Scientists Discover New Approaches to Manipulating AIDS Virus
Researchers at the National Cancer Institute (NCI), part of the
National Institutes of Health, have discovered new information about
how human immunodeficiency virus (HIV), the virus that causes acquired
immune deficiency (AIDS), possibly evades eradication from the body.
In a study published in the August 16, 2004 Journal of Virology*,
NCI HIV and AIDS Malignancy Branch scientists identified several
possible gene targets and two drugs to flush out long-lasting HIV
reservoirs that current treatments do not affect. They also established
a connection between HIV and several other genes not previously
the virus and found new possible targets for blocking HIV replication.
Current AIDS drugs, called antiretrovirals, target HIV replication.
However, these drugs cannot completely eradicate the virus from
the body because HIV rests in some cells in a non-replicating stage
called latent infection. The gene targets uncovered by the NCI researchers
may be used to activate HIV
within these cells, inducing its replication and thereby making
the virus more vulnerable to treatment.
"The persistence of latent HIV reservoirs is one of the main
barriers to the eradication of HIV infection," said principal
investigator Steven Zeichner, M.D., PhD. "Our studies show
that agents targeting specific genes can be used to force HIV out
of latency. In a clinical setting, forcing HIV out of latency while
maintaining good control of HIV replication using antiretroviral
drugs may reduce or eliminate these reservoirs."
The researchers explored gene expression in latently-infected cells,
and found that while these cells appear very similar to uninfected
cells, they have a different pattern of gene expression. For example,
genes whose products appear to create a favorable environment for viral replication such
as those inhibiting cell growth were expressed at a lower level
in latently-infected cells. Such differences in gene expression
point to potential targets for therapy. Causing these genes to be
expressed at a higher level could induce HIV replication, creating
an opening for conventional therapies to operate.
Zeichner and his research fellow, Vyjayanthi Krishnan, Ph.D., had
success doing just that with a compound called resveratrol. Resveratrol
activates Egr1, a gene whose product causes cell growth to slow,
creating favorable conditions for HIV replication. Zeichner believes
resveratrol may mimic the effects of active HIV replication on the
cell cycle. His lab is currently in the process of testing other
agents to target genes involved in cells' transition out of latent
Their success in stimulating replication in latently-infected cells
"suggests that there may be additional new ways to manipulate
HIV latency, and perhaps deplete latently infected reservoirs or
even perhaps eliminate HIV infection," Zeichner said.
Zeichner's team also examined differences in gene expression between
latently-infected cells and actively-infected cells, generating
further possible therapeutic targets. They induced HIV replication in latently-infected
cells and monitored their gene expression patterns over time. A
total of 1740 genes out of 9127 studied showed statistically significant
differences in expression throughout this period. Genes involved
in the MAPK signaling pathway, which promotes viral replication,
were expressed at a higher level; genes preventing transcription
of DNA were expressed at a lower level.
Some of the genes that were expressed differently in infected cells
are genes that have been linked to some cancers, suggesting that
HIV requires some of the same functions that are implicated in the
development of cancer. Many of these genes are already the subject
of drug development efforts directed at cancer and other disorders.
While Krishnan, the first author on the study, cautions that their
data are far from clinical application, she believes "the results
may provide an early hint at strategies that drugs target cellular
activity, rather than the virus itself." Unlike current AIDS
drugs, such therapies "may be less likely to engender drug
resistance by HIV."
For more information about cancer, visit the NCI Web site at http://www.cancer.gov
or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
* Krishnan, V and Zeichner, SL. "Host Cell Gene Expression
During HIV-1 Latency and Reactivation, and Effects Targeting Genes
Differentially Expressed in Viral Latency." Journal of Virology,
Volume Issue. 16 August 2004.