Scientists discover new approaches to purging HIV reservoir

Researchers at the National Cancer Institute (NCI), part of the United States National Institutes of Health, have discovered new information about how HIV could evade eradication from the body. In a study published in the August 16^th, 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 associated with the virus and found new possible targets for blocking HIV replication.

Current AIDS 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., Ph.D. He points out that previous studies have shown that latently infected cells may have a lifespan of up to 60 years.

"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."

There are at least three reasons to investigate the elimination or reduction of HIV reservoirs:

• Eliminating reservoirs might eventually allow people to stop treatment altogether, and reduce the risk of treatment failure for those who do stay on therapy.
• It may reduce the infectivity of people with HIV on treatment if reservoirs of latently infected cells in the genital tract can be purged, thus reducing the risk that local infections or inflammation could activate these cells to pump out virus into the genital fluids.
• It may purge reservoirs of cells that contain drug-resistant virus, but researcher Vyjayanthi Krishnan told aidsmap.com: "Further research is required on gene expression studies on cells that harbour drug resistant virus, to see and confirm if cellular gene expression patterns differ from uninfected cells, and if so , whether these could serve as targets for successful viral reactivation of drug resistant viral forms."

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 favourable 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 favourable 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 infection.

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 for drugs that target cellular activity, rather than the virus itself." Unlike current AIDS drugs, such therapies "may be less likely to engender drug resistance by HIV."