disease initiation and
progression. We studied human immunodeficiency virus type 1 (HIV-1)-infected patients for evidence of urine antibody to a HERV
peptide and investigated correlates with clinical and laboratory
parameters. Forty-three HIV-1-infected patients in documented
asymptomatic, symptomatic, or AIDS stages of disease and 21 age- and
gender-matched, uninfected controls were tested for antibody to
HERV-related peptide 4.1. Urine specimens were examined in a blinded
fashion with the Calypte Biomedical Corp. experimental enzyme
immunoassay for antibody to peptide 4.1. Results were compared with
demographic data, medical history, clinical state of disease, and
results of other laboratory tests. Thirty-six percent of the
asymptomatic (Centers for Disease Control and Prevention [CDC]
category A) and 81.3% of both the symptomatic (CDC category B) and
AIDS (CDC category C) patients were positive for antibody to
HERV-related peptide 4.1. None of the controls were positive. In this
study, antibodies to HERV-related peptide 4.1 were found more
frequently in patients with advanced stages (categories B and C) of
HIV-1 disease than in those patients with an earlier stage (category A)
of HIV disease. In HIV patients, severe immunosuppression, defined as
having had at least one opportunistic infection, correlated with the
expression of antibody to a HERV-related peptide.
| |
INTRODUCTION |
Endogenous retrovirus-like elements
(ERVs) are transposable genetic elements in eukaryotes that
structurally resemble retroviruses and use RNA intermediates in their
replicative cycles. ERVs are normal inherited genetic elements found in
all mammals (11, 18, 26, 29). In the human genome, there are
many families of ERVs, most consisting of multiple copies of the
element. They may be divided into two groups based upon the presence or
absence of long terminal repeats (LTRs). Those with LTRs can be further divided based on infectivity. Infectious elements with LTRs are retroviruses, while noninfectious elements with LTRs are
retrotransposons (18). ERVs lacking LTRs are called
retroposons. Together, these human ERVs (HERVs) comprise several
hundredths of the total genome.
Although infectious endogenous retroviruses have been identified in
nonhuman species, all HERVs that have been identified to date appear to
be noninfectious because of structural defects. Nevertheless, these
HERVs may alter the expression of cellular genes via transposition into
or near the genes or through the activity of transcriptional regulatory
sequences found in the HERV LTRs.
There is considerable evidence for the expression of HERV genes in
human cells (17, 29). However, the mechanisms responsible for the expression of these genes are not clearly understood. In
general, it is known that inflammatory responses induced by injury,
toxic chemical agents, radiation, or infectious agents contribute to
the activation and expression of genes found on transposable genetic
elements (6). More specifically, sequences within short
interspersed element DNA, or Alu sequences, are activated by
human immunodeficiency virus type 1 (HIV-1) infection (16). Moreover, activation and Alu-mediated recombination are
recognized as contributing factors in the progression of some chronic
disorders (27). In addition, with the development of
xenogenic therapies for human diseases, there is the potential for
nonhuman retroelements to be unintentionally incorporated into the
human genome. The effects that these elements may have on human cells
are of increasing concern (13).
The detection of antibodies to proteins encoded by genes found on HERVs
has been reported for a number of infectious, chronic, and malignant
diseases (1a, 3, 21). The presence of these antibodies
indicates that the immune system has been activated, suggesting that
there is a retroelement-associated influence on the immune system. It
is therefore possible that disease progression can be predicted by the
detection of antibodies to HERV-specific antigens (18, 26).
Retrovirus-like elements of interest in the study of human diseases
include those presumably derived from bovine, feline, murine, and human
leukemia viruses (18, 26). Provirus and retrotransposon
precursors of these viruses produce a conserved transmembrane envelope
protein with a molecular mass of approximately 15 kDa, p15E, which is
involved in the suppression of cell-mediated immunity (14, 23,
24). CKS-17A is a 17-amino-acid peptide derived from p15E. It has
been shown to inhibit lymphocyte proliferation and to modulate T-helper
1 and T-helper 2 cell responses (7, 12, 15). For this study,
peptide 4.1, a 17-amino-acid synthetic peptide partially homologous to
CKS-17A, was constructed from p15E amino acid sequence data.
Antibodies against HERV gene products can be detected in various body
fluids, including blood, urine, and oral fluids. A recent evaluation of
the results of a large clinical study showed that there was a
compartmentalized response to the exogenous retrovirus HIV-1.
Antibodies were found in urine but not in blood (25, 28).
The data from that study on urine anti-HERV antibodies and the results
on anti-HIV antibody compartmentalization suggest that, of these two,
the presence of antibodies against HERV gene products in urine may be a
more sensitive indicator of an active immune response (8,
19).
(This work was presented in part at the 96th General Meeting of the
American Society for Microbiology, 19 to 23 May 1996, New Orleans, La.
[1].)
| |
MATERIALS AND METHODS |
Human subjects.
Forty-three HIV-positive patients from the
Infectious Disease Clinic of the Stratton VA Medical Center were
enrolled in this study from August 1995 to March 1996. All patients
were tested and found to be positive for anti-HIV antibodies by the
Wadsworth Laboratories of the New York State Department of Health,
Albany. The control subjects were 21 age-matched, healthy male
volunteers with no known risk factors for HIV infection.
Urine specimens.
At the time of the clinic visit and after
signing a previously approved Institutional Review Board consent form,
each patient provided one urine specimen collected sometime between
late morning and early afternoon (hospital specimen). Thereafter, over
a 2-week period, each patient provided four urine specimens obtained at home. One was obtained in the early morning, one at noon, one in the
late afternoon, and one in the evening. These specimens, collectively
referred to as home urine specimens, were collected at different times
of day in case there was diurnal variation in the level of urine
anti-HERV antibodies. The same specimen collection protocol was
followed for control subjects. Urine specimens were preserved with
Stabilar preservation tablets (RP Cargille Laboratories, Inc., Cedar
Grove, N.J.), stored at room temperature (15 to 30°C) for 1 to 15 days prior to initial testing at the Stratton VA Medical Center, and
then stored for 1 to 2 months at 2 to 8°C before retesting at Calypte
Biomedical Corp., Berkeley, Calif. Data obtained from the standard HIV
urine test (4) have indicated that urine antibodies are
stable for at least 55 days at room temperature and for 12 months at
refrigeration temperature.
Demographic and clinical data were obtained from patient charts.
Subjects were predominately males (there was one female) aged 31 to 54 years. There were 28 Caucasian, 11 black, and 4 Hispanic patients.
Intravenous drug abuse or promiscuous homosexual or heterosexual
behavior was noted. The AIDS surveillance case definitions of the
Centers for Disease Control and Prevention (CDC) were used
(5): category A, asymptomatic, progressive, generalized
lymphadenopathy or acute disease; category B, symptomatic, not category
A or C; and category C, AIDS indicator conditions.
Data collection.
For HIV+ patients, the results
of extensive clinical laboratory blood testing, including tests for
hematocrit, mean corpuscular volume, platelet count, leukocyte (WBC)
count, serum protein, globulin, creatinine, glucose, amylase, serum
glutamic oxalacetic transaminase, hepatitis B surface antigen,
hepatitis B surface antibody, hepatitis B core antibody, hepatitis C
antibody, Toxoplasma immunoglobulin G (IgG) and IgM, and
RPR, which had been obtained in the regular course of clinical care
(data not shown), were collected and recorded for analysis along with
the anti-HERV antibody findings. Subsequent to the analysis of urine
specimens for anti-HERV antibodies, the laboratory values for patients
whose urine specimens were positive (anti-HERV+) and for
those that were negative (anti-HERV
) for anti-HERV
antibodies were compared. Laboratory analyses other than urine analyses
for anti-HERV antibodies were not performed for the HIV
control subjects. CD4 cell counts were determined by flow cytometry with standard methods. HIV loads were determined by an RNA PCR assay
conducted according to procedures established by Laboratory Corporation
of America.
The assay for antibody to a HERV gene product is based on an enzyme
immunoassay for anti-HIV-1 antibody in urine licensed by the Food and
Drug Administration (4). It is an investigational enzyme
immunoassay with peptide 4.1, a synthetic 17-amino-acid peptide
(H2N-GNRLALDYLLAAEGGVC-COOH) (American Peptide Co.,
Sunnyvale, Calif.), the sequence of which is related to that of the
envelope protein of endogenous retroviruses, as the target antigen for detecting urine antibody. For this assay, peptide 4.1 was allowed to
adsorb onto each well of a microwell plate. Urine specimens and
controls were then added to the wells (200 µl/well), and the plate
was covered and incubated at 37°C for 60 min. Following incubation,
the urine and unbound antibodies were removed by aspiration and the
wells were washed six times, with 350 µl of buffered saline each
time. A solution containing alkaline phosphatase conjugated to goat
anti-human IgG was then added to each well (100 µl/well). The plate
was then covered and incubated at 37°C for 60 min. Following incubation, the wells were washed as described above; 100 µl of a
solution containing p-nitrophenylphosphate, the substrate
for alkaline phosphatase, was added to each well; and the plate was covered and incubated at 37°C for 30 min. The enzymatic reaction was
terminated by the addition of 50 µl of a stop solution containing EDTA per well. The absorbance at 405 nm was then determined
spectrophotometrically. Two positive control wells and three negative
control wells were included in each microwell plate. A specimen was
scored positive if the absorbance was 
0.400 and negative if the
absorbance was <0.400. The cutoff value of 0.400 was established in
earlier studies conducted by Calypte Biomedical Corp. on 500 presumed
healthy adults (unpublished data). This value is twice the mean
absorbance maximum found in this population. The specimens were
randomly coded and examined in a blinded fashion, some in duplicate at the Stratton VA Medical Center and then all (singly) at Calypte Biomedical Corp. The test results for the individual specimens were
highly reproducible. A subject was considered positive for anti-HERV
antibody if at least one of the five urine specimens from that subject
was positive.
Statistical analysis.
Results were analyzed by the linear
logistic model with a modified transform (9), Cochran's Q
test (2), and the binomial and hypergeometric probability
functions. The level of significance was 0.05.
| |
RESULTS |
Demographic characteristics of the study subjects and the
laboratory data were obtained during the regular course of clinical care. Demographic and laboratory findings were similar for
anti-HERV+ and anti-HERV patients, except for
the average serum globulin levels, which were significantly lower in
anti-HERV+ subjects than in anti-HERV
subjects (P < 0.01). Although a higher proportion of
anti-HERV+ (70.0%) than anti-HERV (46.2%)
subjects had liver damage (indicated by serum glutamic oxalacetic
transaminase values of >28 IU/ml), the difference was not
statistically significant.
Eight anti-HERV+ (27%) and four anti-HERV
(31%) subjects had had no antiretroviral therapy at the start of the
study. Four subjects among the group who had received >24 months of
antiretroviral therapy had actually received more than 3 years of
antiretroviral therapy; two anti-HERV+ subjects had been
treated for 46 and 59 months, and two anti-HERV subjects
had been treated for 38 and 44 months.
CD4 and WBC counts and viral load findings are summarized in Table
1. As expected, the CD4 counts and viral
loads show a negative correlation (P < 0.01), while
CD4 and WBC counts are positively correlated (P < 0.01). The two groups were similar with respect to CD4 count,
viral load, and WBC count. In addition, for each of these parameters,
the two groups were similar in variability.
Anti-peptide 4.1 antibody findings for subjects grouped according to
CDC AIDS surveillance case definitions are shown in Tables 2 and 3.
The proportion of anti-HERV+ subjects was lower
(P < 0.01) in CDC category A than in categories B and
C (Table 2). All five urine specimens from each of the 21 control
subjects were anti-HERV. For the anti-HERV+
patients in each CDC category, the number of urine specimens testing
positive for antibody to HERV peptide 4.1 ranged from one to five
(Table 3). Home urine specimens collected at different times of day had
no statistically significant differences in the proportions found to be
positive for antibodies to HERV peptide 4.1 (data not shown).
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|
TABLE 2.
Distribution of 43 HIV-1-positive patients by CDC
clinical AIDS categories and by results of the anti-HERV
antibody testa
|
|
| |
DISCUSSION |
Infections with exogenous retroviruses and the associated immune
response to these infections have been associated with several chronic
inflammatory and autoimmune diseases (18, 26, 29). Furthermore, elevated levels of HERV gene products and antibodies to
these products have been associated with the same types of disease.
Because of the association between antiretroviral and HERV gene product
antibodies and these diseases, tests for antibodies to HERV gene
products have been developed. These tests have been used to detect
elevated antibody levels in the blood of animals with retroviral
infections and of humans with rheumatoid arthritis, lupus
erythematosus, and other diseases (3, 11, 21). However, this
is the first report of the detection of elevated levels of anti-HERV
antibodies in the urine of HIV-1-positive patients. The specificity of
the test used in this study appears to be high, since no anti-HERV
antibody was detected in the urine of any of the HIV-negative controls.
However, there appears to be no correlation between the severity of HIV
disease and the percentage of the five specimens from each patient that
were positive. Furthermore, no information regarding the effect of HIV
disease on the expression of HERV genes is available. Finally, there is
currently no way to determine whether antibodies against peptide 4.1 were absent or present but undetected in the HIV-positive patients who
tested negative. Consequently, the sensitivity of the test cannot be determined at this time. Nevertheless, it is interesting that only 36%
of the HIV-positive patients in CDC category A were positive while 81%
of those in both categories B and C were positive (P < 0.01). These results suggest that the test may be useful for monitoring the progression of HIV disease in patients who are initially
HIV positive but negative for antibodies to the HERV-related peptide
4.1. However, to establish the utility of such a test and to address
the question of whether HIV+ and anti-HERV+
patients remain anti-HERV+, a longitudinal study of
HIV+ patients is required.
In this study, there was no noteworthy association of clinical signs or
symptoms with the conversion from anti-HERV to
anti-HERV+ status. This implies that HIV infection alone is
responsible for triggering the production of antibodies to the peptide.
However, it is important to note that considerable evidence suggests
that the expression of HERV genes is important in modulating the immune response and that this HERV-related immunomodulation is in some way
related to the development of specific disease (10, 20, 22).
Immunosuppression, as evidenced by progression to the more advanced
clinical stages of HIV disease (CDC categories B and C), may be
associated with diminished immunosurveillance. This could allow a
higher degree of expression of HERV genes and the production of HERV
gene products. In more advanced disease states associated with HIV
infection, more (or more persistent) expression of HERV antigens would
be expected to result in the increased detectability of antibodies to
these antigens. The much lower levels of antibody potentially
detectable in healthy individuals (none of the controls [n = 21] in this study had levels that reached the cutoff value)
could reflect immune recognition of antigens occasionally produced in
the immunocompetent host. Further studies may involve tests for
antibodies to peptide 4.1, antibodies to other HERV peptides, and
antibodies to retrovirus gene products, as well as tests for the
detection of the antigens themselves. Such studies should be helpful in
developing a better understanding of the association among HIV
infection, the production of retrovirus-related antigens, and the
production of antibodies to these antigens. In addition, investigation
of the roles of cell-mediated immune modulators (cytokines) in the
development of chronic inflammatory diseases could lead to a greater
understanding of the initiation of anti-HERV antibody production.
In summary, the laboratory values for patients in the two HIV-positive
groups in this study were similar except that there was a significantly
greater prevalence of antibody to a HERV gene product detected in
specimens from patients in CDC categories B and C than in those from
patients in CDC category A. This suggests that progression to
symptomatic stages in HIV disease correlates with the presence of
antibodies to HERV gene products in urine.
| |
ACKNOWLEDGMENTS |
This study was supported by Calypte Biomedical Corp. and, in
part, by the U.S. Department of Veterans Affairs.
We thank Lou Smith, Michael Hart, Carol Rheal, and Mary Franke for
their assistance in enlisting patients and for the recording and
compilation of the data. We also thank Miger Ornopia for his technical
assistance in the urine anti-HERV antibody analysis.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Infectious
Disease Section (111D), Stratton VA Medical Center, 113 Holland Ave.,
Albany, NY 12208. Phone: (518) 462-3311, ext. 3080. Fax: (518)
462-3350. E-mail: baltch.aldona{at}Albany.va.gov.
Present address: Triangle Pharmaceuticals, Inc., Durham,
N.C.
Present address: Chronic Illness Research Foundation, Berkeley, Calif.
| |
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Clinical and Diagnostic Laboratory Immunology, November 1999, p. 783-786, Vol. 6, No. 6
1071-412X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
