DENVER—Human herpesvirus 8 (HHV-8) is believed to be the cause of all clinical types of Kaposi’s sarcoma and lymphoproliferative disorders associated with HIV-1 infection. Similarities between endothelial abnormalities in Kaposi’s sarcoma and the plexiform lesions in primary pulmonary hypertension (PPH) led researchers at the University of Colorado Health Sciences Center to study whether HHV-8 infection could be involved in the development of PPH. They found that infection with the virus is linked to PPH, and that PPH may be a form of malignancy.[1]

STUDYING LUNG TISSUE

Samples of lung tissue from 30 patients with severe pulmonary hypertension were evaluated. Sixteen patients had PPH and 14 had secondary pulmonary hypertension. Four patients with other lung diseases and one healthy patient served as negative controls.

The HHV-8 latency-associated nuclear antigen 1 (LANA-1) was found in lung tissue from 10 of the patients with PPH but in none of those with secondary pulmonary hypertension. LANA-1 is a protein highly specific for HHV-8. Interestingly, not only cells within lesions but also bronchoepithelial cells, inflammatory cells, and endothelial cells lining lung vessels were found to be positive for LANA-1.

The same 10 PPH patients who were positive for LANA-1 had tissue samples that were also positive for the viral cyclin gene of HHV-8.

“We have not found a single case of secondary pulmonary hypertension that was HHV-8 positive,” said Norbert F. Voelkel, MD, Director of the Pulmonary Hypertension Center at the University of Colorado Health Sciences Center in Denver. Only cases of PPH were related to HHV-8 infection.

Four of the 16 patients with PPH had mutations of the bone morphogenic protein receptor 2 gene—a mutation associated with PPH. Of these four, two were HHV-8 positive on histochemical and polymerase chain reaction analysis and two were negative.

TUMOR-LIKE CELL GROWTH

Dr. Voelkel’s group believes that the plexiform lesions characterizing PPH are morphologically different from endothelial cells in normal pulmonary arteries. Rather than growing in a flat monolayer, the endothelial cells in plexiform lesions collect in groups of large cells with large nuclei. This process of cell growth seems similar to that seen in tumors.[2]

There is also a complete lack of apoptosis in endothelial cells of plexiform lesions in PPH, they have found. LANA-1 inhibits the function of p53 and prevents apoptosis of latently infected cells. The capacity of LANA-1 and viral cyclin to trigger unregulated cell growth while simultaneously blocking p53-dependent apoptosis may contribute to the oncogenicity of HHV-8. Additionally, factors unique to the plexiform lesions of PPH (eg, the production of inflammatory cytokines) may enhance the replication of HHV-8 in affected tissues.

Dr. Voelkel remarked that these findings raise some interesting questions. Does HHV-8 cause PPH, or does PPH make patients susceptible to HHV-8 infection? “Is it possible that PPH patients are immunosuppressed and this makes it easier for the HHV-8 virus to replicate? Is part of the PPH process immunosuppression? HHV-8 hits like HIV—in lymphocytes. We are also starting to look at this,” he added.

NEW TREATMENT STRATEGIES

Dr. Voelkel admitted that beginning to think of PPH in terms of cancer will be difficult. However, he said, “When you have a virus that can cause cancer [HHV-8] and a disease that is unexplained [PPH], the disease is no longer unexplained if you think along the lines of cell growth and cell proliferation.”

Treating PPH must address this new line of thinking, said Dr. Voelkel. “The focus of treatment will have to be on inhibiting cell proliferation and trying to kill those lumen-obliterating transformed cells. It’s a complete departure from the previous therapy that has been strictly based on vasodilators.”

In fact, Dr. Voelkel argued, most current treatments for PPH don’t work. But what can be done? “First, we have to find a blood test that can identify who is infected with HHV-8 while the patient is still alive. Second, we have to focus on the issue of an immune defect [in PPH]. We should have been aware of such a defect, because of the association of HHV-8 with the AIDS virus.” Third, he said, there is a need for an animal model. “Once you accept the concept of cell transformation in a cancer-like situation, it becomes apparent that the animal models used to study PPH are off base, because they don’t have those transformed cells or the massive obliteration of precapillary arteries.” Dr. Voelkel and colleagues have developed a rat model for use in preclinical trials.

“We are working further to figure out what drugs might be acceptable treatments. We need to get hold of malignant cells and to start testing them. But research can only go so far with the patient,” Dr. Voelkel concluded.

—Verna L. Schwartz, MS