Epidemiological studies on substance-abusing drug users and HIV-I infection, link abuse of cocaine, even more than other drugs, to increased risk for, and progression to clinical disease associated with the virus. The use of cocaine therefore exacerbates host factors that promote HIV replication. Developing therapeutic interventions that curtail the exaggerated production of such host factors could, therefore prove beneficial as adjunct therapies for AIDS. Earlier studies from our and other laboratories have shown that during AIDS pathogenesis there is a shift from a T helper type 1 (Th1) response to a dominant Th2 response (exemplified by host proteins, interleukin (IL)-4 &IL-10). Therefore, in our gene therapy studies we used the approach of delivering antisense (AS) IL-4 DNA trapped in liposomes to virus-infected cells/macaques to curtail virus replication. We achieved successful abrogation of virus replication in cells in culture and, globally, in various macaque tissues. However, liposomes are cost prohibitive, and toxic when administered repeatedly. Alternatively, poly (DL-lactic-co-glycolic acid) (PLGA) particles are biodegradable, have low toxicity and immunogenicity and have been used successfully in humans. We have recently observed that Th2 cytokine, IL-10 is also critical for cocaine-mediated increase in HIV-infected macrophages. Based on these findings, the underlying central hypothesis of this proposal is that blocking IL-10 expression by AS IL-10 DNA approach, will abrogate cocaine-mediated enhancement of HIV-1 replication. In collaboration with Drs. Panyam and Berkland, who can synthesize PLGA particles of varying size &surface chemistry with high precision, we propose to test PLGA/AS IL-10 DNA particles as therapeutic agents for abrogation of cocaine-mediated viral enhancement in cell culture and in vivo using the HIVE hu- NOD/SCID mice that contain xenografts of HIV-1 infected MDMs injected into the basal ganglia. In this application the hypothesis will be tested in 2 interrelated aims:
Specific Aim 1 : Formulate PLGA/AS IL-10 vectors that will efficiently abrogate IL-10 production and HIV-1 replication in vitro.
Specific Aim 2 : Determination of virus inhibitory effects of PEG/ Mannose-conjugated PLGA/AS IL-10 vector(s) (identified from Aim 1) delivered intracranially in hu NOD/SCID mice that are administered cocaine daily.
This proposal aims to use biodegradable nanoparticles encapsulating AS IL-10 DNA as a potential therapeutic agent for inhibition of virus replication in cocaine-abusing individuals with AIDS dementia.
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