AIDS encephalopathy and HIV disease: role of opioids

Summary

Principal Investigator: Robert M Malow
Abstract: [unreadable] DESCRIPTION (provided by applicant): HIV-I infected long-term non progressors (LT-NP), characterized by normal CD4 counts and no HIV related symptoms form least 5-I0 years post infection, represent less than 5% of HIV-I infected patients. However, a significant number of LT-NP progress to AIDS early on, which suggests that in addition to HIV-I, other factors may play a major role in disease progression. For several years we have investigated the premise that drugs of abuse suppress various immune responses that protect the host from HIV infections and progression to AIDS. However ,the role of opioids in the progression of HIV disease in LT-NP has not been clearly elucidated. Among the early efforts, we were also the first to report that intravenous drug users, including opioid users, manifest low NK activity compared to matched control subjects. We further demonstrated that in vivo stereotaxic injection of HIV proteins plus excitatory amino acid agonists into the dorsal hippocampus of neonatal rat brains causes both gross and microscopic neuropathology. These interests merged in a series of preliminary studies demonstrating that opioids potentiate various neuro-immunopathogenic mechanisms mediated by HIV proteins. Thus, we hypothesize that: opioids are cofactors in the pathogenesis of HIV infection in LT-NP acting in svnergy with certain HIV proteins to affect the immune and central nervous systems of the infected host. Several experimental approaches will be used to determine the molecular mechanisms underlying the opioid-mediated neuro-immune-dysfunctions in LT-NP compared to normal progressors (NP) and controls. Total PBMC, cytotoxic T lymphocytes (CTL), dendritic and monocyte subsets from opioid using and non using LT-NP, NP, seronegative opioid users and normal donors will be cultured with [unreadable] HIV-1 (gp-120/tat) or morphine or HIV proteins plus morphine to look for modulation of various immune responses including dysregulation of CTL, dendritic cell functions, cytokines/chcmokines, IL-16, upregulation of HIV entry co-receptors, neurotoxins (matrix mcmlloproteasc-2 and-9,nitric oxide, quinolinic acid)TGF-beta I, apoptosis, STAT-4/6 and CD45 tyrosine phosphatase. Data will be stratified on the basis of HIV disease status, CD4 count, HIV viral RNA copy numbers and opioid use. Further, human brain microvessel endothelial cells, several human CNS cell lines and primary astrocyte and neural progenitor cultures will be used to study the effects of morphine/HIV proteins on adhesion molecules and neurotoxins which help in the transmigration of infected monocytes into the brain. Neurotoxicity will be correlated with the neurotoxin production by treated CNS cells and endothelial ceils. Our preliminary studies show that LT-NP demonstrate that increased IL-16, increased CTL activity and decreased TGF-beta1comparedtoNP. Further studies will elucidate the molecular mechanisms underlying the immune- and neuro-pathogenic effects of opioid in the natural history of HIV disease progression in LT-NP and may ultimately help to define effective therapeutic mechanisms to prolong the disease free state in LT-NP.
Funding Period: 2002-08-20 - 2006-08-31
more information: NIH RePORT

Top Publications

  1. ncbi Human immunodeficiency virus type 1 clade B and C Tat differentially induce indoleamine 2,3-dioxygenase and serotonin in immature dendritic cells: Implications for neuroAIDS
    Thangavel Samikkannu
    Department of Immunology, Institute of Neuroimmune Pharmacology, College of Medicine, Florida International University, Miami, Florida 33199, USA
    J Neurovirol 16:255-63. 2010
  2. ncbi AZT 5'-triphosphate nanoformulation suppresses human immunodeficiency virus type 1 replication in peripheral blood mononuclear cells
    Zainulabedin M Saiyed
    Department of Immunology, College of Medicine, Florida International University, Miami, Florida 33199, USA
    J Neurovirol 15:343-7. 2009
  3. pmc Differential effects of HIV type 1 clade B and clade C Tat protein on expression of proinflammatory and antiinflammatory cytokines by primary monocytes
    Nimisha Gandhi
    Department of Immunology, College of Medicine, Florida International University, Miami, Florida 33199, USA
    AIDS Res Hum Retroviruses 25:691-9. 2009
  4. pmc Upregulation of serotonin transporter by alcohol in human dendritic cells: possible implication in neuroimmune deregulation
    Dakshayani Kadiyala Babu
    Department of Immunology, College of Medicine, Institute of Neuroimmune Pharmacology, Florida International University, Miami, Florida 33199, USA
    Alcohol Clin Exp Res 33:1731-8. 2009
  5. ncbi The role of alcohol on platelets, thymus and cognitive performance among HIV-infected subjects: are they related?
    Maria Jose Miguez-Burbano
    Department of Epidemiology and Public Health, Florida International University, Miami, FL, USA
    Platelets 20:260-7. 2009
  6. pmc Differential regulation of indoleamine-2,3-dioxygenase (IDO) by HIV type 1 clade B and C Tat protein
    Thangavel Samikkannu
    Department of Immunology, College of Medicine, Florida International University, Miami, Florida 33149, USA
    AIDS Res Hum Retroviruses 25:329-35. 2009
  7. pmc Methamphetamine enhances HIV-1 infectivity in monocyte derived dendritic cells
    Madhavan P N Nair
    Department of Immunology, College of Medicine, Florida International University, Miami, FL 33155, USA
    J Neuroimmune Pharmacol 4:129-39. 2009
  8. pmc Proteomic analyses of methamphetamine (METH)-induced differential protein expression by immature dendritic cells (IDC)
    Jessica L Reynolds
    Department of Medicine, Division of Allergy, Immunology and Rheumatology, State University of New York at Buffalo, Buffalo General Hospital, Buffalo, NY 14203, USA
    Biochim Biophys Acta 1774:433-42. 2007
  9. pmc Proteomic analysis of the effects of cocaine on the enhancement of HIV-1 replication in normal human astrocytes (NHA)
    Jessica L Reynolds
    Department of Medicine, Division of Allergy, Immunology and Rheumatology, State University of New York at Buffalo, Buffalo General Hospital, 100 High Street, Buffalo, NY 14203, USA
    Brain Res 1123:226-36. 2006
  10. pmc The flavonoid quercetin inhibits proinflammatory cytokine (tumor necrosis factor alpha) gene expression in normal peripheral blood mononuclear cells via modulation of the NF-kappa beta system
    Madhavan P Nair
    Department of Medicine and Microbiology, Kaleida Health System, Buffalo General Hospital, State University of New York at Buffalo, Buffalo, NY 14203, USA
    Clin Vaccine Immunol 13:319-28. 2006

Scientific Experts

  • M P Nair
  • Jessica L Reynolds
  • Robert M Malow
  • Maria Jose Miguez
  • Thangavel Samikkannu
  • Zainulabedin M Saiyed
  • Supriya D Mahajan
  • Nimisha Gandhi
  • Dakshayani Kadiyala Babu
  • Kurapati V K Rao
  • Jose W Rodriguez
  • K V K Rao
  • Maria Jose Miguez-Burbano
  • Ravikumar Aalinkeel
  • Stanley A Schwartz
  • Shailendra K Saxena
  • Nimisha H Gandhi
  • Joel Fishman
  • Alain Diaz
  • Marina N Papuashvili
  • Zainulabedin Saiyed
  • John E Lewis
  • Samikkannu Thangavel
  • Jose Rodriguez
  • Stanley F Fernandez
  • Ram P Chawda
  • Donald E Sykes
  • Bindukumar B Nair

Detail Information

Publications14

  1. ncbi Human immunodeficiency virus type 1 clade B and C Tat differentially induce indoleamine 2,3-dioxygenase and serotonin in immature dendritic cells: Implications for neuroAIDS
    Thangavel Samikkannu
    Department of Immunology, Institute of Neuroimmune Pharmacology, College of Medicine, Florida International University, Miami, Florida 33199, USA
    J Neurovirol 16:255-63. 2010
    ..These studies suggest that HIV-1 clade B and C Tat proteins may play a differential role in the neuropathogenesis of HIV-associated dementia (HAD) or HIV-associated neurocognitive disorder (HAND)...
  2. ncbi AZT 5'-triphosphate nanoformulation suppresses human immunodeficiency virus type 1 replication in peripheral blood mononuclear cells
    Zainulabedin M Saiyed
    Department of Immunology, College of Medicine, Florida International University, Miami, Florida 33199, USA
    J Neurovirol 15:343-7. 2009
    ..The developed MP-AZTTP nanoformulation can be used for targeting active NRTIs to the brain by application of an external magnetic force and thereby eliminate the brain HIV reservoir and help to treat NeuroAIDS...
  3. pmc Differential effects of HIV type 1 clade B and clade C Tat protein on expression of proinflammatory and antiinflammatory cytokines by primary monocytes
    Nimisha Gandhi
    Department of Immunology, College of Medicine, Florida International University, Miami, Florida 33199, USA
    AIDS Res Hum Retroviruses 25:691-9. 2009
    ..Thus, our result shows for the first time that Tat B and Tat C differentially modulate expression of neuropathogenic molecules that may be correlated with the differences in neuroAIDS manifestation induced by clade-specific infections...
  4. pmc Upregulation of serotonin transporter by alcohol in human dendritic cells: possible implication in neuroimmune deregulation
    Dakshayani Kadiyala Babu
    Department of Immunology, College of Medicine, Institute of Neuroimmune Pharmacology, Florida International University, Miami, Florida 33199, USA
    Alcohol Clin Exp Res 33:1731-8. 2009
    ..We hypothesize that alcohol can modulate SERT and MAO-A expression in DC, leading to reciprocal downregulation of 5-HT in extracellular medium...
  5. ncbi The role of alcohol on platelets, thymus and cognitive performance among HIV-infected subjects: are they related?
    Maria Jose Miguez-Burbano
    Department of Epidemiology and Public Health, Florida International University, Miami, FL, USA
    Platelets 20:260-7. 2009
    ..06). Thymus volume and platelet counts were negatively affected by alcohol and were predictors of cognitive performance and improvements after HAART. These results could have important clinical and therapeutic implications...
  6. pmc Differential regulation of indoleamine-2,3-dioxygenase (IDO) by HIV type 1 clade B and C Tat protein
    Thangavel Samikkannu
    Department of Immunology, College of Medicine, Florida International University, Miami, Florida 33149, USA
    AIDS Res Hum Retroviruses 25:329-35. 2009
    ..These results provide further evidence that the prevalence of HAD may be correlated with the difference in clades of HIV-1...
  7. pmc Methamphetamine enhances HIV-1 infectivity in monocyte derived dendritic cells
    Madhavan P N Nair
    Department of Immunology, College of Medicine, Florida International University, Miami, FL 33155, USA
    J Neuroimmune Pharmacol 4:129-39. 2009
    ....
  8. pmc Proteomic analyses of methamphetamine (METH)-induced differential protein expression by immature dendritic cells (IDC)
    Jessica L Reynolds
    Department of Medicine, Division of Allergy, Immunology and Rheumatology, State University of New York at Buffalo, Buffalo General Hospital, Buffalo, NY 14203, USA
    Biochim Biophys Acta 1774:433-42. 2007
    ..Identification of unique, METH-induced proteins may help to develop novel markers for diagnostic, preventive and therapeutic targeting in METH using subjects...
  9. pmc Proteomic analysis of the effects of cocaine on the enhancement of HIV-1 replication in normal human astrocytes (NHA)
    Jessica L Reynolds
    Department of Medicine, Division of Allergy, Immunology and Rheumatology, State University of New York at Buffalo, Buffalo General Hospital, 100 High Street, Buffalo, NY 14203, USA
    Brain Res 1123:226-36. 2006
    ..Further, our results show for the first time that cocaine differentially regulates the expression of a number of proteins by NHA that may play a role in the neuropathogenesis of HIV-1 disease...
  10. pmc The flavonoid quercetin inhibits proinflammatory cytokine (tumor necrosis factor alpha) gene expression in normal peripheral blood mononuclear cells via modulation of the NF-kappa beta system
    Madhavan P Nair
    Department of Medicine and Microbiology, Kaleida Health System, Buffalo General Hospital, State University of New York at Buffalo, Buffalo, NY 14203, USA
    Clin Vaccine Immunol 13:319-28. 2006
    ..Our results provide direct evidence of the anti-inflammatory effects of quercetin by PBMC, which are mediated by the inhibition of the proinflammatory cytokine TNF-alpha via modulation of NF-kappabeta1 and Ikappabeta...
  11. ncbi Morphine exacerbates HIV-1 viral protein gp120 induced modulation of chemokine gene expression in U373 astrocytoma cells
    Supriya D Mahajan
    Department of Medicine, Division of Allergy, Immunology, and Rheumatology, State University of New York and Buffalo General Hospital, Kaleida Health, 100 High Street, Buffalo, NY 14203, USA
    Curr HIV Res 3:277-88. 2005
    ....
  12. ncbi Cocaine modulates dendritic cell-specific C type intercellular adhesion molecule-3-grabbing nonintegrin expression by dendritic cells in HIV-1 patients
    Madhavan P N Nair
    Department of Medicine, Division of Allergy, Immunology, and Rheumatology, State University of New York and Buffalo General Hospital, 14203, USA
    J Immunol 174:6617-26. 2005
    ..A better understanding of the role of DC-SIGN in HIV infection may help to design novel therapeutic strategies against the progression of HIV disease in the drug-using population...
  13. ncbi Morphine modulates chemokine gene regulation in normal human astrocytes
    Supriya D Mahajan
    Department of Medicine, Division of Allergy, Immunology, and Rheumatology, State University of New York and Buffalo General Hospital, 310 Multi Research Building, Kaleida Health, 100 High Street, Buffalo, NY 14203, USA
    Clin Immunol 115:323-32. 2005
    ..These results support our hypothesis that opiates act as co-factors in the neuropathogenesis of HIV infection...