HIV-1 can hide in latently infected cells, and elimination of these viral reservoirs is a key obstacle to eradicating infection. Little is known about the mechanisms that maintain latency of HIV. A new study has identified genes that are differentially expressed in latently infected cells and has shown that targeting such genes can drive lytic replication, which might make the virus susceptible to antiretroviral drugs.

The authors used DNA microarrays to study gene expression in cell lines that were chronically infected with HIV, both before and during activation of lytic infection with phorbol myristate acetate, and they compared these cells with uninfected control cells. Activation of the lytic cycle and production of virus was confirmed by measuring the expression of the late HIV protein p24 by flow cytometry. Several differences in gene expression were observed between chronically infected cells and uninfected cells, and these genes could have a role in the maintenance of latency. Several genes that encode proteasome subunits and histone deacetylases were upregulated before lytic induction, and other genes were downregulated, including EGR1 (which is involved in cell-cycle regulation), CDC42 (a RHO-family GTPase) and the tyrosine kinase LYN.

The authors reasoned that by targeting genes that are both differentially expressed and possibly important for latency, they could drive the virus out of latency into the lytic cycle. To test this, they targeted the proteasome subunits and EGR1 because specific agents were available to target these molecules. Treating latently infected cells with a proteasome inhibitor or an EGR1 activator induced dose-dependent increases in p24 expression, showing that viral reactivation had occurred — although the exact mechanisms by which these molecules end latency needs further study. The authors also identified several cellular genes that were differentially expressed during active viral replication — targeting these genes might therefore inhibit viral replication.

The identification of genes that are differentially regulated in latent infection provides useful information for further studies of the mechanisms of latency and the cellular functions involved in lytic replication. This study also indicates possible new therapeutic approaches for promoting or inhibiting HIV replication. The ability to drive HIV out of latency into lytic replication means that the virus could be susceptible to antiretroviral drugs, indicating that it might be possible to considerably reduce viral reservoirs.