Despite the success of combined antiretroviral therapy (cART) to diminish peripheral infection, HIV-1 can establish an infection in the central nervous system (CNS), resulting in the development of cognitive, behavioral, and motor deficits associated with HIV-1 associated neurocognitive disorders (HAND). Once infected, the CNS acts as a viral reservoir that is difficult to treat and eradicate. Mononuclear phagocytes (MPs, e.g., perivascular macrophages and microglia) are important reservoirs in the immune-privileged CNS. The proposed studies are designed to address the unique dynamics of HIV infection in CNS and explore novel therapeutic strategies that target MPs, ensure viable delivery across the blood-brain barrier (BBB) to eliminate the HIV reservoir and reduce inflammation. HIV-induced activation and viral replication in MPs are relevant targets that will be approached through multiple pharmacological agents. Three unique and independently identified strategies will be investigated as novel therapeutic agents to reduce HIV replication within MPs: JAK inhibitors that block/interrupt the activation state of MPs and that can reduce inflammation, MP-specific ribonucleoside chain terminators and their phosphate prodrugs for increased delivery to the CNS, and NADPH oxidase inhibitors that are known to cross the BBB which indirectly could reduce NF8- dependent HIV-1 transcription. Selected therapeutic agents will be analyzed for their in vitro antiviral potency, and to assess biochemistry, toxicology, and cellular pharmacology parameters. Specific small molecule candidates which fulfill potency criteria will be evaluated in vivo to assess CNS pharmacology and response (including behavior and pathology) to treatment using two distinct retrovirus CNS animal models we have previously established: SCID mouse model intracranially injected with HIV-1 infected MPs, and CD4+ depleted macaque model infected with SIVmac239. Results from these studies will identify new adjunctive therapeutic strategies which together with current cART could provide improved targeted therapy to MPs. The ultimate goal is to suppress virus and eliminate these HIV-1 reservoirs in the CNS that should lead to improved treatments to reduce risk(s) of developing HAND.
Chronic infection and inflammation results in the development of HIV-1 associated neurocognitive disorders (HAND) in a substantial number of people living with HIV (PLHIV). In the era of combined antiretroviral therapy (cART), it has become apparent that eradication of HIV-1 cannot occur without elimination of viral reservoirs, including the central nervous system (CNS). Our approach is to investigate new adjunctive therapeutic strategies from three distinct classes of compounds to target improved therapy to viral reservoirs in the CNS (i.e., mononuclear phagocytes, MP) and eliminate these reservoirs and/or reduce risk of developing HAND.
|Tyor, William R; Bimonte-Nelson, Heather (2018) A mouse model of HIV-associated neurocognitive disorders: a brain-behavior approach to discover disease mechanisms and novel treatments. J Neurovirol 24:180-184|
|Reeves, Patrick M; Abbaslou, Mojgan A; Kools, Farah R W et al. (2017) Ruxolitinib sensitizes ovarian cancer to reduced dose Taxol, limits tumor growth and improves survival in immune competent mice. Oncotarget 8:94040-94053|
|Gavegnano, Christina; Bassit, Leda C; Cox, Bryan D et al. (2017) Jak Inhibitors Modulate Production of Replication-Competent Zika Virus in Human Hofbauer, Trophoblasts, and Neuroblastoma cells. Pathog Immun 2:199-218|
|Gavegnano, Christina; Brehm, Jessica H; Dupuy, Franck P et al. (2017) Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors. PLoS Pathog 13:e1006740|
|Anderson, Albert M; Schinazi, Raymond F; Tyor, William R (2016) HIV latency reversal research and the potential effects on the central nervous system: is concern warranted? J Int AIDS Soc 19:21008|
|Hollenbaugh, Joseph A; Montero, Catherine; Schinazi, Raymond F et al. (2016) Metabolic profiling during HIV-1 and HIV-2 infection of primary human monocyte-derived macrophages. Virology 491:106-14|
|Bonifati, Serena; Daly, Michele B; St Gelais, Corine et al. (2016) SAMHD1 controls cell cycle status, apoptosis and HIV-1 infection in monocytic THP-1 cells. Virology 495:92-100|
|Haile, Woldeab B; Gavegnano, Christina; Tao, Sijia et al. (2016) The Janus kinase inhibitor ruxolitinib reduces HIV replication in human macrophages and ameliorates HIV encephalitis in a murine model. Neurobiol Dis 92:137-43|
|Nguyen, Laura A; Domaoal, Robert A; Kennedy, Edward M et al. (2015) Pre-steady state kinetic analysis of HIV-1 reverse transcriptase for non-canonical ribonucleoside triphosphate incorporation and DNA synthesis from ribonucleoside-containing DNA template. Antiviral Res 115:75-82|
|Gogineni, Vedanjali; Schinazi, Raymond F; Hamann, Mark T (2015) Role of Marine Natural Products in the Genesis of Antiviral Agents. Chem Rev 115:9655-706|
Showing the most recent 10 out of 17 publications