This application proposes to investigate how Trim37, as a hypothesized component of the human innate immune system, influences HIV-1 replication dynamics in the presence or absence of opiods. Published research from several independent laboratories has revealed that opiods increase HIV replication ex vivo in human immune cells and in vivo in mice and rhesus macaques. It has been hypothesized that the mechanism for the observed increases in HIV-1 replication is due to opioids'well-documented ability to modulate cytokine and cytokine receptor signaling and expression. One recent study with murine dendritic cells has shown that the mu-opioid receptor, which is the receptor responsible for morphine's drug-induced effects, can be induced by the toll-like receptor 4 ligand, lipopolysaccharide (LPS). Unpublished research in the Mansky lab has demonstrated that Trim 37 is packaged into HIV-1 particles and decreases virus infectivity by reducing viral DNA synthesis. It has been previously observed that the expression of Trim37 results in the inability of TRAF proteins 2 and 6 to stimulate NF-KB binding to DNA. Notably, NF-KB is one of the major human transcription factors that transcribes HIV-1;tumor necrosis factor alpha (TNFalpha) and LPS both stimulate NF-KB's binding to DNA. This proposal seeks to determine whether various mammalian Trim37 proteins can also restrict HIV-1 infectivity in cell lines and primary cells. Both single-cycle replication and spreading HIV-1 infection assays will be performed in the presence of varying amounts of Trim37 to determine each Trim37 protein's antiretroviral effect. Due to the observations that both Trim37 and opioids can modulate NF-KB signaling, experiments will also be conducted in the presence of opioids. Additionally, experiments to determine whether Trim37's expression or localization changes in the presence of opioids, interferons I, II, and III, and TNFalpha will also be done. The determination of whether opioids alter the ability of Trim 37 to restrict HIV replication could help yield insight into the restriction mechanisms involved. Given that many of the 33.4 million HIV-1 infected people worldwide use opioids, these studies have the potential to improve global human health among HIV-1 infected opioid users.
In the United States, over 1.1 million people, many of whom are injecting opioid drug users, are infected with the human immunodeficiency virus (HIV), the cause of AIDS. This study investigates the mechanistic contributions that Trim37 and opioids, both of which impact the human innate immune system, have on the function of the human innate immune response to HIV infection. These studies will result in a better understanding about how the innate immune system functions in the presence or absence of HIV-1 infection and/or opioid use, which could ultimately contribute to the future development of novel drugs to treat viral infections and opioid drug-addiction, thus advancing the improvement of human health worldwide.
|Rawson, Jonathan M; Heineman, Richard H; Beach, Lauren B et al. (2013) 5,6-Dihydro-5-aza-2'-deoxycytidine potentiates the anti-HIV-1 activity of ribonucleotide reductase inhibitors. Bioorg Med Chem 21:7222-8|