Abstract
Background
Serum prostate specific antigen (PSA) levels have been used for many years as a biomarker for prostate cancer. This usage is under scrutiny due to the fact that elevated PSA levels can be caused by other conditions such as benign prostatic hyperplasia and infections of or injury to the prostate. As a result, the identification of specific pathogens capable of increasing serum levels of PSA is important. A potential candidate responsible for elevated PSA is human herpesvirus 8 (HHV-8). We have reported previously that HHV-8 is capable of infecting and establishing a latent infection in the prostate. In this current study we test the hypothesis that HHV-8 infection is associated with elevated PSA levels. Circulating cytokine levels between men with elevated PSA and controls are also compared.
Methods
HHV-8 serostatus was determined among men with elevated serum PSA (≥4ng/ml; n=168, no prostate cancer on biopsy) and age-matched controls (PSA<4ng/ml; n=234), Circulating cytokine levels were determined among a subset of each group (116 with elevated PSA and 85 controls).
Results
Men with an elevated serum PSA were significantly more likely to be HHV-8 seropositive (42.9%) than the age-matched cancer-free men (22.2%; OR 2.51; 95% CI 1.48 – 4.29, P=00001). Comparison of circulating cytokine levels between men with elevated serum PSA and controls indicated that elevated serum PSA is associated with a pro-inflammatory response with a mixed Th1/Th2 response while HHV-8 infection was associated with significantly higher levels of IL12p70, IL-10 and IL-13 indicating a Th2 immune response.
Conclusions
We found a significant association between HHV-8 infection and increased levels of serum PSA. In an age of patient-centered medicine, men with an elevated serum PSA should be considered for HHV-8 serology testing to determine if HHV-8 is responsible for the elevated PSA.
Keywords: Prostate specific antigen, human herpesvirus 8, HHV-8, Tobago
Introduction
Prostate specific antigen (PSA) is a serine protease glycoprotein produced by prostate epithelial cells [1]. Increased PSA serum levels have been used extensively as a screening tool for prostate cancer but this use is currently controversial as increased levels can also occur with benign conditions including infections of the prostate and urinary system, as well as benign prostatic hyperplasia (BPH)[2]. As a result, it is important to identify specific infectious agents capable of increasing serum levels of PSA.
A potential candidate for establishment of chronic prostatic infection resulting in chronic inflammation and increased levels of serum PSA is human herpesvirus 8 (HHV-8). HHV-8 is the newest member of the human herpesvirus family and is capable of infecting B cells, macrophages, dendritic and endothelial cells [3,4]. We have previously reported that HHV-8 is capable of infecting and establishing a latent infection in prostatic epithelial cells of both Caucasian men as well as men from Tobago [5,6]. We have also reported that among Tobago men, HHV-8 is associated with prostate cancer [7]. Our hypothesis is that HHV-8 infection establishes a chronic infection leading to chronic inflammation which increases the risk of prostate cancer. If HHV-8 infection results in chronic inflammation of the prostate it is reasonable to hypothesize that infection will also result in increased serum PSA levels due to the damage inflicted on the prostate by chronic inflammation.
HHV-8 is spread sexually and viral DNA has been found in semen and prostates of seropositive men [5,8,9]. Uniquely among sexually transmitted diseases, HHV-8 encodes for expression of several proteins capable of initiating and sustaining pro-inflammatory responses. These include a viral IL-6 (vIL-6), viral macrophage inflammatory proteins 1, 2 and 3 (vMIP-1, 2 and 3), and viral G-protein coupled receptor (vGPCR)[10-14]. The vMIP proteins have been reported to serve as chemoattractants of immune cells [12,13,15] and vGPCR has been reported to increase angiogenesis [16]. Taken together, HHV-8 may be responsible for inducing a chronic, pro-inflammatory immune response in the microenvironment of the prostate, leading to the development of prostatitis and increased levels of serum PSA. In support of this we previously reported that serum PSA values were elevated among HHV-8 seropositive men [17]
The Tobago Prostate Cancer Survey is a population-based prostate cancer screening survey of men aged 40-79, residing on the Caribbean island, Tobago [18,19]. Participants were screened by determining serum levels of PSA and a digital rectal exam (DRE). Men who screened positive with an abnormal DRE and/or elevated PSA value (greater than or equal to 4 ng/ml) were recommended for a prostate biopsy to determine the presence or absence of prostate cancer. As a result of this screening process, the Tobago Prostate Cancer Survey participants can be divided into three groups; cancer cases (screening positive, biopsy confirmed prostate cancer); cancer free, elevated PSA cases (elevated PSA, biopsy negative samples); and controls (screening negative samples). In the present study we tested the hypothesis that HHV-8 infection is associated with elevated circulating PSA levels and elicits a pro-inflammatory response by analyzing samples from the Tobago Prostate Cancer Survey representing cancer free, elevated PSA cases and cancer free, normal PSA controls. We compared HHV-8 serostatus and circulating cytokine profiles between the two groups. We also compared cytokine profiles between HHV-8 seropositive and seronegative men.
Methods and Materials
Subjects
A full description of the Tobago Prostate Survey has been previously described[18]. Briefly, this is a population-based prostate cancer screening in Tobago. The protocol was approved by both the Institutional Review Boards of the University of Pittsburgh and the Division of Health and Social Services, Tobago House of Assembly. Participants in the study were recruited mostly by public service announcement and by word of mouth. Each participant received a PSA test and a digital rectal exam (DRE). Those patients having an elevated serum PSA (≥4.0 ng/ml) or an abnormal digital rectal exam (DRE) were referred to Tobago Regional Hospital for sextant biopsy. Histopathological examination of hematoxylin and eosin staining on all biopsy samples was performed by a pathologist at the University of Pittsburgh to determine cancer status. Subjects who had an elevated serum PSA and whose biopsies were found to be cancer free represent the elevated serum PSA group (n=168). The control group consisted of age-matched men (between the ages of 40 and 79) with normal PSA (<4 ng/ml) and DRE (n=234). Body mass index (BMI) was available on a subset of the elevated PSA cases (n=132) and the control cases (n=193). Co-morbidity data was available on a subset of elevated PSA cases (n=167) and control cases (n=87).
HHV-8 Serology
HHV-8 serostatus was determined using an indirect immunofluorescence assay that measures antibodies against lytic viral proteins as previously described [7].
Circulating Cytokine Measurements
Serum samples were collected by centrifugation of whole blood samples from each subject and kept frozen until assayed. Serum levels of the cytokines interferon gamma (IFN-γ), IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL12p70, IL-13 and tumor necrosis factor alpha (TNFα) were measured using the Multi-Spot Detection System MSD® (Meso Scale Diagnostics, Rockville, MD; Proinflammatory Panel 1) according to the manufacturer’s instructions. MSD plates were read on a MSD™ SECTOR imager 2400 and analysis of data performed using the MSD™ Discovery Software Suite. Cytokine levels that were below the standard curve were assigned a value of zero while levels that were above the standard curve were given the value of the highest concentration in the standard curve.
Statistics
The SPSS statistical package was used for statistical analyses (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.). The relationship between both age and BMI between groups was determined using independent Student’s T-test. The relationships between co-morbidities and cancer status were determined using a Pearson’s Chi-Square test with a Bonferroni correction. The relationship between HHV8 serology and PSA status was determined using a Pearson’s Chi-Square test.
For each cytokine evaluated, individual levels were eliminated as outliers if they were further than 3 standard deviations from the mean of the sample group. This amounted to 0 to 5 samples declared as outliers for each cytokine. Cytokine levels were analyzed using a multivariate General Linear Model using Dunnett’s post-hoc tests for pairwise comparisons. A p < 0.05 was deemed statistically significant. Binary logistic regression models were constructed using pro-inflammatory cytokine levels as predictor variables to predict elevated PSA across HHV-8 serostatus. The forward Wald method was used to determine which cytokines should be included in the model.
Results
HHV-8 Serology
Serum samples from the Tobago Prostate Survey analyzed in this study were from men (between the ages of 40 and 79) with elevated PSA values (≥4ng/ml) and biopsy-negative prostates (n=168) and age-matched controls (normal DRE and serum PSA; n=234). The HHV-8 serostatus for each individual was determined as described in Methods and Materials. As shown in Table I, there were no significant differences in age or BMI between elevated PSA and control groups nor were there significant differences between the HHV-8 seropositive and seronegative subjects within the control group and between the elevated PSA and controls among the HHV-8 seronegative subjects. There were also no significant differences in co-morbidities between PSA cases and controls (Table II). As shown in Table III, the HHV-8 seroprevalence rate was significantly higher among the elevated PSA group compared to the control group. Men with an elevated PSA were more likely to be HHV-8 seropositive (42.9%) than the age-matched cancer-free controls (22.2%; OR, 2.51; 95% CI, 1.48 – 4.29, p=0.00001).
Table I.
Age and Body Mass Index (BMI) Analyses Between Groups
| Group | Age | BMI | ||||
|---|---|---|---|---|---|---|
| n | Mean +/− S.D. | p-value* | n | Mean +/− S.D. | p-value* | |
| Total Samples | ||||||
| Elevated PSA | 168 | 64.54 +/− 9.621 | 0.308 | 132 | 28.52 +/− 18.95 | 0.424 |
| Controls | 234 | 63.64 +/− 8.110 | 193 | 30.12 +/− 16.81 | ||
| Among Samples Tested for Cytokine Levels | ||||||
| Elevated PSA | 168 | 64.54 +/− 9.621 | 0.181 | 132 | 28.52 +/− 18.95 | 0.664 |
| Controls | 87 | 63.67 +/− 7.548 | 68 | 29.56 +/− 7.25 | ||
| HHV8 Seropositive Controls | 39 | 64.67 +/− 8.004 | 0.268 | 32 | 30.41 +/− 8.83 | 0.368 |
| HHV8 Seronegative Controls | 48 | 62.85 +/− 7.137 | 36 | 28.81 +/− 5.50 | ||
| HHV-8 Seronegative , Elevated PSA | 57 | 64.95 +/− 8.572 | 0.182 | 46 | 27.27 +/− 4.91 | 0.185 |
| HHV-8 Seronegative, Controls | 48 | 62.85 +/− 7.137 | 36 | 28.81 +/− 5.50 | ||
Student’s T-Test; significance at p <= 0.05
Table II.
Comorbidity Comparisons
| Condition | Elevated PSA Cases (%) |
Controls (%) | p* | |
|---|---|---|---|---|
| Inflammatory Conditions | ||||
| Emphysema | 6/166 (3.6) | 1/86 (1.2) | 0.41 | |
| Chronic Bronchitis |
8/166 (4.8) | 1/86 (1.2) | 0.17 | |
| Arthritis | 37/166 (22.3) | 17/87 (19.5) | 0.67 | |
| Osteoporosis | 4/165 (2.4) | 4/87 (4.6) | 0.5 | |
| Hepatitis | 1/164 (0.6) | 0 | NA | |
| Cirrhosis | 0 | 0 | NA | |
| Diverticulitis | 2/164 (1.2) | 2/87 (2.3) | 0.61 | |
| Cancer (other than Prostate) | 1/165 (0.6) | 0 | NA | |
| Sexually Transmitted Diseases | ||||
| Gonorrhea | 30/167 (18.0) | 14/87 (16.1) | 0.73 | |
| Syphillis | 16/167 (9.6) | 1/87 (1.1) | 0.21 | |
| NSAID use (past 12 months) |
||||
| Aspirin | 32/167 (19.2) | 17/87 (19.5) | 0.99 | |
| Ibuprofen | 12/167 (7.2) | 7/87 (8.0) | 0.78 | |
| Smoker | 72/167 (43.1) | 29/87 (33.3) | 0.14 | |
| Diabetes | 23/166 (13.9) | 18/87 (20.7) | 0.19 | |
| Stroke | 9/166 (5.4) | 2/86 (2.3) | 0.34 | |
| Vascular Disease/ Heart Disease |
||||
| Hypertension | 59/167 (35.3) | 34/87 (39.1) | 0.66 | |
| Heart disease | 10/166 (6.0) | 9/86 (10.5) | 0.22 | |
Table III.
HHV-8 Serology
| HHV-8 Serology Group Comparisons | % Seropositive (n/total) |
p-value* | OR(95% CI) |
|---|---|---|---|
| Cancer Free, Elevated PSA | 42.9 (72/168) |
0.00001 | 2.51 (1.48-4.29) |
| Cancer Free, Normal PSA Controls | 22.2 (52/234) |
Chi-square analysis; significance at p<=0.05
Circulating Cytokine Levels
Circulating cytokine levels were determined in a subset of 116 men with elevated PSA and 85 control subjects. The cytokines measured in this study can be divided into three categories; Pro-inflammatory (TNFα, IL-1β, IL-6, IL-8), Th1 (IFNγ, IL-2, IL12-p70) and Th2 (IL-4, IL-10, IL13). Circulating serum levels of each cytokine were determined as described in Materials and Methods. As shown in Table IV, cytokine analyses demonstrated significantly increased levels in the men with elevated PSA compared to the controls in the pro-inflammatory cytokines TNFα, IL-1β, IL-6 and IL-8, the Th1 cytokines IFNγ and IL-2, and the Th2 cytokines IL-4, IL-10, and IL13. The levels of the Th1 cytokine, IL12-p70, were also elevated in the PSA group compared to the controls, but it did not reach the level of significance (p=0.161).
Table IV.
Comparison of Cytokine Levels between Elevated PSA Cases and Controls
| Cytokine | Elevated PSA Cases (n=116) Mean ± SD |
Control Cases (n=85) Mean ± SD |
p |
|---|---|---|---|
| Pro-Inflammatory | |||
| TNFα | 1.68±1.41 | 0.32±0.60 | <0.001 |
| IL-1β | 0.42±1.28 | 0.17±0.39 | 0.030 |
| IL-6 | 1.98±3.86 | 0.94±2.01 | 0.011 |
| IL-8 | 170.85±322.55 | 31.00±71.26 | <0.001 |
| TH1 Response | |||
| IFNγ | 4.87±5.18 | 1.96±1.83 | <0.001 |
| IL-2 | 0.59±0.78 | 0.22±0.32 | <0.001 |
| IL-12p70 | 4.76±4.38 | 3.67± | 0.161 |
| TH2 Response | |||
| IL-4 | 0.27±0.22 | 0.13±0.19 | <0.001 |
| IL-10 | 0.35±0.35 | 0.18±0.24 | <0.001 |
| IL-13 | 0.43±0.38 | 0.39±0.33 | <0.001 |
To determine the effect of HHV-8 infection alone (not confounded by elevated PSA) on circulating cytokine levels, a comparison within controls was performed, stratified by HHV-8 serostatus. As shown in Table V, significant differences were found between HHV-8 seropositive and seronegative men within the control group in serum levels of the proinflammatory cytokine IL-8, the Th1 cytokine IL-12p70, and the Th2 cytokines IL-4, IL-10 and IL-13. Mean levels of IL12p70, IL-10 and IL-13 were significantly higher in HHV-8 seropositive controls while the mean levels of IL-8 and IL-4 were significantly higher among HHV-8 seronegative controls.
Table V.
Comparison of Cytokine Levels in Control Group Stratified by HHV-8 Serology
| Cytokine | Control Cases HHV-8 Seropositive (n=38) Mean ± SD |
Control Cases HHV-8 Seronegative (n=47) Mean ± SD |
p |
|---|---|---|---|
| Pro-Inflammatory | |||
| TNFα | 0.40±0.84 | 0.26±0.26 | 0.126 |
| IL-1β | 0.16±0.14 | 0.17±0.52 | 0.885 |
| IL-6 | 0.65±0.86 | 1.17±2.57 | 0.487 |
| IL-8 | 28.43±50.06 | 33.04±84.86 | 0.043 |
| CRP | 4170.67±5308.57 | 4577.74±5881.15 | 0.495 |
| TH1 Response | |||
| IFNγ | 1.86±1.81 | 2.05±1.88 | 0.875 |
| IL-2 | 0.17±0.25 | 0.27±0.36 | 0.112 |
| IL-12p70 | 5.88±3.63 | 1.92±2.21 | <0.001 |
| TH2 Response | |||
| IL-4 | 0.08±0.11 | 0.18±0.22 | 0.003 |
| IL-10 | 0.21±0.32 | 0.14±0.14 | 0.043 |
| IL-13 | 0.54±0.37 | 0.28±0.26 | <0.001 |
To determine the effect of elevated PSA (not confounded by HHV-8 infection) on circulating cytokine levels, a comparison was performed on the HHV-8 seronegative men stratified by PSA status. As shown in Table VI, significant differences were found between men with elevated PSA and controls in serum levels of the proinflammatory cytokines TNFα and IL-8, the Th1 cytokines IFNγ and IL-12p70 and the Th2 cytokine IL-10. The levels of TNFα, IL-8, IFNγ, IL-12p70 and IL-10 were higher among the elevated PSA samples compared to the control samples.
Table VI.
Comparison of Cytokine Levels in HHV-8 Seronegative Groups
| Cytokine | Elevated PSA Cases HHV-8 Seronegative (n=54) Mean ± SD |
Control Cases HHV-8 Seronegative (n=47) Mean ± SD |
p |
|---|---|---|---|
| Pro-Inflammatory | |||
| TNFα | 1.60±1.67 | 0.26±0.26 | <0.001 |
| IL-1β | 0.15±0.27 | 0.17±0.52 | 0.993 |
| IL-6 | 1.55±1.61 | 1.17±2.57 | 0.227 |
| IL-8 | 164.90±354.07 | 33.04±84.86 | 0.005 |
| TH1 Response | |||
| IFNγ | 4.56±4.15 | 2.05±1.88 | <0.001 |
| IL-2 | 0.35±0.55 | 0.27±0.36 | 0.912 |
| IL-12p70 | 5.04±4.33 | 1.92±2.21 | <0.001 |
| TH2 Response | |||
| IL-4 | 0.20±0.19 | 0.18±0.22 | 0.861 |
| IL-10 | 0.31±0.28 | 0.14±0.14 | 0.007 |
| IL-13 | 0.44±0.35 | 0.28±0.26 | 0.588 |
Pooling elevated PSA cases and controls across HHV-8 serostatus, using binary logistic regression, models were created to determine which cytokines were most closely associated with elevated PSA status. We identified two competing models worth reporting; the first model (complex) has the highest overall predictive power of the models we evaluated, but incorporates a greater number of predictor variables, which could limit its practical application. The second (simple) model has the next highest predictive value per predictor. It incorporates fewer predictor variables, making its practical application easier. The first model, which includes TNFα, IL-4, IL-13, IL-8, IL-6 and IL-12-p70 as predictors (Table VII, Pooled-Complex Model), correctly predicted individuals with elevated PSA in 88.9% of cases (Nagelkerke pseudo- R2 = 0.780). The second model, which includes TNFα and IL-4 as predictors (Table VII, Pooled – Simple Model), correctly predicted individuals with elevated PSA in 84.7% of cases (Nagelkerke pseudo-R2 = 0.629). Among the HHV8 seronegative individuals (to remove the influence of HHV-8 infection), a model including TNFα and IL-13 correctly predicted individuals with elevated PSA in 88.8% of cases (Nagelkerke pseudo- R2 =0.752). A model including TNFα and IL-4 correctly predicted HHV-8 seropositive individuals with elevated PSA 94.5% of the time (Nagelkerke pseudo- R2 =0.867).
Table VII.
Binary logistic regression models constructed to predict elevated PSA based on HHV8 status.
| Pooled - Simple Model | Pooled –Complex Model | HHV-8 negative | HHV-8 positive | |||||
|---|---|---|---|---|---|---|---|---|
| Co- efficient |
Odds Ratio (95% C.I.) |
Co- efficient |
Odds Ratio (95% C.I.) |
Co- efficient |
Odds Ratio (95% C.I.) |
Co- efficient |
Odds Ratio (95% C.I.) |
|
| Constant | −2.574 | 0.076 | −5.388 | 0.005 | −5.450 | 0.004 | −5.628 | 0.004 |
| TNFα | 3.001 | 20.106 (7.502, 62.515) |
4.477 | 87.928 (16.964, 455.744) |
5.612 | 273.752 (21.888, 3423.828) |
4.495 | 89.604 (39.157, 297.865) |
| IL4 | 4.943 | 140.252 (10.792, 182.781) |
5.145 | 171.607 (3.315, 212.485) |
23.009 | 9.839 (2.1224,1.78810) |
||
| IL13 | 2.729 | 15.323 (4.700, 21.094) |
6.941 | 1034.104 (39.447, 27,108.818) |
||||
| IL8 | 0.011 | 1.012 (1.004,1.018) | ||||||
| IL6 | 0.848 | 2.335 (1.281, 3.764) |
||||||
| IL12-P70 | −0.2 | 0.819 (0.697, 0.963) |
||||||
| Block Chi Square | 119.542, df=2, p<0.001 | 164.347, df=6, p<0.001 | 80.995, df=1, p<0.001 | 93.121, df=2, p<0.001 | ||||
| % Correct Predictions | 84.7% | 88.9% | 88.8% | 94.5% | ||||
| Nagelkerke pseudo- R2 |
0.629 | 0.780 | 0.752 | 0.867 | ||||
Discussion
We have previously reported that in the Tobago Prostate Cancer Survey, men with prostate cancer are significantly more likely to be HHV-8 seropositive than age-matched controls (OR 2.24; CI 1.29-3.90, p=0.003 [7]). Further, we have also shown that HHV-8 can infect the prostate, establishing a chronic infection and as a result, potentially modulate the immune response [5,6]. The current study demonstrates that HHV-8 infection in Tobago is significantly associated with elevated PSA levels. We would expect that HHV-8 infection in the U.S. will also be associated with elevated PSA even though the seroprevalence to HHV-8 is lower compared to Tobago (3-10% [7,20] vs 31.9% (this study)). It will be important to determine if HHV-8 infection is associated with elevated PSA in the U.S.
Comparison of circulating cytokine levels between men with elevated PSA and controls indicated that elevated PSA results in a pro-inflammatory response (increased levels of TNFα, IL1-β, IL-6 and IL-8) with a mixed Th1/Th2 response (increased levels of IFNγ, IL-2, IL-4, IL-10 and IL-13). Elevated PSA levels are common when prostatic inflammation is present [21-23]. Recent reports indicate that PSA is a double-edged sword when used as a biomarker of prostate cancer (reviewed in [24]) as it also serves as an indicator of inflammation based on subsequent biopsies that did not show cancer [22]. As a result, the findings in the current study, along with previous studies, suggest that circulating PSA levels serve as an indicator of inflammation in the prostate and therefore are not necessarily a specific biomarker for cancer.
Previous studies from our laboratory have shown that both lytic and latent HHV-8 infections are present in the prostate samples of seropositive men [5,6]. In the present study, we compared circulating cytokine levels based on HHV-8 serostatus and found that among HHV-8 seropositive individuals there were significantly higher mean levels of IL12p70, IL-10 and IL-13 (Table V). The higher IL-10 and IL-13 levels indicate a Th2 immune response is occurring in response to HHV-8 infection. IL-13 plays a pivotal role in the Th2 immune response which, during chronic inflammation, can also function to suppress unrestricted inflammation. This serves a central role in the maintenance of tissue homeostasis and host survival [25]. Increased levels of IL-13 in the men with HHV-8 suggest that the immune response is working to mitigate the chronic infection induced by the virus. IL-10 is known to polarize the macrophage to an M2 response which is involved in tissue remolding and maintenance [26]. Increased levels of IL-10 and IL-13 in the HHV-8 seropositive control men suggest that HHV-8 is pushing the immune response towards containment of a chronic infection and results in a chronic inflammatory condition in the prostate.
To separate the influence of HHV-8 infection on circulating cytokine levels among men with elevated PSA and controls, an analysis of the cytokine results was performed on HHV-8 seronegative men with elevated PSA and controls. In HHV-8 seronegative men with elevated PSA we found significantly increased levels of TNFα, IL-8, IFNγ, and IL-12p70 (Table VI), suggesting the presence of a pro-inflammatory immune response which is consistent with inflammation in the prostate.
We evaluated two sets of logistic regression models using cytokine levels to predict elevated PSA. The first set of models pooled all patients together regardless of their HHV8 serostatus (Table VII, pooled simple and complex models). These models would be useful when a patient’s serostatus is not known. The second set of models were specific to patients of a given serostatus. For a patient that is HHV8 positive, using the model specifically based on HHV8 positive patients would be a significant improvement in predictive power over both the simple and complex pooled models (Table VII). Elevated levels of TNFα were associated with elevated PSA in all four models. Pooling across HHV-8 serostatus the best model for elevated PSA also included increased levels of IL-4, IL-6, IL-8, IL-12p70 and IL-13; a proinflammatory, Th2 immune response. Analysis within HHV-8 serostatus also revealed a proinflammatory (TNFα) and Th2 response (IL-13 among HHV-8 seronegative cases and IL-4 among HHV-8 seropositive cases; Table VII).
Conclusion
The data presented in this study demonstrate that both HHV-8 infection and elevated PSA levels are associated with increased proinflammatory cytokines and a predominant Th2 immune response. In addition, we report for the first time a significant association between HHV-8 infection and increased levels of PSA. In an age of patient-centered medicine, men with an elevated PSA should be considered for HHV-8 serology testing to determine if HHV-8 is responsible for the elevated PSA.
Acknowledgements
This work was supported by the Department of Defense (DAMD17-99-1-9015), National Institutes of Health (R01CA84950) and a University of Pittsburgh Sponsored Grant (30507). The University of Pittsburgh Cancer Institute and the Tobago Division of Health and Social Services provided in-kind support.
Footnotes
Conflicts of Interest: The authors declare no conflicts of interest or competing financial interests.
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