PATHWAYS OF HIV NEURODEGENERATION AND DIMETHYL FUMARATE (DMF/MMF) NEUROPROTECTION
Aldovini Anna
University Of Pennsylvaniacity: Philadelphia country: United States (us)
Grant 3R01MH095671-01S1 from National Institute Of Mental Health
Abstract: HIV-associated neurocognitive disorders (HAND) remain prevalent despite the use of antiretroviral therapy (ART), and CNS inflammation & neurodegeneration associated with HIV replication in macrophages/microglia remain as neuropathological features. Persistent systemic inflammation & monocyte activation, CNS inflammation, macrophage activation, correlate with HAND in patients on ART. Thus, although ART is the backbone of HIV therapy, there is a critical need for adjunctive therapies to suppress persistent inflammation and virus replication, and to decrease the high burden of HAND- associated disability. Accordingly, drugs that suppress inflammation and HIV replication systemically and within the CNS are especially attractive as adjunctive neuroprotectants. We are proposing a dual-investigator MPI study (Kolson, Aldvoni) to investigate a novel drug, dimethyl fumarate, (DMF, Fumaderm(R)), now in a phase III clinical trial for multiple sclerosis) as a candidate neuroprotectant for HAND. Using our HIV neurotoxicity model we found that DMF and its primary in vivo metabolite, MMF, suppress a) HIV replication, b) associated inflammatory responses, and c) neurotoxin production in monocyte- derived macrophages (MDM). DMF/MMF also d) induces monocyte antioxidant responses and e) suppresses chemotaxis. In addition, using transcriptome analyses of HIV-infected T lymphocytes and MDM, we also demonstrated that HIV reprograms host gene expression in a cell-dependent manner to modulate pathways of virus spread, inflammatory mediators, and apoptosis, which can intersect pathways of HIV/MDM neurotoxin production & neurodegeneration. Because DMF is orally-deliverable, CNS- penetrating, and minimally toxic, we hypothesize that DMF can be an effective neuroprotectant in HAND and we further hypothesize that transcriptome analyses can identify host pathways modified by DMF/MMF that underlie its neuroprotection. We will 1) Define mechanisms of DMF/MMF suppression of HIV replication and MDM neurotoxin production by HIV replication and Tat expression~ 2) Define DMF/MMF effects on suppression of monocyte & macrophage activation through anti-oxidant responses & other pathways~ 3) Determine mechanisms of DMF/MMF modulation of monocyte chemotaxis & transendothelial migration~ and 4) Determine the ability of DMF/MMF to suppress monocyte activation and induce antioxidant responses in SIV-infected rhesus macaques. This should provide a rationale for a future clinical trial in HIV patients
Keywords: Acanthophis antarcticus toxin Aa c; Anti-inflammatory; Anti-Inflammatory Agents; Antioxidants; antiretroviral therapy; Apoptosis; Brain; CCL2 gene; CD14 gene; CD4 Positive T Lymphocytes; Cell Adhesion Molecules; Cells; Chemotaxis; Chronic; Clinical Trials; Controlled Study; CX3CL1 gene; CXCL12 gene; disability; Disease; Disease Progression; Drug Delivery Systems; Drug usage; Elements; Endothelial Cells; Europe; Excitatory Neurotoxins; FCGR3B gene; Fumaderm; Fumarates; Future; Gene Expression; Gene Expression Profile; gene induction; Genes; HIV; HIV Envelope Protein gp120; HIV Infections; HIV therapy; Human; Immune; immune activation; Immune response; In Vitro; in vivo; Individual; Inflammation; Inflammation Mediators; Inflammatory Response; Investigation; Lead; Macaca mulatta; macrophage; Macrophage Activation; Mediating; Microglia; migration; Modeling; monocyte; Multiple Sclerosis; Nerve Degeneration; Neurocognitive; Neuroglia; neuroinflammation; Neurons; Neuropathogenesis; neuroprotection; Neuroprotective Agents; neurotoxicity; Neurotoxins; novel; NQO1 gene; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Pilot Projects; Production; Psoriasis; Research Personnel; response; Role; Signal Pathway; SIV; Stromal Cell-Derived Factor 1; T-Lymphocyte; Tissues; Vertebral column; Viral Load result; Virus; Virus Replication
Relevance: Chronic inflammation persists in HIV-infected individuals despite systemic suppression of HIV replication by ART. Such inflammation can drive disease progression, both systemically and within the CNS. Dimethylfumarate (DMF) is a safe, effective anti- inflammatory drug (used in Europe to treat psoriasis) with CNS-protective, anti- inflammatory effects in multiple sclerosis patients. We will determine its potential neuroprotective use against HIV with investigations that should lead to a neuroprotection trial in HIV patients
Project start date: 2011-09-26
Project end date: 2016-05-31
Budget start date: 26-SEP-2011
Budget end date: 31-MAY-2012
3R01MH095671-01S1 (2012): $395964
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Aldovini Anna
SIV DNA VACCINES AND MUCOSAL IMMUNITY
Aldovini Anna, Associate Professor
Harvard University (medical School)city: Boston country: United States (us)
Abstract: This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. SIV DNA vaccines and mucosal immunity More than 80 percent of global transmission of HIV infection occurs via mucosal routes. The ability of vaccines to induce mucosal immunity may be required for protection against HIV infection and the immunodeficiency syndrome that emerges after infection. Various AIDS vaccine candidates are currently under development, each with potential advantages and disadvantages. DNA vaccines have features that make them attractive vaccine candidates for HIV and the combination of DNA vaccination plus recombinant vaccinia is one of the favored approaches in AIDS vaccine development
Keywords: Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; AIDS Vaccine Development; AIDS Vaccines; AIDS Virus; Computer Retrieval of Information on Scientific Projects Database; CRISP; Deoxyribonucleic Acid; Development; Disadvantaged; DNA; DNA Vaccines; Funding; Grant; HIV; HIV Infections; HTLV-III; HTLV-III Infections; HTLV-III-LAV Infections; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; hypoimmunity; immune deficiency disorder; immunodeficiency; Immunodeficiency Disorder; Immunodeficiency Syndrome; Immunologic Deficiency Syndromes; Immunological Deficiency Syndromes; Infection; Institution; Investigators; LAV-HTLV-III; Lymphadenopathy-Associated Virus; Mucosal Immunity; Naked DNA Vaccines; National Institutes of Health; National Institutes of Health (U.S.); NIH; Recombinants; Research; Research Personnel; Research Resources; Researchers; Resources; Route; Simian Immunodeficiency Viruses; SIV; Source; T-Lymphotropic Virus Type III Infections, Human; Transmission; transmission process; United States National Institutes of Health; Vaccination; vaccine candidate; Vaccines; Vaccines, DNA; Vaccines, Recombinant DNA; Vaccinia; Virus-HIV
Project start date: 2010-05-01
Project end date: 2011-04-30
Budget start date: 1-MAY-2010
Budget end date: 30-APR-2011
5P51RR000168-49_8705 (2010): $65759
ORAL VACCINATION FOR AIDS PREVENTION IN RHESUS MACAQUES
Aldovini Anna, Associate Professor
Children´s Hospital Bostoncity: Boston country: United States (us)
Grant 5R01DE019060-04 from National Institute Of Dental & Craniofacial Research
Abstract: The severity of the AIDS epidemic in the developing world combined with the limited resources that some of these countries have available for health care render the need of an AIDS vaccine more urgent every day. When tested in Rhesus macaques, the candidate vaccines developed thus far, evaluated predominantly via the intramuscular route, do not protect from chronic infection but provide a reduction in the viremia set point and a delay of progression to AIDS. The control of viremia and the length of disease-free infection depend on the model of infection used for the vaccine evaluation in non-human primates. As substantial virus replication occurs in the gastrointestinal tract in addition to the lymphoid organs, the ability of vaccines to induce immunity both in mucosal and systemic compartments may be required for prevention of HIV infection and AIDS. We have established vaccination regimens that stimulate mucosal responses with an SIV DNA vaccine, which consists of a single plasmid carrying an SIV proviral genome that produces noninfectious particles, whether the vaccination occurs via the rectal or nasal route. We have the appropriate tools to measure SIV-specific IgA levels in mucosal secretions, mucosal cell-mediated responses, and SIV-specific systemic responses. As a consequence, we believe that we are uniquely placed to determine the effectiveness of oral DNA vaccination and how stimulation of virus-specific mucosal responses can affect the efficacy of a HIV/SIV vaccine. Exploring vaccination regimens administered via the oral route may be important to establish regimens capable of providing substantial control of viral replication in the gastrointestinal tract. Towards this goal we propose 1. To evaluate whether different doses of a DNA plasmid expressing the Hepatitis C Virus 70 kD E2 Envelope protein and combined with PLG micro particles stimulate significant anti- Hepatitis C Virus 70 kD E2 immune responses systemically and mucosally when administered orally to Rhesus macaques. 2. To evaluate whether a liposome or a micro particle formulation of a DNA-MVA SIV vaccine stimulates broader mucosal and systemic responses after oral administration. 3. To evaluate which of the two above regimens provides the best protection from vaginal SIV challenge. 4. To evaluate whether the better of the two above regimens can be further improved in its protection from progression to AIDS by the simultaneous administration of a similarly formulated DNA-MVA intradermal immunization. AIDS vaccines may need to engender a substantially greater level and breadth of immunity than other vaccines. It is important to explore approaches that may enhance the quality and not simply the quantity of the immune response because an efficacious vaccine will have to provide protection at times other than the peak of the immune response. The simultaneous presence of both mucosal and systemic immunity may be important in preventing the establishment of a chronic HIV/SIV infection and in controlling disease progression if infection occurs. Oral vaccination may be best suited at providing virus-specific responses that reside in the gastrointestinal tract where a significant amount of HIV and SIV replication occurs during the infection. Toward this goal we intend to investigate strategies that should maximize the quality and quantity of immune responses produced by our SIV DNA vaccine in all the compartments of the immune system. The objective of the studies proposed here is to evaluate which of two different formulations of the DNA/MVA vaccine provides the most diverse immune responses when administered orally and the most significant protection from disease progression after viral challenge. Antiviral immunity in the genital tract is not only critical because of the role that these responses can play at the time of sexual exposure to HIV but also because of the role that these responses may play in preventing vertical transmission. The results of such studies should be highly valuable for AIDS vaccine development
Keywords: Acquired Immunodeficiency Syndrome; Acute; Affect; AIDS prevention; AIDS Vaccine Development; AIDS Vaccines; Animals; anti-hepatitis C; Antigens; Antiviral Agents; Cells; Chronic; Control Groups; Country; Data; design; Disease Progression; DNA; DNA Vaccines; DNA/MVA vaccine; Dose; Drug Formulations; Drug or chemical Tissue Distribution; Effectiveness; efficacy evaluation; env Gene Products; Epidemic; Evaluation; Exposure to; Female; Foundations; Funding; Gastrointestinal tract structure; Genital system; Genome; Goals; Grant; Healthcare; Hepatitis C virus; HIV; HIV Infections; HIV/SIV vaccine; Home environment; illness length; Immune response; Immune system; Immunity; Immunization; Immunoglobulin A; Immunoglobulin G; improved; Infection; Intramuscular; Life; Liposomes; Lymphoid; Macaca mulatta; Measures; Mediating; memory CD4 T lymphocyte; Modeling; nonhuman primate; Nose; Oral; Oral Administration; Oral cavity; Organ; particle; Peripheral Blood Mononuclear Cell; plasmid DNA; Plasmids; Play; prevent; Prevention; Primates; Proteins; Recombinants; rectal; Regimen; research study; Resources; response; RNA; Role; Route; Severities; SHIV vaccine; simian human immunodeficiency virus; Site; SIV; SIV Vaccines; Source; Staging; Systemic infection; Testing; Time; tool; transmission process; Vaccinated; Vaccination; vaccine candidate; vaccine evaluation; Vaccines; Vagina; Vertical Disease Transmission; Viral; Viral Antigens; Viral Load result; Viremia; Virus; Virus Replication
Project start date: 2008-05-01
Project end date: 2013-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: RFA-DE-08-003
5R01DE019060-04 (2011): $655327
5R01DE019060-03 (2010): $653698
PATHWAYS OF HIV NEURODEGENERATION AND DIMETHYL FUMARATE (DMF/MMF) NEUROPROTECTION
Aldovini Anna
University Of Pennsylvaniacity: Philadelphia country: United States (us)
Grant 1R01MH095671-01 from National Institute Of Mental Health
Abstract: HIV-associated neurocognitive disorders (HAND) remain prevalent despite the use of antiretroviral therapy (ART), and CNS inflammation & neurodegeneration associated with HIV replication in macrophages/microglia remain as neuropathological features. Persistent systemic inflammation & monocyte activation, CNS inflammation, macrophage activation, correlate with HAND in patients on ART. Thus, although ART is the backbone of HIV therapy, there is a critical need for adjunctive therapies to suppress persistent inflammation and virus replication, and to decrease the high burden of HAND- associated disability. Accordingly, drugs that suppress inflammation and HIV replication systemically and within the CNS are especially attractive as adjunctive neuroprotectants. We are proposing a dual-investigator MPI study (Kolson, Aldvoni) to investigate a novel drug, dimethyl fumarate, (DMF, Fumaderm(R)), now in a phase III clinical trial for multiple sclerosis) as a candidate neuroprotectant for HAND. Using our HIV neurotoxicity model we found that DMF and its primary in vivo metabolite, MMF, suppress a) HIV replication, b) associated inflammatory responses, and c) neurotoxin production in monocyte- derived macrophages (MDM). DMF/MMF also d) induces monocyte antioxidant responses and e) suppresses chemotaxis. In addition, using transcriptome analyses of HIV-infected T lymphocytes and MDM, we also demonstrated that HIV reprograms host gene expression in a cell-dependent manner to modulate pathways of virus spread, inflammatory mediators, and apoptosis, which can intersect pathways of HIV/MDM neurotoxin production & neurodegeneration. Because DMF is orally-deliverable, CNS- penetrating, and minimally toxic, we hypothesize that DMF can be an effective neuroprotectant in HAND and we further hypothesize that transcriptome analyses can identify host pathways modified by DMF/MMF that underlie its neuroprotection. We will 1) Define mechanisms of DMF/MMF suppression of HIV replication and MDM neurotoxin production by HIV replication and Tat expression~ 2) Define DMF/MMF effects on suppression of monocyte & macrophage activation through anti-oxidant responses & other pathways~ 3) Determine mechanisms of DMF/MMF modulation of monocyte chemotaxis & transendothelial migration~ and 4) Determine the ability of DMF/MMF to suppress monocyte activation and induce antioxidant responses in SIV-infected rhesus macaques. This should provide a rationale for a future clinical trial in HIV patients. Chronic inflammation persists in HIV-infected individuals despite systemic suppression of HIV replication by ART. Such inflammation can drive disease progression, both systemically and within the CNS. Dimethylfumarate (DMF) is a safe, effective anti- inflammatory drug (used in Europe to treat psoriasis) with CNS-protective, anti- inflammatory effects in multiple sclerosis patients. We will determine its potential neuroprotective use against HIV with investigations that should lead to a neuroprotection trial in HIV patients
Keywords: Acanthophis antarcticus toxin Aa c; Anti-inflammatory; Anti-Inflammatory Agents; Antioxidants; antiretroviral therapy; Apoptosis; Brain; CCL2 gene; CD14 gene; CD4 Positive T Lymphocytes; Cell Adhesion Molecules; Cells; Chemotaxis; Chronic; Clinical Trials; Controlled Study; CX3CL1 gene; CXCL12 gene; disability; Disease; Disease Progression; Drug Delivery Systems; Drug usage; Elements; Endothelial Cells; Europe; Excitatory Neurotoxins; FCGR3B gene; Fumaderm; Fumarates; Future; Gene Expression; Gene Expression Profile; gene induction; Genes; HIV; HIV Envelope Protein gp120; HIV Infections; HIV therapy; Human; Immune; immune activation; Immune response; In Vitro; in vivo; Individual; Inflammation; Inflammation Mediators; Inflammatory Response; Investigation; Lead; Macaca mulatta; macrophage; Macrophage Activation; Mediating; Microglia; migration; Modeling; monocyte; Multiple Sclerosis; Nerve Degeneration; Neurocognitive; Neuroglia; neuroinflammation; Neurons; Neuropathogenesis; neuroprotection; Neuroprotective Agents; neurotoxicity; Neurotoxins; novel; NQO1 gene; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phase III Clinical Trials; Pilot Projects; Production; Psoriasis; Research Personnel; response; Role; Signal Pathway; SIV; Stromal Cell-Derived Factor 1; T-Lymphocyte; Tissues; Vertebral column; Viral Load result; Virus; Virus Replication
Relevance: Chronic inflammation persists in HIV-infected individuals despite systemic suppression of HIV replication by ART. Such inflammation can drive disease progression, both systemically and within the CNS. Dimethylfumarate (DMF) is a safe, effective anti- inflammatory drug (used in Europe to treat psoriasis) with CNS-protective, anti- inflammatory effects in multiple sclerosis patients. We will determine its potential neuroprotective use against HIV with investigations that should lead to a neuroprotection trial in HIV patients
Project start date: 2011-09-26
Project end date: 2016-05-31
Budget start date: 26-SEP-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-11-014
1R01MH095671-01 (2011): $350816