JAIDS Journal of Acquired Immune Deficiency Syndromes:
Brief Report: Epidemiology and Prevention
Risk Factors Influencing Antibody Responses to Kaposi's Sarcoma-Associated Herpesvirus Latent and Lytic Antigens in Patients Under Antiretroviral Therapy
Guadalupe, Moraima PhD*†; Pollock, Brad H MPH, PhD‡; Westbrook, Steven DMD§‖‖; Redding, Spencer DDS, MEd§‖‖; Bullock, Delia MD‖; Anstead, Gregory MD‖‖‖; Agan, Brian K MD‡‡§§; Marconi, Vincent C MD‡‡§§; Barbieri, Sharon RDH**; Sankar, Vidya DMD, MS§; Rebeles, Jennifer BS*; Flahive, Yvette BS*; Schoolfield, John MS††; Wang, Linding PhD*†; Lei, Xiufen MD, PhD*†; Dow, Dorothy MD†; Yeh, Chih-Ko PhD, BDS§‖‖; Dang, Howard PhD¶; Infante, Anthony J MD, PhD†; Gao, Shou-Jiang PhD*†‖
From *Greehey Children's Cancer Research Institute, †Departments of Pediatrics, ‡Epidemiology and Biostatistics, §Dental Diagnostic Science, ‖Medicine, ¶Community Dentistry, **Dental Hygiene, and ††Academic Technology Services, University of Texas Health Science Center at San Antonio, San Antonio, TX; ‡‡Infectious Disease Clinical Research Program Uniformed Services, University of the Health Sciences, Bethesda, MD; §§San Antonio Military Medical Center, San Antonio, TX; and ‖‖South Texas Veterans Healthcare System, San Antonio, TX.
Received for publication July 27, 2010; accepted September 21, 2010.
This work is in part supported by the National Institute of Health (NIH, grants CA119889, CA096512, CA124332, DE017333, RR001346, and DE14138) and the National Institute of Allergy and Infectious Diseases, NIH, under Interagency Agreement Yl-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.
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 US 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); and the 12th International Workshop on Kaposi's Sarcoma-Associated Herpesvirus and Related Agents, Charleston, SC, September 13-16, 2009 (poster presentation).
The authors have no conflicts of interest to disclose.
Correspondence to: Shou-Jiang Gao, PhD, Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr. San Antonio, TX 78229 (e-mail: email@example.com).
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jaids.com).
Background: Kaposi's sarcoma-associated herpesvirus (KSHV) seropositivity and lytic antibody titer are predictors for Kaposi's sarcoma.
Methods: We examined demographic, viral, and immunologic 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 less than 200 than greater than 200 (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.11-0.61) and CD8 cells/mm3 less than 400 than greater than 400 (OR, 0.26; 95% CI, 0.07-0.67). Overall seropositivity rate was higher in patients with CD4 cells/mm3 less than 200 than greater than 200 (OR, 2.34; 95% CI, 1.37-4.02) and HIV copies/mL greater than 400 than less 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, 0.324; 95% CI, 0.16-0.46) were higher in patients with HIV infection greater than 15 than less than 15 years. Hispanics had higher lytic seropositivity rate (OR, 1.71; 95% CI, 1.07-2.73) and antibody level (adjusted difference mean optical density, 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 Kaposi's sarcoma predictors.
Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with Kaposi's sarcoma (KS), a common malignancy in HIV-infected patients.1 Individuals at a higher risk for KS have a higher KSHV seroprevalence.2-6 Detection of KSHV DNA and antibodies precedes KS onset.2,3,7,8
Although HIV infection accelerates KS development,9 the time from KSHV seroconversion to KS onset varies from months to years,2,3 suggesting involvement of cofactors. Higher KSHV lytic antibody titers are associated with advanced disease10,11 and patients with lytic antibodies have higher KS incidence rates.12,13 Furthermore, KS incidence and disease status are positively correlated with detection and load of peripheral blood KSHV DNA2,7,8,12,14-17 and KS regressed after antiherpesviral treatments that inhibit lytic replication.18-20 Thus, KSHV lytic replication and lytic antibody titer are predictors for KS development.
The advent of highly active antiretroviral therapy (HAART) has reduced KS incidence.21 AIDS-KS regression resulting from HAART is associated with decreased blood KSHV load and lytic antibody titers.10,14,17,22-25 Nevertheless, some HIV-infected patients continue to develop KS.26-28 As patients with HIV live longer, their likelihood of developing KS becomes higher. Identification of cofactors for KS development in the HAART era is of particular importance.
Although serologic assays are useful for examining association of KSHV serostatus with KS progression, detection of latent and lytic antibodies remains inconsistent.29-31 It is unclear what factors might affect KSHV seropositivity. Extensive characterizations of KSHV infection have been performed in patients with AIDS-KS, but fewer were in patients with HIV without KS.2,3,13,32 We investigated clinical correlates and risk factors for antibody responses to KSHV antigens in a cohort of patients with HIV receiving HAART.
Patients with HIV 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 cells.33 Besides using genuine uninfected controls, these cells have minimal crossreactivity with human autoantibodies. Lytic antigen ORF65 antibodies were detected by an enzyme-linked immunosorbent assay.6 Samples with optical density (OD) values greater than three times of average OD of a panel of negative controls plus five times of standard deviations were defined as positive. Sera were tested at 1:50 dilution. Sets of serum samples from patients with KS and blood donors previously tested seropositive and seronegative, respectively, were included as controls.34,35 Both assays have been extensively evaluated in previous studies.29,34,35 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 nonnormal 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 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).
We determined KSHV serostatus in 383 patients with HIV (see Table, Supplemental Digital Content 1, http://links.lww.com/QAI/A104). 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% versus 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 studies.2-4,6 Surprisingly, Hispanics had a higher seropositivity rate than non-Hispanics (32% versus 25%; OR, 1.71; 95% CI, 1.07-2.73; P = 0.024) when analyzed by ORF65 serostatus.
Analysis of HIV-related factors and coinfections based on ANY serostatus revealed a higher seropositivity rate in patients with CD4 T cells/mm3 less than 200 than greater than 200 (53% versus 33%; OR, 2.34; 95% CI, 1.37-4.02; P = 0.002), HIV copies/mL greater than 400 than less than 400 (42% versus 32%; OR, 1.70; 95% CI, 1.09-2.65; P = 0.019), with than without syphilis (56% versus 34%; OR, 2.48; 95% CI, 1.28-4.79; P = 0.007), and with than without hepatitis (47% versus 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 greater than 15 years than less than 15 years when defined by ORF65 serostatus (40% versus 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 (see Figure 1A, Supplemental Digital Content 2, http://links.lww.com/QAI/A105). Lower CD4 T cell count persisted in Hispanics regardless ORF65 serostatus (P = 0.004 and 0.001, respectively) and in ORF65+ patients regardless of Hispanic status (P < 0.001 and 0.001, respectively) (see Figure 1B, Supplemental Digital Content 2, http://links.lww.com/QAI/A105). 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 less than 200 than greater than 200 (35% versus 67%; OR, 0.26; 95% CI, 0.11-0.61; P = 0.002), CD8 T cells/mm3 less than 400 than greater than 400 (28% versus 64%; OR, 0.22; 95% CI, 0.07-0.67; P = 0.007), and duration of HIV infection greater than 15 years than less than 15 years (45% versus 62%; OR, 0.42; 95% CI, 0.18-1.02; P = 0.057), although the latter 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% versus 71%; OR, 3.41; 95% CI, 0.93-12.45; P = 0.064) and longer duration of HIV infection (87% versus 73%; OR, 5.28; 95% CI, 1.50-18.59; P = 0.010) increased detection rates of lytic antibodies (Table 2).
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 greater than 15 than less than 15 years (adjusted difference mean OD [admOD] = 0.324; 95% CI, 0.16-0.46; P = 0.001) and with CD4 T cells/mm3 less than 200 than greater than 200 (admOD = 0.105; 95% CI, -0.01-0.19; P = 0.063), although the latter 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) (see Figure 2, Supplemental Digital Content 3, http://links.lww.com/QAI/A106). 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).
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, whereas 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).
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 antigen.30,31 Cross-examination with multiple assays including both latent and lytic antigens may increase the sensitivity and specificity for identifying KSHV-infected patients.29,35 As expected, our LAN A, ORF65, and BOTH seropositivity rates are within the reported ranges; however, the ANY rate (36%) is at the higher estimates.2-6
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, the 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 count.36
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 remains unclear. A previous report has also shown dependence of detecting LANA antibodies on CD4 T cell counts.37 These findings explain why previous studies failed to observe an association of LANA seropositivity with CD4 T cell count and HIV load.4,11,15,38
In the early AIDS epidemic, patients rapidly progressed to KS after KSHV seroconversion with over half developing KS within 12 months.2,3,39 We found higher KSHV seropositivity rates and lytic antibody levels in patients with duration of HIV infection greater than 15 years than less 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, classic KS is commonly found in elderly men.1 Whereas 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 decade.40 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 (Tables 1 and 3). KSHV epidemiology in South Texas is distinct with a slightly higher seroprevalence in the general population than other US regions (15% versus less than 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 stage,41 suggesting a viral factor might contribute to an increased risk and a more advanced KS stage. Nevertheless, association of Hispanics with ORF65 seropositivity, although not ORF65 antibody level, was confounded by other factors. Although Hispanics and non-Hispanics had a similar duration of HIV infection and HIV load suggesting their comparable treatments, Hispanics had lower CD4 and CD8 T cell counts than non-Hispanics (see Figure 1A, Supplemental Digital Content 2, http://links.lww.com/QAI/A105). 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 used 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 patients with HIV 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.
We thank Dr. Philip LoVerde for his constructive comments, Jodi A. Tullman, MS, RN, CCRC, and Robert A. Aakhus, BBA, MT, for their help in recruiting study subjects at the HIV Unit at San Antonio Military Medical Center, and technical helps of members of Dr. Gao's laboratory.
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KSHV; Kaposi's sarcoma; latent and lytic antibodies; risk factors; HIV/AIDS
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