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Herpesvirus and HIV type 1 infections: A seroepidemiologic study of relationships in selected populations

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Herpesvirus and HIV type 1 infections: A seroepidemiologic study of relationships in selected populations

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Content HERPESVIRUS AND HIV TYPE 1 INFECTIONS:
A SEROEPIDEMIOLOGIC STUDY OF RELATIONSHIPS
IN SELECTED POPULATIONS
by
William James Gauderman Jr.
A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(Biometry)
December 1988
UMI Number: EP54909
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UMI EP54909
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P.O. Box 1346
Ann Arbor, Ml 48106 - 1346
UNIVERSITY OF SOUTHERN CALIFORNIA
TH E GRADUATE SCHO O L
U N IV E R S IT Y PARK
LOS AN G ELES. C A L IF O R N IA 9 0 0 0 7
This thesisj written by
William James Gauderman Jr.
under the direction of h±s....Thesis Committeej
and approved by all its members, has been pre
sented to and accepted by the Dean of The
Graduate School, in partial fulfillment of the
requirements for the degree of
Master of Science
Dean
THESIS COMMITTEE
/ ] Chatrman
DEDICATION
To mom^ dad, and Andy for their love and support
throughout my school career.
11
i ACKNOWLEDGMENTS
j
I I would like to express my sincere appreciation to Dr.
Joyce Niland, the Chairman of my committee, for her
guidance throughout the development of my thesis. Special
I
thanks to Dr. Stanley Azen for his assistance on my thesis
t
as well as for his support during my entire graduate
training, and to Dr. Mark Krailo for his expert insights
into many of the theoretical and analytical problems
Lncountered. Finally, I would like to thank Sherry1 Baker
for her GENEROUS help with Epilog programming, and Cheryl
Faucett Hagerty for her assistance in formatting the final
product.
Ill
TABLE OF CONTENTS
DEDICATION............................................... ii
ACKNOWLEDGMENTS..........................................iii
LIST OF TABLES........................................ V
I
LIST OF FIGURES...........................................vi
Chapter Page
I. INTRODUCTION ..................................... 1
II. MATERIALS AND METHODS............................ 4
III. RESULTS..............................................10
IV. DISCUSSION......................................... 24
REFERENCES............................................... 28
IV
LIST OF TABLES
Table Page
1. Demographic Characteristics of Subjects with
CMV, EBV, and HIV-1 Antibody Testing ........... 5
Frequency of CMV and EBV Antibody Positivity
by Anti-HIV-1 11
Frequency of CMV Antibody Positivity by HIV-1
Antibody Status and Type of Sexual Exposure
for Untreated Sexually Active Subjects ........ 12
Factors Significantly Associated with Anti-HIV-1
Status by Stepwise Logistic Regression
Procedure........................................14
Immunologic Parameters (Mean + sd) by
Anti-HIV-1 and Anti-CMV Status ................. 16
Immunologic Parameters (Mean + sd) by
Anti-HIV-1 and Anti-EBV Status ................. 18
LIST OF FIGURES
Figure Page
1. Cumulative Proportion Surviving AIDS by Anti-CMV
Status for Subjects Who Were Anti-HIV-1(+) at
Study E n t r y .................................... 19
2. Cumulative Proportion Surviving AIDS by Anti-EBV
Status for Subjects Who Were Anti-HIV-1(+) at
Study E n t r y .................................... 21
3. Cumulative Proportion Surviving Death by Anti-CMV
Status for Subjects Who Developed AIDS after
Entry into Study................................22
4. Cumulative Proportion Surviving Death by Anti-EBV
Status for Subjects Who Developed AIDS after
Entry into Study................................2 3
VI
CHAPTER I
INTRODUCTION
The Transfusion Safety Study (TSS) is a National
Heart, Lung, and Blood Institute (NHLBI) funded investiga
tion of the transmission of infections through blood
products. The TSS was organized as a collaborative multi
centered project prior to the routine screening of donors
for the human immunodeficiency virus (HIV-1). From Sep
tember, 1984 through February, 1985 the TSS collected and
stored a repository of approximately 250,000 blood samples
from donors to participating services in areas of high AIDS
prevalence: Los Angeles, Miami, New York and San Fran
cisco. After the testing of repository samples for HIV-1
was completed, donors and recipients of HIV-1 positive and
negative blood were identified and enrolled for study by
the TSS. In addition, treated and untreated congenital
disorder patients and their sexual and household contacts
were identified from clinics in these four cities, as well
as in Seattle and Detroit, cities with low AIDS prevalence
at that time. All subjects were followed longitudinally
for serologic, virologie, immunologic, and clinical
studies. The availability of these subjects has provided a
i_j
unique opportunity to investigate certain risk factors
associated with the pathogenesis of HIV-1 infection, as
yell as aspects of its clinical manifestations.
Soon after the first descriptions of the acquired
immunodeficiency syndrome (AIDS), which was initially
I
recognized predominantly in homosexual men, it became
apparent that herpesvirus infections were prominent among
affected individuals.^ Initially, it was not clear whether
the herpesvirus infections occurred because of the inde
pendent increased prevalence among homosexual men,^ because
they were opportunistic infections resulting from the
immunosuppression associated with AIDS,^ or because they
were etiologic agents or associated features of AIDS
(defining conditions (e.g. Kaposi's Sarcoma,or B-cell
lymphomas) . ^ ^ With the recognition of HIV-1 as the etio
logic agent of AIDS, it was hypothesized that one or more
of the herpesviruses might act as cofactors and activate
latent HIV-l, enhance HIV-1 expression, or otherwise
contribute directly or indirectly to the pathogenesis of
AIDS.^ This theory was substantiated by studies which
showed that cytomegalovirus (CMV), herpes simplex virus
(HSV), Epstein-Barr virus (EBV), and several other viruses
were able to transactivate the HIV-1 genome in vitro.
The goal of this thesis was to ascertain whether the
prevalence of either CMV or EBV could be correlated with
the prevalence of HIV-1, and whether the presence of these
herpesvirus infections was associated with altered expres
sion or progression of HIV-1 infection.
CHAPTER II
MATERIALS AND METHODS
Study Subjects
The TSS began enrolling subjects in March, 1985 and by
April, 1987, when the data were analyzed, approximately
2800 subjects had been recruited. A sample of 1171 of
these subjects were tested for antibody positivity to CMV,
'EBV, and HIV-1 at their time of enrollment into the study.
For the purposes of this analysis, subjects were grouped
according to the type of blood product they received: 350
subjects received concentrate, 227 received single donor
units, and 594 received no blood product. The concentrate
group was comprised exclusively of hemophiliacs; the single
donor unit group consisted of congenital disorder patients
(hemophiliacs and congenital anemias) and other transfusion
recipients; the untreated group included donors, untreated
congenital disorder patients, and persons having household
or sexual contact with congenital disorder patients. Table
1 summarizes the demographic characteristics of these three
study groups.
TABLE 1
Demographic Characteristics of Subjects
with CMV, EBV, and HIV-1 Antibody Testing
Type of
Blood
Product
Total
Number
Sex
Male Female
Age (yrs)
Uhi te
Race
Black Other^
Concentrate 350 343 (98)^ 7 ( 2) 26.5 (1-74)*^ 257 (73) 30 ( 9) 63 (18)
Single Donor
Uni ts
227 126 (56) 101 (44) 25.6 (0-81) 118 (52) 81 (36) 28 (12)
Untreated 594 236 (40) 358 (60) 30.0 (0-71) 361 (61) 121 (20) 112 (19)
^ Includes all other races and those for whom race is missing
^ Frequency <%)
^ Mean (Range)
Laboratory Methods
HIV-1 antibody status was assessed with a commercially
available ELISA assay used as described by the manufacturer
(Abbott and Genetic Systems), and repeatedly positive
results were confirmed by a protein immunoblot procedure
i(SmithKline Bioscience, Inc., Los Angeles). CMV and EBV
Lntibody status were assessed with an ELISA test developed
at the City of Hope in Los Angeles as described by Lang et
al.^^ Although antibody to early antigen (EA) was also
measured, for purposes of this thesis EBV antibody status
|Was determined by viral capsid antigen (VCA) solely,
without regard to EA status.
To determine immunology marker levels, a complete
blood count and differential, platelet count and analysis
by flow cytometry of leukocyte subsets were performed. A
quality control protocol was followed as described else
where. Flow cytometry analysis used two-color immuno
fluorescence and an EPICS C flow cytometer, as has been
previously described^^' Absolute numbers of circulating
CD4 (T helper) and CDS (T suppressor/cytotoxic) cells were
evaluated by multiplying the percentage of lymphocytes
expressing the appropriate marker by the absolute lympho
cyte count (ALC).
Statistical Analyses^
In order to ascertain whether prevalence of CMV anti
body positivity (anti-CMV(+)) and EBV antibody positivity
(anti-EBV(+)) were correlated with HIV-1 antibody positi-
1
yity (anti-HIV-1(+)), the Mantel-Haenszel chi-square test
jwas performed within study group, adjusting for age group.
Age groupings were: less than 13, 13 through 29, and 30 or
jgreater years. Mantel-Haenszel age-adjusted odds ratios
were also calculated. To further investigate the relation
ship of CMV and EBV with HIV-1, a stepwise logistic
regression was performed. The dependent variable was anti-
HIV- 1 status and the independent covariates were : anti-CMV,
anti-EBV, age group, sex, homosexual status (a dichotomous
variable reflecting any homosexual contact vs. none), and
type of blood product received (concentrate, single donor
units, or untreated).
To investigate the association between anti-CMV and
'anti-EBV positivity and the expression of HIV-1 infection,
mean levels of absolute CD4, absolute CDS, CD4/CD8 ratio,
and absolute lymphocyte count were evaluated. The subjects
included in the analysis (N=998) were those who had test
results for all of the above immunology markers, and who
did not have AIDS at entry or develop AIDS within 24 months
of entry. Testing for differences in mean levels based on
herpesvirus status was stratified by anti-HIV-1 status,
using factorial analysis of variance (ANOVA). The depen
dent measure was the immunology marker of interest (trans
formed to ensure normality using the Kolomogorov D
Ltatistic) and the independent factors were herpesvirus
status and age group. In cases where a significant
herpesvirus-age group interaction was encountered a two-
sample t-test was performed for each age group to test for
'differences based on herpesvirus status.
Of the 1171 subjects, 343 (29%) were anti-HIV-1 posi
tive at entry and by April 1, 1988, 42 (12%) had developed
AIDS. However, date of diagnosis of AIDS was known for only
37 subjects. Survival analysis was carried out to ascer
tain whether the anti-CMV or anti-EBV status of these 34 3
anti-HIV-1 positive subjects affected their probability of
Leveloping AIDS. Of the 42 AIDS-post-entry subjects, 21
(50%) had died prior to March 1, 1988 (date of death was
known for only 17, however). Survival analysis was also
performed to determine whether anti-CMV or anti-EBV status
influenced probability of death among the 42 AIDS cases.
In both analyses, an individual who did not develop the
endpoint of interest was censored at his last visit. Also,
those subjects with a missing date of AIDS diagnosis, date
of death, or vital status were assumed to represent a
random sample of those experiencing the event, and were
8
excluded from the analysis. Relative hazard rates compar
ting groups stratified by herpesvirus status were calculated
as the quotient of observed (O) to expected (E) ratios, and
jthe Mantel-Cox statistic was used to test for deviations of
jthese rates from unity.
All analyses were performed using the Statistical
Analysis System (SAS— SAS Institute Inc., Cary, N.C.),
(
Biomedical Series P (BMDP— BMDP Statistical Software Inc.,
Los Angeles, CA), or EPILOG (Epicenter Software, Pasadena,
CA) statistical software packages. The significance level
jwas set at 0.05 and all tests were performed using a two-
sided alternative.
CHAPTER III
RESULTS
Table 2 shows the rates of anti-CMV and anti-EBV posi
tivity by anti-HIV-1 status for the three study groups.
For the untreated group, the rate of anti-CMV(+) for anti-
HIV- 1(4") subjects (74%) was significantly higher than for
anti-HIV-1(-) subjects (51%, p=0.007). The corresponding
age-adjusted odds ratio was 2.40, with 95% confidence
limits of 1.28 to 4.51. The other two groups did not show
significantly higher rates of anti-CMV(+) in the anti-
HIV-1 (+) subjects. In fact, for those treated with concen
trate, the rate of anti-CMV(+) was actually lower for anti-
HIV-1 (+) subjects (49%) than for anti-HIV-1(-) subjects
(55%). No groups showed significant differences in rates
of anti-EBV(t) based on anti-HIV-1 status.
It was hypothesized that the significant difference
found in anti-CMV rates for the untreated group was due to
their increased rate of homosexual activity. Of the 594
^untreated subjects, 432 (73%) were sexually active and
indicated their sexual preference. For these subjects.
Table 3 gives the rates of anti-CMV positivity by their
anti-HIV-1 status and type of sexual exposure. For the
10
TABLE 2
Frequency of CMV and EBV Antibody Positivity
by Anti = MIV^1 Status
Type of
Blood
Product
Anti-HIV-1
Status N
Anti -CMV(+) Anti -EBV(+)
n (%)
O.R.®
(95% C.I.) n (%)
O.R.®
(95% C.I.)
Concentrate Positive 259 128 (49) 0.71 177 (68) 1.50
Negative 91 50 (55) (0.42,1.19) 50 (55) (0.89,2.55)
Single Positive 37 24 (65) 1.58 28 (76) 1.19
Donor Units Negative 190 92 (48) (0.72,3.47) 124 (65) (0.48,2.94)
Untreated Positive 53 39 (74) 2.40^ 47 (89) 1.87
Negative 541 276 (51) (1.28,4.51) 411 (76) (0.75,4.66)
The age-adjusted odds of being anti-CMV<+) for an anti-HIV-1(+) subject
versus an anti-HIV-1(-) subject, using Mantel-Haenszel method of adjustment,
Significant difference in rate of anti-CMV positivity between anti-HIV-1(+)
and anti-HIV-l(-) untreated subjects, using Mantel-Haenszel test.
controlling for age (p = 0.007).
11
TABLE 3
Frequency of CMV Antibody Positivity by HIV-1 Antibody Status and
Type of Sexual Exposure for Untreated Sexually Active Subjects
Type of
Sexual
Exposure
Anti-HIV-1
Status N n
Anti
<%)
-CMV(+)
O.R.®
(95% C.I.)
All Sexually Positive 52 39 (75) 2.37b
Active Subjects Negative 380 217 (57) (1.24,4.54)
Heterosexual Posi t ive 20 11 (55) 0.99
Negative 372 212 (57) (0.39,2.48)
Homosexual Positive 32 28 (88) 4.67
Negative 8 5 (63) (0.78,27.97)
The age-adjusted odds of being anti-CMV(+) for an anti-HIV-1<+) subject
versus an anti-HIV-l(-) subject, using Mantel-Haenszel method of adjustment,
Significant difference in rate of anti-CMV positivity between anti-HIV-1( + )
and anti-HIV-l(-) untreated subjects, using Mantel-Haenszel test.
controlling for age (p = 0.009),
12
subset as a whole, the rate of anti-CMV(+) for anti-
HIV-1 (+) subjects (75%) was significantly higher than for
anti-HIV-1(-) subjects (57%, p=0.009). These rates were
similar to those seen in the entire untreated group, as was
jthe age-adjusted odds ratio (2.37 with 95% confidence
bounds of 1.24 to 4.54). However, looking at heterosexuals
jonly, the rates of anti-CMV positivity between anti-
HIV-1 (+) and anti-HIV-1(-) subjects were nearly equal (55%
versus 57%, with an age-adjusted odds ratio of 0.99). On
the other hand, in the homosexual group, the rate of anti-
CMV (+) for anti-HIV-1(+) subjects was 88% compared to only
63% for anti-HIV-1(-) subjects, with a corresponding odds
ratio of 4.67. The significance level for this latter rate
was 0.09, indicating a trend for association between CMV
and HIV-1 antibody positivity in those subjects reporting
homosexual activity.
j Table 4 shows the results of the stepwise logistic
regression. The predictors that entered the model were the
jtype of blood treatment, homosexual status, and age group.
Once these variables entered the model, neither anti-CMV
nor anti-EBV status were found to be significantly associ
ated with anti-HIV-1 status. Although initially anti-CMV
Ltatus was found to be significantly associated with anti-
HIV- 1 status (p=0.04), once homosexual status entered the
model this association was drastically diminished (p=0.60).
13
TABLE 4
Factors Significantly Associated with Anti-HIV-1 Status
by Stepwise Logistic Regression Procedure
Variable Comparison Coeff ici ent S.E. OR®
Type of
Blood Single vs None 1.53 0.281 4.63
Product Cone, vs None 4.21 0.249 67.63
Type of
Sexual
Exposure
Homosexual vs
Heterosexual 3.95 0.409 52.15
Age 13-29 vs <13 1.12 0.259 3.07
Group 30+ vs <13 1.01 0.261 2.74
Constant -4.03 0.307 0.02
OR = exp(coefficient)
14
This result parallels our earlier observations regarding
the role of type of sexual exposure in these associations
(Table 3).
Further analyses were performed to ascertain whether
anti-CMV(I) and anti-EDV( + ) , in conjuction with anti-HIV-1
status, were associated with alterations in the immune
Lystem. Table 5 shows the mean (± sd) levels of absolute
CD4, absolute CD8, CD4/CD8 ratio, and absolute lymphocyte
count by anti-HIV-1 and anti-CMV status. For the anti-
HIV-1 (+) subjects treated with concentrate, the mean levels
of the CD4/CD8 ratio in the anti-CMV(+) and anti-CMV(-)
groups were significantly different (0.66 vs. 0.87,
p=0.014). In the analyses of absolute CD4, CD8, and lymph-
jocyte count for these same subjects, significant inter
actions between anti-CMV status and age group were found.
In all three cases, significant differences in mean levels
of the immunology markers were found in the 3 0+ age group
(N = 75) . The mean levels for anti-CMV(+) and anti-CMV(-)
subjects in this age group were 499 and 3 69 for absolute
jcD4 (p=0.04) , 798 and 534 for absolute CD8 (p=0.002) , and
1822 and 1278 for absolute lymphocyte count (p=0.002),
respectively. The anti-HIV-1(+) subjects who received
single donor units or who were untreated showed no signif
icant differences in mean levels of any immunology marker
Lue to anti-CMV status.
15
TABLE 5
Immunologic Parameters (Mean + sd)
by Anti-HIV-1 and Anti-CMV Status
Type of
Blood
Product
Concentrate
Abs. CD4
Abs. CDS
CD4/CD8
ALC
Anti-HIV-1(+)
Anti-CMV(+) Anti-CMV(-)
(N = 108)
499 + 301
825 + 446
0.66 + 0.32
1838 + 805
(N = 106)
564 + 359b
796 + 729b
0.87 + 0.62
1916 + 1190^
a
Anti-HIV-l(-)
Anti-CMV(+) Anti-CMV(-)
(N = 46)
895 + 506
673 + 405
1.48 + 0.70
2366 + 1307
(N = 35)
1038 + 649
740 + 398
1.51 + 0.54
2578 + 1326
Single Donor
Units
Abs. CD4
Abs. CDS
CD4/CD8
ALC
(N = 22)
605 + 339
719 + 438
0.96 + 0.44
2184 + 1247
(N = 10)
1294 + 978
1290 + 962
1.22 + 0.81
3832 + 2427
(N = 87)
1327 + 817
893 + 586
1.64 + 0.73
3805 + 2553
(N = 88)
1317 + 834
810 + 446
1.75 + 0.81
3657 + 2073
None
Abs. CD4
Abs. CDS
CD4/CD8
ALC
(N = 33)
520 + 203
843 + 482
(N = 13)
644 + 537
747 + 481
0.74 + 0.37 0.94 + 0.46
1975 + 655 2081 + 1472
(N = 237)
1128 + 669
653 + 365
1.91 + 0.85
2567 + 1292
(N = 213)
1091 + 517
602 + 301®
1.99 + 0.85
2476 + 1105
a
Significant difference between anti-CMV(+) and anti-CMV(-), within anti-HIV-1
status, using factorial analysis of variance, adjusting for age (p < 0.05).
Significant difference between anti-CMV( + ) and anti-CMV(-), within anti-HIV-1
status, using two-sample t-test, for 30-or-older age group (N=54 anti-CMV(+),
N=21 anti-CMV(-), p < 0.05)
16
Anti-HIV-1(-) subjects treated with either concentrate
or single donor units showed no significant differences in
mean immunology marker levels due to anti-CMV status.
However, in the untreated anti-HIV-1(-) group, significant
{differences between anti-CMV(+) and anti-CMV(-) subjects
I
were observed in mean levels of absolute CDS (653 versus
602, p=0.0026), CD4/CD8 ratio (1.91 versus 1.99, p=0.04),
and absolute lymphocyte count (2567 versus 2476, p=0.006).
Table 6 shows mean levels and standard deviations of
the four immunology markers by anti-HIV-1 and anti-EBV
status. For anti-HIV-1(+) subjects treated with concen
trate, the mean level of CD4/CD8 ratio for the anti-EBV(+)
^group (0.72) was significantly different than for the anti-
EBV (-) group (0.87, p=0.02). The subset of these subjects
who were 30 years or older showed significant differences
in mean levels of absolute CD8 (760 vs. 621 for anti-EBV(+)
and anti-EBV(-) respectively, p=0.04). Aside from these
two findings, no differences were detected in immunology
markers based on anti-EBV status among the groups tested.
Figure 1 shows survival curves of the probability of
'developing AIDS by anti-CMV status, for subjects who were
anti-HIV-1(+) at entry. The relative hazard of anti-CMV(+)
compared to anti-CMV(-) subjects was 0.82, which was not
significantly different from one. It is interesting to
note that the relative hazard ratio for anti-CMV(+) versus
17
TABLE 6
Immunologie Parameters (Mean + sd)
by Anti-HIV-1 and Anti-EBV Status
Type of
Blood
Pi'odue I
Anti-HIV-1<+)
Anti-EBV(+) Anti-EBV(-)
Anti-HIV-l(-)
Ant1-EBV(+) Anti-fcBV(-)
Concentrate (N
=
145) CN 69) (N = 46) (N 35)
Abs. CD4 500 + 309 596 + 369 821
+
441 1134 + 676
Abs. CDS 806 +
459 821
+ 830^ 669 +
434 745 + 354
CD4/CD8 0.72
+
0.52 0.87
+ 0.46® 1.45
+
0.75 1.55 + 0.44
ALC 1852
+
875 1928 + 1259 2206
+
1216 2789 + 1375
Single Donor
Units (N = 25) (N 7) (N 117) (N = 58)
Abs. CD4 623
+
331 1524 + 1096 1244 +
757 1480 + 929
Abs. CDS 737 +
455 1473
+ 1053 812
+
433 931 + 660
CD4/CD8 1.04
+
0.64 1.06
+ 0.32 1.64 +
0.75 1.80 + 0.81
ALC 2222
+ 1180 4402 + 2735 3623 +
2148 3947 + 2636
None (N 41) CN = 5) Abs. CD4 515 + 203 881
+ 819 1083
+
573 1211 + 688
Abs. CDS 818
+
485 801 + 477 611
+
333 695 + 343
CD4/CD8 0.77
+
0.40 1.01 + 0.33 1.97 +
0.87 1.89
+ 0.80
ALC 1929
+
683 2630 + 2179 2434 +
1137 2846 + 1389
^ Significant difference between anti-EBV(+) and anti-EBV(-), within anti-HIV-1
status, using factorial analysis of variance, adjusting for age (p < 0.05).
^ Significant difference between anti-EBV( + ) and anti-EBV(-), within anti-HIV-1
status, using two-sample t-test, for 30-or-older age group N=19 anti-EBV(-), p < 0.05).
18
FIGURE 1
Cumulative Proportion Surviving AIDS by Anti-CMV Status
for Subjects Who Were Anti-HIV-U + ) at Study Entry
2 0.95
CL
0.85
Plot Total Cbs.
Symbol No. AIDS
186 18
156 19
0/E
Ratio
M-C
P-value
u 0.80 19.8 0.91 0.551
17.2 1.11
912
730 547 365
Time (Days)
182
Hantel-Cox Statistic
19
anti-CMV(-) is actually less than one. Similarly, Figure 2
shows the survival curves of probability of developing AIDS
by anti-EBV status. The relative hazard of anti-EBV(+)
versus anti-EBV(-) subjects was 1.23, again not signif
icantly different from one.
Figure 3 shows survival curves of the probability of
death for anti-CMV(+) vs. anti-CMV(-) AIDS subjects. The
relative hazard for anti-CMV(+) compared to anti-CMV(-)
subjects was 0.68, which was not significantly different
jfrom one. Figure 4 shows the corresponding survival curves
based on anti-EBV status. The relative hazard of anti-
EBV (+) versus anti-EBV(-) subjects was 0.76, again not
significantly different from one.
20_ ,
FIGURE 2
Cumulative Proportion Surviving AIDS by Anti-EBV Status
for Subjects Who Were Anti-HIV-1C+) at Study Entry
0.95
3 0.90
t 0.85
CVE M-C
Ratio P-value
Plot Total Cbs. E; ?).
Svdjol No. ^ AIDS
246 28 26.5 1.06 0.5ES
96 9 10.5 0.86
Stratum
Ü 0.80
912 73 0 547 365 182
Time (Days)
Mantel-Cox Statistic
21
FIGURE 3
Cumulative Proportion Surviving Death by Anti-CMV Status
for Subjects Who Developed AIDS after Entry into Study
1.00
4 >
O
o>
c
* >
L
3
§ .
o
0.75
%
0.50
I
u
0.25
Plot Total Cbs.
is
Q/E
Ratio
M-C
Stratun Syibol No, Dths P-value
Anti-OW(+)
Anti-OW(-)
13
17
6
11
7.6
9.4
0.79
1.17
0.425
I
182 365
Time (Days)
547
Mantel-Cox Statistic
22
FIGURE 4
Cumulative Proportion Surviving Death by Anti-EBV Status
for Subjects Who Developed AIDS after Entry into Study
1.00
S
> 0.75
3
C
o
o
Q .
O
0.50
0.25
Stratum
Plot
SvfTbol
Total
No,
Cbs.
Ddg
C/E
Ratio
*
M-C
P-value
Anti-EBV<+)
Anti-EBV(-)
25
5
14
3
14.6
2.4
0.96
1.26
0.660
182 365
Time (Days)
547
Mantel-Cox Statistic
23
CHAPTER IV
DISCUSSION
The results presented here indicate that for subjects
treated with blood products, the prevalence of antibody to
CMV and EBV did not appear to be associated with the
prevalence of anti-HlV-1. On the other hand, there was a
significant association between CMV and HlV-1 antibody
seropositivity among the untreated subjects. When this
group was subdivided based on sexual preference, the
association was nonexistent in the heterosexual population.
However, the results did demonstrate an increase in the
prevalence of anti-CMV(+) among anti-HlV-1(+) homosexual
subjects, perhaps indicating that some of the risk factors
Lor acquisition of CMV and HlV-1 are the same. In addi
tion, these results suggest that homosexuality modifies the
anti-CMV/anti-HIV-1 relationship. Hence, the significant
association seen for untreated patients should probably not
be generalized to the entire group, but rather restricted
to the homosexuals.
There were no differences detected in the high preva
lence rates of anti-EBV positivity for any of the groups.
It may be that there was such a high background rate of EBV
24
jthat any additional effect of HIV-1 could not be detected.
Furthermore, using the anti-VCA result to determine anti-
EBV status had the disadvantage that we could not discrim
inate between active and inactive EBV infection. Thus,
■these results do no rule out the possibility of an
I
association between HIV-1 and active EBV infection.
Re1event immunologic paramaters were evaluated with
reference to anti-HIV-1 status, and antibody positivity for
CMV and EBV was significantly associated with decreases of
CD4/CD8 ratio in anti-HIV-1(+) subjects treated with
concentrate. In addition, we observed a trend of lower,
jthough non-significant, CD4/CD8 ratios in the other anti-
HIV-1 (+) subgroups. These findings are consistent with
previous reports which have shown that infection with CMV
and EBV can independently reduce the CD4/CD8 ratio, though
less dramatically than infection with HlV-1.^^'^^ Also, in
30 year and older anti-HIV-1(+) subjects treated with
concentrate, CMV antibody positivity was associated with
increased absolute CD8 and, unlike the anti-HIV-1(+)
concentrate treated group as whole, increased absolute CD4
and lymphocyte counts. Thus, it appears that CMV antibody
positivity is associated with alterations in the expression
of HIV-1, but primarily in older hemophiliacs.
Although associated with reductions of CD4/CD8 ratios
in anti-HIV-1(+) subjects, CMV and EBV antibody status did
25
not significantly alter the probability of development of
AIDS. Furthermore, eight of the anti-HIV-1(+) individuals
who were seronegative for CMV and EBV at the outset of the
study went on to develop AIDS, suggesting that these agents
are not necessary for the progression of HIV-1 infection.
)
It must be cautioned, however, that CMV and EBV seroneg
ative status at the time of enrollment would not preclude
jthe subsequent acquisition of these infections, and thus
jtheir possible influence upon the appearance of AIDS.
However, among four subjects who had AIDS at enrollment,
jthree were anti-CMV(-) and two were anti-EBV(-) at that
time. In addition, CMV and EBV antibody status did not
significantly alter the probability of death for those who
developed AIDS post-entry.
The above conclusions were based on survival analyses
which were performed under the assumption that subjects
with missing diagnosis or death date(s) represented a
random sample of those experiencing the event. If this
were untrue, using the Mantel-Cox statistic would not be
proper for detecting differences between groups. Instead,
jthe survival curves should be adjusted according to the
method developed by Turnbull,and comparisons should be
performed utilizing the permutâtional test proposed by
I ,7
Gehan. Furthermore, because the exact time that these
subjects became anti-HIV-1 positive was unknown, possible
26
blases may have been introduced into the survival analyses,
Lince, of necessity, entry into the study was used as time
zero.
Because this was a cross-sectional study, no state
ments can be made about causal relationships, only about
associations between factors. Thus, it is still unclear
whether antibody positivity for CMV or EBV increases the
risk of becoming anti-HIV-1 positive, or vice versa.
Similarly, it can not be determined whether herpesvirus
status is responsible for the alterations seen in immu
nology markers. It may be that changes in the immune
system predispose an individual to become antibody positive
for CMV or EBV. In order to answer questions about cause
and effect, a longitudinal analysis needs to be done.
We may, however, conclude that HIV-1 infection can
certainly be acquired and progress independently of anti-
CMV and anti-EBV status. It may well be that the transact
ivation and pathogenesis of HIV-1 infection can be
influenced by and proceed via a variety of mechanisms.
Once HIV-1 infection is established, the diversity of
possible relevant influences upon the pathogenesis and
progress of the infection underscores the remarkable adapt
ability of this virus, and emphasizes the challenge
inherent in devising effective means for its control.
27
REFERENCES
Quinnan GV, Masur H, Rook AH, et al. Herpesvirus
infections in the acquired immune deficiency syndrome. JAMA
1984 ; 252:72-7.
2. Detels R, Visscher BR, Fahey JL, Schwartz K, Greene
RS, Madden DL, Sever JL, Gottlieb MS. The relation of
cytomegalovirus and Epstein-Barr virus antibodies to T-cell
subsets in homosexually active men. JAMA 1984; 251:1719-22.
3. Sonnabend J, Witkin SS, Purtilo DT. Acquired immuno
deficiency syndrome, opportunistic infections and malig
nancies in male homosexuals (A hypothesis of etiologic
■factors in pathogenesis). JAMA 1983; 249:2370-74.
j4. Marmor M, Friedman-Dien AE, Zolla-Pazner S, Stahl RE,
Rubinstein P, Laubenstein L, William DC, Klein RJ, Spigland
I. Kaposi's sarcoma in homosexual men— a seroepidemiologic
case-control study. Ann Intern Med 1984 ; 100:8 09-15.
5. Rogers MF, Morens DM, Stewart JA, Kaminski RM, Spira
TJ, Feorino PM, Larsen SA, Francis DP, Wilson M, Kaufman L,
The Task Force on AIDS. National case-control study of
Kaposi's sarcoma and Pneumocystis carinii pneumonia in
homosexual men: Part 2, Laboratory results. Ann Intern Med
1983 ; 99 :151-58.
|ô. Hochberg FH, Miller G, Schooley RT, Hirsch MS, Feorino
P, Henle W. Central-nervous-system lymphoma related to
Epstein-Barr virus. N Engl J Med 1983 ; 309:745-48.
|7. Ziegler JL, Beckstead JA, Volberding PA, et al. Non-
Hodgkin's lymphoma in 90 homosexual men— relation to
generalized lymphadenopathy and the acquired immuno-
jdeficiency syndrome. N Engl J Med 1984 ; 311:565-70.
■8. Gendelman HE, Phelps W, Feigenbaum L, et al. Trans
activation of the human immunodeficiency virus long
terminal repeat sequence by DNA viruses. Proc Natl Acad Sci
1986; 83:9759-63.
28
9. Davis MG, Kenney SC, Kamine, et al. Immediate-early
gene region of human cytomegalovirus trans-activates the
promoter of human immunodeficiency virus. Proc Natl Acad
Sci 1987; 84:8642-46.
10. Skolnik PR, Kosloff BR, Hirsch MS. Bidirectional
interactions between human immunodeficiency virus type I
and cytomegalovirus. J Infect Dis 1988; 157:508-14.
11. Kenney S, Kamine J, Markovitz D, et al. Epstein-Barr
ÿirus immediate-early gene product trans-activates gene
expression from the human immunodeficiency virus long
terminal repeat. Prod Natl Acad Sci 1988; 85:1652-56.
12. Lang DJ, Kovacs AAS, Zaia JA, Niland JC, Operskalski
EA, Doelken G, Vyas GN, Azen SP, Mosley JW, Gauderman WJ,
and the Transfusion Safety Study. Seroepidemiologic Study
of Cytomegalovirus and Epstein-Barr Virus Infections in
Relation to Human Immunodeficiency Virus Type I Infection
jin Selected Populations. (in progress) .
13. Parker J, et al. Leukocyte immunophenotyping of
recipients of blood product— a multisite flow cytometry
study: organization, standardization, quality control, and
data management, (in progress).
14. Gjersett G, et al. Clinical and immunology status of
treated patients with congenital clotting disorder, (in
progress).
15. Sullivan JL, Brewster FE, Brettler DB, et al. Hemo
philiac immunodeficiency: Influence of exposure to factor
jVIII concentrate, LAV/HTLV-III, and herpesviruses. J
Pediatr 1986; 108:504-10.
16. Rinaldo CR, Ho M, Hamoudi WH, Gui X-E, DeBiasio L.
Lymphocyte subsets and natural killer cell responses during
cytomegalovirus mononucleosis. Infect Immun 1983; 40:472-
77.
17. Finkelstein DM, Wolfe RA. Methods of Survival Anal
ysis. Statistical Methods for Cancer Studies, edited by
Richard G. Cornell. Marcel Dekker Inc., New York. 1984.
29

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Creator Gauderman, William James (author)

Core Title Herpesvirus and HIV type 1 infections: A seroepidemiologic study of relationships in selected populations

Degree Master of Science

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

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