Impact of HIV Infection and Kaposi Sarcoma on Human Herpesvirus-8 Mucosal Replication and Dissemination in Uganda

PLOS ONE, Jan 2009

Introduction Kaposi sarcoma (KS) is the leading cause of cancer in Uganda and occurs in people with and without HIV. Human herpesvirus-8 (HHV-8) replication is important both in transmission of HHV-8 and progression to KS. We characterized the sites and frequency of HHV-8 detection in Ugandans with and without HIV and KS. Methods Participants were enrolled into one of four groups on the basis of HIV and KS status (HIV negative/KS negative, HIV positive/KS negative, HIV negative/KS positive, and HIV positive/KS positive). Participants collected oral swabs daily and clinicians collected oral swabs, anogenital swabs, and plasma samples weekly over 4 weeks. HHV-8 DNA at each site was quantified by polymerase chain reaction (PCR). Results 78 participants collected a total of 2063 orals swabs and 358 plasma samples. Of these, 428 (21%) oral swabs and 96 (27%) plasma samples had detectable HHV-8 DNA. HHV-8 was detected more frequently in both the oropharynx of persons with KS (24 (57%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p = 0.002) and the peripheral blood (30 (71%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p<0.001). In a multivariate model, HHV-8 viremia was more frequent among men (IRR = 3.3, 95% CI = 1.7–6.2, p<0.001), persons with KS (IRR = 3.9, 95% CI = 1.7–9.0, p = 0.001) and persons with HIV infection (IRR = 1.7, 95% CI = 1.0–2.7, p = 0.03). Importantly, oral HHV-8 detection predicted the subsequent HHV-8 viremia. HHV-8 viremia was significantly more common when HHV-8 DNA was detected from the oropharynx during the week prior than when oral HHV-8 was not detected (RR = 3.3, 95% CI = 1.8–5.9 p<0.001). Genital HHV-8 detection was rare (9 (3%) of 272 swabs). Conclusions HHV-8 detection is frequent in the oropharynx and peripheral blood of Ugandans with endemic and epidemic KS. Replication at these sites is highly correlated, and viremia is increased in men and those with HIV. The high incidence of HHV-8 replication at multiple anatomic sites may be an important factor leading to and sustaining the high prevalence of KS in Uganda.

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Impact of HIV Infection and Kaposi Sarcoma on Human Herpesvirus-8 Mucosal Replication and Dissemination in Uganda

et al. (2009) Impact of HIV Infection and Kaposi Sarcoma on Human Herpesvirus-8 Mucosal Replication and Dissemination in Uganda. PLoS ONE 4(1): e4222. doi:10.1371/journal.pone.0004222 Impact of HIV Infection and Kaposi Sarcoma on Human Herpesvirus-8 Mucosal Replication and Dissemination in Uganda Christine Johnston 0 Jackson Orem 0 Fred Okuku 0 Mary Kalinaki 0 Misty Saracino 0 Edward 0 Katongole-Mbidde 0 Merle Sande 0 Allan Ronald 0 Keith McAdam 0 Meei-Li Huang 0 Linda 0 Drolette 0 Stacy Selke 0 Anna Wald 0 Lawrence Corey 0 Corey Casper 0 Esper Georges Kallas, University of Sao Paulo, Brazil 0 1 Department of Medicine, University of Washington, Seattle, Washington, United States of America, 2 Laboratory Medicine, University of Washington, Seattle, Washington, United States of America, 3 Deparment of Epidemiology, University of Washington, Seattle, Washington, United States of America, 4 Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center , Seattle , Washington, United States of America, 5 Uganda Cancer Institute, Mulago Hospital, Makerere University , Kampala , Uganda , 6 Uganda Virus Research Institute , Entebbe , Uganda , 7 Infectious Diseases Institute, Mulago Hospital, Makerere University , Kampala, Uganda, 8 Academic Alliance for AIDS care in Africa, Kampala , Uganda Introduction: Kaposi sarcoma (KS) is the leading cause of cancer in Uganda and occurs in people with and without HIV. Human herpesvirus-8 (HHV-8) replication is important both in transmission of HHV-8 and progression to KS. We characterized the sites and frequency of HHV-8 detection in Ugandans with and without HIV and KS. Methods: Participants were enrolled into one of four groups on the basis of HIV and KS status (HIV negative/KS negative, HIV positive/KS negative, HIV negative/KS positive, and HIV positive/KS positive). Participants collected oral swabs daily and clinicians collected oral swabs, anogenital swabs, and plasma samples weekly over 4 weeks. HHV-8 DNA at each site was quantified by polymerase chain reaction (PCR). Results: 78 participants collected a total of 2063 orals swabs and 358 plasma samples. Of these, 428 (21%) oral swabs and 96 (27%) plasma samples had detectable HHV-8 DNA. HHV-8 was detected more frequently in both the oropharynx of persons with KS (24 (57%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p = 0.002) and the peripheral blood (30 (71%) of 42 persons with KS vs. 8 (22%) of 36 persons without, p,0.001). In a multivariate model, HHV-8 viremia was more frequent among men (IRR = 3.3, 95% CI = 1.7-6.2, p,0.001), persons with KS (IRR = 3.9, 95% CI = 1.7-9.0, p = 0.001) and persons with HIV infection (IRR = 1.7, 95% CI = 1.0-2.7, p = 0.03). Importantly, oral HHV-8 detection predicted the subsequent HHV-8 viremia. HHV-8 viremia was significantly more common when HHV-8 DNA was detected from the oropharynx during the week prior than when oral HHV-8 was not detected (RR = 3.3, 95% CI = 1.8-5.9 p,0.001). Genital HHV-8 detection was rare (9 (3%) of 272 swabs). Conclusions: HHV-8 detection is frequent in the oropharynx and peripheral blood of Ugandans with endemic and epidemic KS. Replication at these sites is highly correlated, and viremia is increased in men and those with HIV. The high incidence of HHV-8 replication at multiple anatomic sites may be an important factor leading to and sustaining the high prevalence of KS in Uganda. - Funding: Early Detection Initiative, Fred Hutchinson Cancer Research Center (LC) Joel Meyers Infectious Disease Scholarship Grant, Fred Hutchinson Cancer Research Center (CJ) Clinical Scientist Development Award, Doris Duke Charitable Foundation (CC), National Institutes of Health: K23 A154162 (CC), K24 A1071113 (AW), National Center for Research Resources K30 RR022293 (CJ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. African (endemic) Kaposi sarcoma (KS) was originally described in Uganda in the 1960s [1]. Today, KS is one of the leading causes of cancer in Uganda, in children and adults of both genders [2], largely attributable to the dramatic increase in KS incidence in persons with HIV infection [3]. HIV associated (epidemic) KS has very high morbidity and mortality and has become a significant health problem in this region [4]. Human herpesvirus-8 (HHV-8) is the causative agent of all forms of KS [5,6], and infection is endemic in Uganda, with an estimated seroprevalence between 36% and 60% [7,8,9,10]. Despite this high seroprevalence, both endemic and epidemic KS occur in a minority of persons who are HHV-8 infected, and little is known about the underlying mechanisms determining the transition from asymptomatic HHV-8 infection to KS disease. Specifically, what role the site, persistence, and quantity of HHV-8 replication play in progression to KS is unclear. HHV-8 replic (...truncated)


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Christine Johnston, Jackson Orem, Fred Okuku, Mary Kalinaki, Misty Saracino, Edward Katongole-Mbidde, Merle Sande, Allan Ronald, Keith McAdam, Meei-Li Huang, Linda Drolette, Stacy Selke, Anna Wald, Lawrence Corey, Corey Casper. Impact of HIV Infection and Kaposi Sarcoma on Human Herpesvirus-8 Mucosal Replication and Dissemination in Uganda, PLOS ONE, 2009, 1, DOI: 10.1371/journal.pone.0004222