Human herpes virus 8 in HIV and non-HIV infected patients with pulmonary arterial hypertension in France

Abstract

Kaposi's sarcoma-associated herpesvirus or human herpesvirus 8 (HHV8) is a vasculotrope virus associated with Kaposi's sarcoma, HIV-associated Castleman's disease and primary effusion lymphoma. Other associations, in particularly multiple myeloma, have been clearly disproved by additional analysis after initial positive reports [1]. Cool et al. [2] have recently demonstrated the presence of HHV8 in the lungs of patients with pulmonary arterial hypertension (PAH) ascertained by immunochemistry with antibody directed against latency-associated nuclear antigen 1 (LANA-1) and polymerase chain reaction assay to detect the viral cycline gene of HHV8. In that study, evidence of HHV8 was found in 10 out of 16 patients with idiopathic PAH, in one out of three patients with PAH related to HIV infection, and in none of 12 patients with PAH related to other conditions. The authors suggested a role for HHV8 in the development of PAH [2]. Later, the presence of HHV8 antibodies, against a structural HHV8 protein called K8.1 and against LANA-1, was tested in plasma samples from non-HIV-infected German patients with PAH, but no difference was found between patients and controls [3]. In addition, HHV8-DNA sequences were not detected by polymerase chain reaction in nine PAH lungs studied in Japan, indicating that other factors than HHV8 are more likely to be the cause of PAH in that population [4]. Moreover, whereas the geographical distribution of Kaposi's sarcoma mirrors HHV8 prevalence, it seems unlikely for PAH in which no ethnic predisposition has been observed to date. As Mediterranean countries have higher prevalence rates of HHV8 infection, we studied a cohort of French patients with PAH in order to test whether there were possible links between HHV8 and PAH in this country. The aim of the study was to evaluate the prevalence of HHV8 antibodies in plasma samples from HIV and non-HIV-infected patients with PAH. Ninety-three patients with PAH were enrolled in the study: 47 with idiopathic or familial PAH, 34 with PAH related to HIV infection, and 12 with PAH associated with other conditions. Antibodies directed against LANA-1 were detected using an immunofluorescence assay on the primary effusion lymphoma BC-3 cell line, and the positive samples were confirmed using an immunofluorescence assay that detects antibodies to HHV8 lytic antigens (KSHV IgG IFA; Biotrin, Dublin, Ireland). HHV8 antibodies were detected in one out of 47 [2.1%; confidence interval (CI) 0–6.3%] patients with idiopathic or familial PAH and in two out of 12 (16.7%; CI 0–38.7%) patients with PAH related to other conditions. In the 34 patients with PAH related to HIV infection, eight had HHV8 antibodies (23.5%; CI 9.3–37.8%). These results indicate that the prevalence of antibodies for HHV8 in HIV-infected and non-HIV-infected patients with PAH is similar to that previously reported for corresponding individuals without PAH. The seroprevalence of HHV8 in healthy individuals in France has been estimated at 2%, and between 22 and 35% among HIV-infected individuals from the United States and northern Europe using LANA tests [5,6]. This suggests that there is no trend in favour of an increased serological evidence of HHV8 infection in PAH in HIV-infected patients or in non-HIV-infected patients. In addition, a reduced immunological response to viruses has never been reported in PAH, and there is no scientific basis supporting the hypothesis of a defective humoral response to HHV8, which could explain the low prevalence of HHV8-specific antibodies in plasma samples of PAH patients. Our present results are based on serological evidence of HHV8 infection, and one may hypothesize that HHV8 infection could be restricted to patients’ lungs. However, such compartmentalized HHV8 infection without serological evidence has not been reported to date. We conclude that there is no evidence in favour of an association between PAH and HHV8 in a French cohort of HIV-seropositive and seronegative patients.