Infections with human herpesviruses (HHVs), such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Kaposi's sarcoma-associated herpesvirus (KSHV), cause an enormous amount of morbidity and mortality worldwide. Although nearly everyone becomes infected with one or more of these viruses, most have no significant illness from them. However, in young infants or people immunocompromised by HIV or having a transplant, these viruses frequently cause a range of severe infections and cancers. Vaccines or drugs to prevent these infections or their complications would have profound public health implications, but first additional research is required to better understand the underlying pathogenesis. As such, we carry out translational research studies, utilizing cohorts of children in Africa and North America as well as epidemiologic, clinical, and molecular approaches, to address fundamental questions about how to prevent and treat HHV-related diseases.
We are particularly interested in the role of HHV infections very early in life. For example, CMV infects approximately 1% of all infants in utero, which frequently results in neurologic sequelae like deafness and mental retardation; postnatal infections, however, are normally benign. Similarly, high risk for Burkitt's lymphoma, one of the most common childhood cancers in Africa, appears to be due to EBV infection in early infancy combined with exposure to malaria. We have established a cohort of children in Uganda who were followed every week during the first year of life to study CMV and EBV infection. The precise timing of infection with these viruses was established by weekly PCR testing. Comprehensive data were collected regarding epidemiologic and biologic risks of acquisition, including detailed behavioral questionnaires, determination of the viral exposure by household contacts, and collection of blood for measurement of virus-specific neutralizing maternal antibodies. Symptoms of illness associated with infection were captured using standardized physical exams and clinical histories, and blood was collected to evaluate the humoral and cellular immune responses to these viruses that are associated with control of viral replication.
Another recent focus of our group has been to elucidate the mechanism of action of the HIV protease inhibitor (PI) nelfinavir to inhibit HHV replication, and investigate the drug's potential to prevent and treat HHV-related diseases. We discovered that nelfinavir is able to block in vitro replication of all HHVs tested to date, at concentrations that are achieved in patients taking doses that are FDA-approved for treatment of HIV. This activity is unique to nelfinavir among PIs, and appears to result from effects of nelfinavir on host cell pathways that are required for viral replication, rather than on the virus itself. Interestingly, at least some of these cellular effects also confer nelfinavir's increasingly appreciated antitumor activities. Because nelfinavir is safe for use in humans, we have undertaken a phase 1/2 trial of nelfinavir for the treatment of Kaposi's sarcoma in Africa and the US. In addition, because nelfinavir is also safe during pregnancy, we are testing whether nelfinavir given to HIV-infected women during pregnancy can prevent congenital CMV infection.