After sexual exposure HIV crosses the mucosal barrier, establishes a nidus of infected cells which amplify the initial infectious inoculum and initiates subsequent systemic dissemination through the lymphatic and vascular systems. Several lines of evidence have indicated that chronic exposure to drugs of abuse is associated with an increased risk for the acquisition and faster progression of HIV infection. The large cohort of HIV-infected individuals who are recreational drug users and play a major role in disseminating infection must be effectively treated by any proposed regimen to reduce the spread of HIV infection. Design of effective treatments for this population would likely be enhanced by delineating the mechanisms by which substance increases the risk of HIV transmission and the impact of substance abuse on the efficacy of treatment. We hypothesize exposure to drugs of abuse such as opioid or amphetamine contributes to the increased rate of HIV infection in substance abusers by altering the lymphoid microenvironment to facilitate infection and replication of HIV in lymphoid tissues. A major barrier that impeded investigation of the early events of HIV infection, particularly the effect of substance abuse, is the lack of an animal model that is infectible by HIV. Recently, more robust humanized mouse models such as hu-NSG mice have been developed using highly immunodeficient mice transplanted with human hematopoietic stem cells. These mice display extensive engraftment of the mouse lymphoid tissues with human T cells, B cells, macrophages and dendritic cells enabling them to be infected with HIV by the intravenous, intraperitoneal, rectal or vaginal routes. We propose to combine this novel in vivo experimental model for investigating HIV transmission with a systems biology approach to analyze and characterize the effect of drugs of abuse on the initial and subsequent cellular targets of HIV infection during the establishment of HIV infection and generate microarray data sets to identify genes modulated by opioids or meth usage that contributes to their enhancement of the initiation and spread of HIV infection. Results from this proposed study will provide a multi-scale understanding of HIV infection in humanized mice using systems biology analysis of dedicated experiments and modeling that should permit us to develop a mechanistic and quantitative grasp of how HIV infection is initiated and spread in lymphoid tissues and how it is affected by substance abuse.
In order reduce HIV transmission in the population of substance abusers, we need to understand the mechanisms by which substance abuse enhances HIV infection and increases transmission. We propose to use combine experimental results using a novel humanized mouse model consisting of mice populated with human hematopoietic stem cells with systems biology analysis to study the mechanism by which substance abuse increases HIV transmission and accelerates disease course.
|Flerin, Nina C; Chen, Huabiao; Glover, Tynisha D et al. (2017) T-Cell Receptor (TCR) Clonotype-Specific Differences in Inhibitory Activity of HIV-1 Cytotoxic T-Cell Clones Is Not Mediated by TCR Alone. J Virol 91:|
|Khan, Jalal A; Mendelson, Avital; Kunisaki, Yuya et al. (2016) Fetal liver hematopoietic stem cell niches associate with portal vessels. Science 351:176-80|
|Thomas, Tynisha; Seay, Kieran; Zheng, Jian Hua et al. (2016) High-Throughput Humanized Mouse Models for Evaluation of HIV-1 Therapeutics and Pathogenesis. Methods Mol Biol 1354:221-35|
|Seay, Kieran; Khajoueinejad, Nazanin; Zheng, Jian Hua et al. (2015) The Vaginal Acquisition and Dissemination of HIV-1 Infection in a Novel Transgenic Mouse Model Is Facilitated by Coinfection with Herpes Simplex Virus 2 and Is Inhibited by Microbicide Treatment. J Virol 89:9559-70|
|Bergman, Aviv; Gligorijevic, Bojana (2015) Niche construction game cancer cells play. Eur Phys J Plus 130:|
|Kadolsky, Ulrich D; Yates, Andrew J (2015) How is the effectiveness of immune surveillance impacted by the spatial distribution of spreading infections? Philos Trans R Soc Lond B Biol Sci 370:|
|Babad, J; Mukherjee, G; Follenzi, A et al. (2015) Generation of ? cell-specific human cytotoxic T cells by lentiviral transduction and their survival in immunodeficient human leucocyte antigen-transgenic mice. Clin Exp Immunol 179:398-413|
|Costantini, Lindsey M; Irvin, Susan C; Kennedy, Steven C et al. (2015) Engineering and exploitation of a fluorescent HIV-1 gp120 for live cell CD4 binding assays. Virology 476:240-8|
|Seay, Kieran; Church, Candice; Zheng, Jian Hua et al. (2015) In Vivo Activation of Human NK Cells by Treatment with an Interleukin-15 Superagonist Potently Inhibits Acute In Vivo HIV-1 Infection in Humanized Mice. J Virol 89:6264-74|
|Smith, Cameron; Pechuan, Ximo; Puzio, Raymond S et al. (2015) Potential unsatisfiability of cyclic constraints on stochastic biological networks biases selection towards hierarchical architectures. J R Soc Interface 12:20150179|
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