Herpesvirus-associated Pulmonary Hypertension?

Herpesviruses have brilliantly adapted to survive in their host of choice, employing specialized gene products that facilitate their transmission, replication (through cell lysis), and persistence (through latency). Unfortunately, the actions of many of these viral gene products negatively impact infected cells (1), ultimately leading to malignancies and lymphoproliferative diseases, particularly in immunodeficient individuals (2). In 1994, a novel ? herpesvirus homologous to Epstein-Barr virus was detected in Kaposi's sarcoma (KS) lesions from patients with AIDS, and was named Kaposi's sarcoma-associated herpesvirus (KSHV or human herpesvirus 8, HHV-8) (3). This initial finding immediately sparked an intense investigation into the manner in which a herpesvirus could trigger this neoplasm, which was composed of transformed spindle cells with potent angioproliferative properties. The causal role of KSHV has also been established in other malignancies, such as primary effusion lymphoma, and in benign diseases, such as multicentric Castleman's disease, a lymphadenopathy with polyclonal hypergammaglobulinemia (4).

In 2003, Cool and colleagues demonstrated the presence of KSHV in primary pulmonary hypertension (PPH), a disease of the pulmonary arterial wall that is histologically characterized by a lumen-occluding vascular or plexiform lesion containing endothelial and smooth muscle cells (5). Clinically, PPH is characterized by an elevation in pulmonary arterial pressure and eventual heart failure. Although genetic mutations in bone morphogenic protein receptor 2 have been detected in familial cases of PPH (6), no other genetic mutation had been uniformly detected in PPH, leading these investigators to speculate that an infectious agent, plausibly KSHV, may play a causative role in PPH. Their evidence for KSHV infection in PPH stemmed from an initial screen of laser-capture microdissected (LCM) plexiform lesions in which they detected open reading frame (ORF) 26 from KSHV in 4 of 15 patients. Further polymerase chain reaction (PCR) and immunohistochemical analysis by this group revealed the presence of KSHV genome (v-cyclin encoded by ORF72) and KSHV-encoded latency-associated nuclear antigen-1 (LANA-1), respectively, in plexiform lesions and cells outside these lesions (5). However, these results generated immediate controversy as Henke-Gendo and colleagues (7) reported that KSHV infectivity (based on plasma seropositivity) did not differ between the PPH and healthy control groups they studied. Cool and colleagues (7) countered with previously published data showing that nearly 20% of serum samples are negative in patients with KS. However, three independent research groups, using sophisticated immunohistochemical and PCR techniques, have subsequently failed to consistently show the presence of KSHV in PPH lung lesions (8-10). In this issue of the Journal (pp. 1581-1585) Henke-Gendo and colleagues (11) call into further question whether KSHV is associated with PPH since their sensitive PCR techniques failed to detect KSHV genome in formalin-fixed lung sections despite evidence of LANA-1 positivity in approximately 62% of these samples.

Conflicting results are common in biomedical research, and differential findings are often simplistically explained by sampling and/or analysis differences. Nevertheless, detection of KSHV genome and protein products is complicated by a number of technical issues relating to the complex lytic and latent phases of this herpesvirus, the status of the tissue analyzed (i.e., fresh vs. fixed; LCM plexiform lesions vs. whole tissues), and the relative abundance of KSHV-infected cells in the analyzed tissue. Immunohistochemical localization of LANA-1 has proven to be a reliable diagnostic tool in screening for the presence of KSHV in KS lesions. The KSHV genome has been detected by PCR in various diseases, including multiple myeloma, Bowen disease, sarcoidosis, and idiopathic pulmonary fibrosis, but LANA-1 staining in tissues associated with these diseases has proven to be elusive, leading many to question the presence and role of KSHV in each (2). Surprisingly, both Cool and coworkers (5) and Henke-Gendo and colleagues (11) showed strong LANA-1 staining in PPH lesions. In both studies, the LANA-1 staining observed in PPH plexiform lesions was suggestive of the "speckled" nuclear pattern classically observed in KS lesions. However, Henke-Gendo and colleagues (11) conclude that the LANA-1 staining they observed was a false-positive finding since they failed to detect KSHV genome by PCR in their lung samples.

Although the bulk of the published data now indicates that it very unlikely that KSHV is present in PPH, it is too soon to rule out the presence of and a putative role for other herpesviruses (or some yet-to-be-discovered virus) in PPH for several reasons. First, there is a striking similarity between the plexiform lesions observed in PPH and cutaneous KS; both exhibit slitlike vascular spaces with sheets of endothelial cells expressing factor 8-related antigen and vascular endothelial growth factor. Second, PPH is a heterogeneous disease, which involves a complex interplay of several genetic and environmental factors. Third, the murine viral equivalent of KSHV has been shown to profoundly remodel the lung (12, 13). Finally, novel antiviral approaches may be in order for the treatment of PPH given the beneficial effects of valacyclovir in idiopathic pulmonary fibrosis (14) and sirolimus in renal-transplant recipients (15). At the very least, clarification of the presence of KSHV in PPH will benefit from the implementation of novel genomic and proteomic detection techniques to LCM plexiform lesions.

Conflict of Interest Statement: Neither of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

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