ACTG Highlights

Preclinical 01
Antiviral Research Branch, NIAID Division of Microbiology and Infectious Diseases
Seven herpesviruses are known to infect humans: herpes simplex viruses (HSV) 1
and 2, varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and
the more recently discovered human herpesviruses (HHV) 6 and 7. Active opportunistic
infections caused by herpesviruses have been detected in up to 50 percent of people with
AIDS at autopsy. The most serious of these infections is CMV retinitis, which can lead to
blindness and has been found to occur in 5 to 38 percent of persons with AIDS. Chronic
HSV ulceration (in the mouth or genital area) as well as shingles caused by reactivation of
VZV (the chickenpox virus) also affect a small but significant percent of people infected
with HIV. Hairy leukoplakia, the result of oral EBV infection, is considered predictive of
the development of AIDS in HIV-infected persons. Besides the herpesvirus family of
diseases, genital warts, caused by specific human papillomaviruses, are another significant
viral opportunistic infection in people with AIDS.
NIAID's Antiviral Substances Program was created 20 years ago to identify and
develop new agents to treat human viral infections. In 1989, it was expanded into the
Antiviral Research Branch (ARB), now headed by Catherine Laughlin, Ph.D. The ARB
does not support research on drugs against HIV itself but does support research on drugs
against viral Ols associated with HIV disease.
This preclinical research falls into two broad categories: drug discovery and
development, and animal model development.
Drug Discovery and Development
Drug discovery efforts are funded through grants, contracts, and cooperative
agreements. Currently, the ARB supports eight cooperative agreements for research on
designing drugs specific for molecular targets of several viruses, including HSV and CMV.
Recent progress includes:
* Using antiviral, drug-resistant mutants to identify targets for the design of new
antiviral agents.
* Identifying HSV viral sequences that may serve as targets for antiviral drug design.
* Synthesizing a new type of antiviral drug, anti-sense oligonucleotides, that have the
potential to specifically interfere with virus replication without causing toxicity to
the cell.
* Generated human monoclonal antibodies to CMV that will be used as a component
of ganciclovir-containing drug delivery systems called immunoliposomes.
Because almost all currently licensed antiviral therapies were discovered by screening
of natural proiducts or existing drugs, the Branch also supports two in vitro screening
facilities through contracts. These facilities evaluate compounds submitted by academic,
industrial, and government investigators for activity against a panel of herpes and
respiratory viruses, including the opportunistic viruses HSV, CMV, VZV, and EBV. More
than 100 compounds have been evaluated in both primary and conformatory tests. Ten of