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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Acquir Immune Defic Syndr. Author manuscript; available in PMC Jan 1, 2012.
Published in final edited form as:
PMCID: PMC3051282
NIHMSID: NIHMS253007

Risk Factors Influencing Antibody Responses to Kaposi’s Sarcoma-Associated Herpesvirus Latent and Lytic Antigens in Patients Under Antiretroviral Therapy in South Texas

Moraima Guadalupe, PhD,* Brad H. Pollock, MPH, PhD,§§ Steven Westbrook, DMD,[proportional, variant] Spencer Redding, DDS, MEd,[proportional, variant] Delia Bullock, MD,# Gregory Anstead, MD,#[proportional, variant] Brian K. Agan, MD,+§ Vincent C. Marconi, MD,+§ Sharon Barbieri, RDH,** Vidya Sankar, DMD, MS, Jennifer Rebeles, BS,* Yvette Flahive, BS,* John Schoolfield, MS,‡‡ Linding Wang, PhD,* Xiufen Lei, MD, PhD,* Dorothy Dow, MD, Chih-Ko Yeh, PhD, BDS,[proportional, variant] Howard Dang, PhD, Anthony J. Infante, MD, PhD, and Shou-Jiang Gao, PhD*#

Abstract

Background

Kaposi’s sarcoma-associated herpesvirus (KSHV) seropositivity and lytic antibody titer are predictors for Kaposi’s sarcoma (KS).

Methods

We examined demographic, viral and immunological factors that influence KSHV latent and lytic antibodies in HIV-infected patients.

Results

Detection rate of KSHV latent but not lytic antibodies was lower in patients with CD4 cells/mm3 ≤200 than >200 (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.11–0.61) and CD8 cells/mm3 ≤400 than >400 (OR, 0.26; 95% CI, 0.07–0.67). Overall seropositivity rate was higher in patients with CD4 cells/mm3 ≤200 than >200 (OR, 2.34; 95% CI, 1.37–4.02) and HIV copies/mL >400 than ≤400 (OR, 1.70; 95% CI, 1.09–2.65). Lytic antibody level was inversely correlated with CD4 count (P<0.001). Lytic seropositivity (OR, 2.47; 95% CI, 1.35–4.50) and antibody level (adjusted difference mean optical density [admOD], 0.324; 95% CI, 0.16–0.46) were higher in patients with HIV infection >15 than ≤15 years. Hispanics had higher lytic seropositivity rate (OR, 1.71; 95% CI, 1.07–2.73) and antibody level (admOD, 0.111; 95% CI, 0.03–0.18) than non-Hispanics.

Conclusions

Lower CD4 and CD8 counts impair antibody response to KSHV latent antigens. Immune deterioration, long-term HIV infection and Hispanic status are risk factors for KS predictors.

Keywords: KSHV, Kaposi’s sarcoma, Latent and lytic antibodies, Risk factors, HIV/AIDS

INTRODUCTION

Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with Kaposi’s sarcoma (KS), a common malignancy in HIV-infected patients1. Individuals at a higher risk for KS have a higher KSHV seroprevalence26. Detection of KSHV DNA and antibodies precedes KS onset2,3,7,8.

While HIV infection accelerates KS development9, the time from KSHV seroconversion to KS onset varies from months to years2,3, suggesting involvements of cofactors. Higher KSHV lytic antibody titers are associated with advanced disease10,11 and patients with lytic antibodies have higher KS incidence rates12,13. Furthermore, KS incidence and disease status are positively correlated with detection and load of peripheral blood KSHV DNA2,7,8,12,1417, and KS regressed following anti-herpesviral treatments that inhibit lytic replication1820. Thus, KSHV lytic replication and lytic antibody titer are predictors for KS development.

The advent of highly active antiretroviral therapy (HAART) has reduced KS incidence21. AIDS-KS regression due to HAART is associated with decreased blood KSHV load and lytic antibody titers10,14,17,2225. Nevertheless, some HIV patients continue to develop KS2628. As HIV patients live longer, their likelihood of developing KS becomes higher. Identification of cofactors for KS development in the HAART era is of particular importance.

While serologic assays are useful for examining association of KSHV serostatus with KS progression, detection of latent and lytic antibodies remains inconsistent2931. It is unclear what factors might affect KSHV seropositivity. Extensive characterizations of KSHV infection have been performed in AIDS-KS patients, but fewer were in HIV patients without KS2,3,13,32. We investigated clinical correlates and risk factors for antibody responses to KSHV antigens in a cohort of HIV patients receiving HAART.

METHODS

HIV patients under HAART without KS were recruited from the Family Focused AIDS Clinical Treatment and Services Clinic, San Antonio Military Medical Center HIV Unit and Audie L. Murphy Memorial Veterans Hospital Immunosuppression Clinic in San Antonio. The protocol was approved by the Institutional Review Boards of participating sites. Written informed consent was obtained from patients. CD4 and CD8 T cell counts and HIV loads were obtained from the Frederic C. Bartter General Clinical Research Center. Demographic, medical information, other coinfections and comorbid conditions was collected.

Latency-associated nuclear antigen (LANA) antibodies were detected by an immunofluorescence antibody assay using BCP-1 cells3, and confirmed with recombinant KSHV-infected rat precursor cells33. Besides using genuine uninfected controls, these cells have minimal cross-reactivity with human autoantibodies. Lytic antigen ORF65 antibodies were detected by an enzyme-linked immunosorbent assay6. Samples with optical density (O.D.) values ≥3 times of average O.D. of a panel of negative controls plus 5 times of standard deviations were defined as positive. Sera were tested at 1:50 dilution. Sets of serum samples from KS patients and blood donors previously tested seropositive and seronegative, respectively, were included as controls34,35. Both assays have been extensively evaluated in previous studies29,34,35. Serostatus was scored based on the presence of antibodies to LANA alone (“LANA”), ORF65 alone (“ORF65”), any of LANA and ORF65 including LANA and ORF65 dually positive samples (“ANY”), and both LANA and ORF65 only (“BOTH”).

Given their non-normal distribution, differences of variables between seropositive and seronegative patients were examined using the Mann-Whitney U test. The magnitude of association between outcome and dichotomous independent predictors of KSHV seropositivity was estimated using odds ratio (OR) and corresponding 95% confidence interval (CI), and multivariate analyses were conducted using unconditional logistic regression analysis adjusted for age and ethnicity. We included preselected first order interaction terms to assess potential effect measure modification.

Relative ORF65 antibody level was analyzed using a general linear model (GLM) after log transformation of data with reference groups identified for each factor. We performed univariate analysis examining association between predictor variables and antibody level as well as multivariate analyses adjusted for age and ethnicity. Analyses were performed with STATA/SE 10.0 (StataCorp., College Station, TX).

RESULTS

We determined KSHV serostatus in 383 HIV patients (Supplementary Table). The overall LANA, ORF65, ANY and BOTH seropositivity rates were 21%, 30%, 36% and 13%, respectively. Logistic regression analysis with ANY serostatus adjusted for age and ethnicity showed a higher seropositivity rate in males than females (40% vs 13%; OR, 4.94; 95% CI, 2.14–11.44; P<0.001) (Table 1). Similar results were observed with other serostatus, which were consistent with previous studies24,6. Surprisingly, Hispanics had a higher seropositivity rate than Non-Hispanics (32% vs 25%; OR, 1.71; 95% CI, 1.07–2.73; P=0.024) when analyzed by ORF65 serostatus.

TABLE 1
Multivariable Logistic Regression Analysis of KSHV Serostatus and Risk Factors in HIV Patients (n=383)a

Analysis of HIV-related factors and coinfections based on ANY serostatus revealed a higher seropositivity rate in patients with CD4 T cells/mm3 ≤200 than >200 (53% vs 33%; OR, 2.34; 95% CI, 1.37–4.02; P=0.002), HIV copies/mL >400 than ≤400 (42% vs 32%; OR, 1.70; 95% CI, 1.09–2.65; P=0.019), with than without syphilis (56% vs 34%; OR, 2.48; 95% CI, 1.28–4.79; P=0.007), and with than without hepatitis (47% vs 33%; OR, 1.76; 95% CI, 1.07–2.90; P=0.027) (Table 1). No association was found between KSHV seropositivity and any comorbid conditions (data not shown).

The association of CD4 T cell count and HIV load with KSHV seropositivity persisted when serostatus was defined by ORF65 but not by LANA and BOTH, indicating ORF65 seropositivity as the main contributing factor (Table 1). A higher seropositivity rate was also found in patients with duration of HIV infection >15 years than ≤15 years when defined by ORF65 (40% vs 25%; OR, 2.47; 95% CI, 1.35–4.50; P=0.003).

We analyzed the interactions of variables. When adjusted for other factors, lower CD4 T cell count remained as a risk factor for ORF65 and ANY serostatus (data not shown). Association of HIV load with ORF65 and ANY serostatus was not affected by duration of HIV infection and CD8 T cell count but disappeared after adjusting for CD4 T cell count. Association of duration of HIV infection with ORF65 serostatus was not altered by other factors. In contrast, association of Hispanic status with ORF65 serostatus disappeared after adjusting for other factors. Interestingly, Hispanics had lower CD4 and CD8 T cell counts than Non-Hispanics (P<0.001 and =0.025, respectively) but no difference was found for HIV load and duration of HIV infection (Supplementary Fig. 1A). Lower CD4 T cell count persisted in Hispanics regardless ORF65 serostatus (P=0.004 and 0.001, respectively), and in ORF65+ patients regardless Hispanics status (P<0.001 and =0.001, respectively) (Supplementary Fig. 1B). In contrast, the difference of CD8 T cell count between Hispanics and Non-Hispanics disappeared when ORF65 serostatus was considered.

The results thus far indicated an association of CD4 T cell count, HIV load, or duration of HIV infection with ORF65 but not LANA serostatus. We examined effects of these factors on antibody detection in KSHV-infected patients by logistic regression adjusting for age and ethnicity (Table 2). HIV load had no effect on detection of latent or lytic antibodies. However, detection rate of latent antibodies was lower in those with CD4 T cells/mm3 ≤200 than >200 (35% vs 67%; OR, 0.26; 95% CI, 0.11–0.61; P=0.002), CD8 T cells/mm3 ≤400 than >400 (28% vs 64%; OR, 0.22; 95% CI, 0.07–0.67; P=0.007) and duration of HIV infection >15 years than ≤15 years (45% vs 62%; OR, 0.42; 95% CI, 0.18–1.02; P=0.057) though the later was not statistically significant. Thus, lower CD4 and CD8 T cell counts impeded antibody responses to latent antigens. In contrast, lower CD4 T cell count (92% vs 71%; OR, 3.41; 95% CI, 0.93–12.45; P=0.064) and longer duration of HIV infection (87% vs 73%; OR, 5.28; 95% CI, 1.50–18.59; P=0.010) increased detection rates of lytic antibodies (Table 2).

TABLE 2
Multivariable Logistic Regression Analysis Assessing the Effects of HIV-Related Factors on the Detection Rates of KSHV Latent and Lytic Antibodies in KSHV-Infected Patientsa

The ORF65 serostatus may reflect KSHV lytic replication status. We examined the main and interaction effects of KSHV-associated risk factors on relative ORF65 antibody levels in ANY+ patients (Table 3). HIV load, CD8 T cell count or other coinfections had no effect on ORF65 antibody level. In contrast, ORF65 antibody level was higher in patients with duration of HIV infection >15 than ≤15 years (adjusted difference mean O.D. [admOD]=0.324; 95% CI, 0.16–0.46; P=0.001) and with CD4 T cells/mm3 ≤200 than >200 (admOD=0.105; 95% CI, −0.01–0.19; P=0.063) though the later was not statistically significant. ORF65 antibody level was negatively correlated with CD4 T cell counts (r=0.407; P<0.001) and positively with duration of HIV infection at a marginal level (r=0.157; P=0.065) but not correlated with CD8 T cell count (P=0.827) nor with HIV load (P =0.135) (Supplementary Fig. 2). Consistent with ORF65+ rate, Hispanics had higher ORF65 antibody levels than Non-Hispanics (admOD=0.111; 95% CI, 0.03–0.18; P=0.012) (Table 3).

TABLE 3
Mean ORF65 Antibody Levels and Risk Factors for Higher ORF65 Antibody Levels in KSHV-Infected Patientsa

Analysis of risk factor interactions showed a lower CD4 T cell count as a strong factor for a higher ORF65 antibody level when adjusted for other factors (data not shown). Duration of HIV infection remained a factor for a higher ORF65 antibody level while CD8 T cell count and HIV load showed no association. The association of Hispanic status with higher ORF65 antibody levels was not affected by CD8 T cell count, HIV load and duration of HIV infection but was marginally influenced by CD4 T cell count (admOD=0.074; 95% CI, −0.01–0.14; P=0.071).

DISCUSSION

A serologic assay with one antigen may be insufficiently sensitive to identify all KSHV-infected patients. Indeed, inconsistencies were observed among assays based on single antigen30,31. Cross-examination with multiple assays including both latent and lytic antigens may increase the sensitivity and specificity for identifying KSHV-infected patients29,35. As expected, our LANA, ORF65 and BOTH seropositivity rates are within the reported ranges; however, the ANY rate (36%) is at the higher estimates26.

We found an overall higher KSHV seropositivity rate among patients with lower CD4 T cell counts or higher HIV loads (Table 1). Both factors could influence immune surveillance, and hence KSHV lytic replication and serostatus. Indeed, both factors were associated with lytic seropositivity. However, a higher ORF65 antibody level was only associated with a lower CD4 T cell count (Table 3). Furthermore, association of HIV load with ORF65 seropositivity was marginally affected by CD4 T cell count (data not shown). Thus, immune status is likely a better predictor than HIV load for opportunistic diseases, confirming the observation that HIV load does not always predict immune status including CD4 T cell count36.

In contrast to KSHV lytic antibodies, lower CD4 and CD8 T cell counts, and longer duration of HIV infection affected detection of latent antibodies (Table 2). Whether this observation can be extended to all latent antigens remain unclear. A previous report has also shown dependence of detecting LANA antibodies on CD4 T cell counts37. These findings explain why previous studies failed to observe an association of LANA seropositivity with CD4 T cell count and HIV load4,11,15,38.

In the early AIDS epidemic, patients rapidly progressed to KS following KSHV seroconversion with over half developing KS within 12 months2,3,39. We found higher KSHV seropositivity rates and lytic antibody levels in patients with duration of HIV infection >15 years than ≤15 years (Table 3). These associations were not confounded by other factors, indicating that longer duration of HIV infection is an independent predictor for KSHV seropositivity and higher lytic antibody levels. Of note, classical KS is commonly found in elderly men1. While HIV infection and resulting immunosuppression were dominant factors controlling KS development in early HIV epidemics, HAART has reduced their effects as manifested by the reduced KS incidence in the last decade40. As patients live longer, other factors such as duration of HIV infection have emerged as cofactors.

We found higher ORF65+ rates and higher ORF65 antibody levels in Hispanics than in non-Hispanics (Table 1 and and3).3). KSHV epidemiology in South Texas is distinct with a slightly higher seroprevalence in the general population than other US regions (15% vs ≤12%)34, and a unique spectrum of KSHV genotypes including 75% K15M subtype and 50% K1C3/K15M mosaic genotype. These predominant genotypes are associated with Hispanics and an advanced KS stage41, suggesting a viral factor might contribute to an increased risk and a more advanced KS stage. Nevertheless, association of Hispanics with ORF65 seropositivity, though not ORF65 antibody level, was confounded by other factors. While Hispanics and Non-Hispanics had similar duration of HIV infection and HIV load suggesting their comparable treatments, Hispanics had lower CD4 and CD8 T cell counts than Non-Hispanics (Supplementary Fig. 1A). Thus, genetic or environmental factors might contribute to worse HIV-induced immune deterioration resulting in higher risks for KSHV seropositivity and higher lytic antibody levels.

A limitation of this study is its cross-sectional nature. Our subjects were enrolled in a prospective cohort study; however, we lacked sufficient cumulative follow-up experience to elucidate the direct relationship between KSHV infection or lytic replication, and incident KS. Although we utilized three referral clinics, our population might not be reflective of the general HIV population. Strengths include the diversity of the population with a high proportion of Hispanics, and simultaneous examination of KSHV latent and lytic antibodies.

In summary, besides high HIV load and deteriorated immunity, extended duration of HIV infection, probably a result of HAART, increased the risk for KSHV seropositivity and lytic antibody level, and thus may contribute to a higher risk for developing KS. South Texas Hispanic HIV patients appear at a higher risk for KS than other US regions. Results of this study should be considered for long-term management of HIV patients in the HAART era.

Supplementary Material

Acknowledgments

We thank Dr. Philip LoVerde for his constructive comments, Jodi A. Tullman, MS, RN, CCRC and Robert A. Aakhus, BBA, MT for their helps in recruiting study subjects at the HIV Unit at San Antonio Military Medical Center, and technical helps of members of Dr. Gao’s laboratory.

This work is in part supported by National Institute of Health (NIH, grants CA119889, CA096512, CA124332, DE017333, RR001346, and DE14138) and National Institute of Allergy and Infectious Diseases, NIH, under Inter-Agency Agreement Y1-AI-5072. Support for this work (IDCRP-014) was also provided by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense (DoD) program executed through the Uniformed Services University of the Health Sciences.

Footnotes

The content of this publication is the sole responsibility of the authors and does not necessarily reflect the views or policies of the NIH or the Department of Health and Human Services, the DoD or the Departments of the Army, Navy or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government.

Findings have been presented in part at the 11th International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies, October 5–7, 2008, Bethesda, MD (poster presentation); 12th International Workshop on Kaposi’s Sarcoma-Associated Herpesvirus and Related Agents, Charleston, South Carolina, September 13–16, 2009 (poster presentation).

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