Regulation of APOBEC3G in Primary Immune Cells
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: As the acquired immunodeficiency syndrome (AIDS) global pandemic escalates, physicians and patients continue to contend with the emergence of drug-resistant viral strains and with adverse side-effects associated with current drugs. The identification of new targets for drug development is thus critical at this juncture. Current therapies block different aspects of the life cycle of the human immunodeficiency virus (HIV), the virus that causes AIDS. The most effective regimens involve combination therapies aimed at blocking the activity of the viral reverse transcriptase and protease proteins. The FDA recently approved a drug to block viral fusion; and other drugs, targeting other aspects of the virus, are in various stages of development. Our studies focus on an, as yet, unexplored method of combating the virus and involve enhancing the action of an innate antiviral factor naturally produced by human immune cells. Human CD4+ T cells harbor an enzyme, APOBEC3G (“A3G”), which has the potential to completely block the spread of HIV. A3G is expressed in the cytoplasm of cells and, under certain conditions, is incorporated into budding virions, where it later exerts its antiviral activity. Unfortunately, despite this factor, HIV remains able to infect CD4+ T cells. This is because HIV has evolved a mechanism to counteract the activity of A3G. The mechanism is mediated by a viral protein called Vif. Vif eliminates A3G from T cells before the enzyme can perform its antiviral function. If A3G expression could be enhanced above its natural levels, it is possible that the activity of Vif could be overwhelmed. Under this scenario, A3G would then be able to resume its natural role as an antiviral factor and suppress the spread of the virus. Such a therapeutic could be of value to AIDS patients, particularly if it is administered in combination with other therapies targeting other aspects of the virus. Our preliminary studies indicate that certain cytokines, chemicals naturally produced by human cells, can stimulate T cells so that they increase their expression of the A3G enzyme. Our studies trace this upregulation back to the level of transcription, indicating that the upregulation of A3G gene is the end-result of a signaling cascade within the cell. In order to expand upon these studies, we plan to further decipher the nature of the signaling pathway leading to increased expression of A3G. Furthermore, we would like to determine whether cytokines also negatively regulate A3G present in resting CD4+ T cells by promoting its shift into an inactive large RNA-protein complex. Taken together, these studies should provide a balanced picture about the role of cytokines in the regulation of the expression and activity of A3G. Finally, we plan to examine the effects of tilting that balance by "forcing" A3G to be expressed at high levels in primary cells. The insights gained from these studies would further expand our understanding of the biology of A3G and could lead to new strategies for preserving its potent antiviral action despite the effects of HIV Vif. In addition, they could shed light on the viability of a therapeutic strategy that focuses on upregulating A3G expression.