Polymorphisms of the Kappa Opioid Receptor and Prodynorphin Genes: HIV Risk and HIV Natural History

Objective:Studies indicate cross-desensitization between opioid receptors (eg, kappa opioid receptor, OPRK1) and chemokine receptors (eg, CXCR4) involved in HIV infection. Whether gene variants of OPRK1 and its ligand, prodynorphin (PDYN), influence the outcome of HIV therapy was tested. Methods:Three study points, admission to the Women's Interagency HIV Study, initiation of highly active antiretroviral therapy (HAART), and the most recent visit, were chosen for analysis as crucial events in the clinical history of the HIV patients. Regression analyses of 17 variants of OPRK1 and 11 variants of PDYN with change of viral load (VL) and CD4 count between admission and initiation of HAART and initiation of HAART to the most recent visit to Women's Interagency HIV Study were performed in 598 HIV+ subjects, including African Americans, Hispanics, and Whites. Association with HIV status was done in 1009 subjects. Results:Before HAART, greater VL decline (improvement) in carriers of PDYN IVS3+189C>T and greater increase of CD4 count (improvement) in carriers of OPRK −72C>T were found in African Americans. Also, greater increase of CD4 count in carriers of OPRK1 IVS2+7886A>G and greater decline of CD4 count (deterioration) in carriers of OPRK1 −1205G>A were found in Whites. After HAART, greater decline of VL in carriers of OPRK1 IVS2+2225G>A and greater increase of VL in carriers of OPRK1 IVS2+10658G>T and IVS2+10963A>G were found in Whites. Also, a lesser increase of CD4 count was found in Hispanic carriers of OPRK1 IVS2+2225G>A. Conclusions:OPRK1 and PDYN polymorphisms may alter severity of HIV infection and response to treatment.

[1]  J. Ott,et al.  Association of polymorphisms of the mu opioid receptor gene with the severity of HIV infection and response to HIV treatment. , 2012, The Journal of infectious diseases.

[2]  Anna B. Rachlin,et al.  Blockade of kappa opioid receptors attenuates the development of depressive-like behaviors induced by cocaine withdrawal in rats , 2012, Neuropharmacology.

[3]  K. Anastos,et al.  A C17T polymorphism in the mu opiate receptor is associated with quantitative measures of drug use in African American women , 2012, Addiction biology.

[4]  E. Meloni,et al.  Kappa Opioid Receptor Signaling in the Basolateral Amygdala Regulates Conditioned Fear and Anxiety in Rats , 2011, Biological Psychiatry.

[5]  Y. S. Zhu,et al.  Association between heroin dependence and prodynorphin gene polymorphisms , 2011, Brain Research Bulletin.

[6]  G. Bakalkin,et al.  Prodynorphin promoter SNP associated with alcohol dependence forms noncanonical AP-1 binding site that may influence gene expression in human brain , 2011, Brain Research.

[7]  V. Yuferov,et al.  Cell‐specific effects of variants of the 68‐base pair tandem repeat on prodynorphin gene promoter activity , 2011, Addiction biology.

[8]  G. Bardi,et al.  Protein Kinase Cζ Mediates μ-Opioid Receptor-induced Cross-desensitization of Chemokine Receptor CCR5* , 2011, The Journal of Biological Chemistry.

[9]  J. Ott,et al.  Association of polymorphisms of the cannabinoid receptor (CNR1) and fatty acid amide hydrolase (FAAH) genes with heroin addiction: impact of long repeats of CNR1 , 2010, The Pharmacogenomics Journal.

[10]  K. Shianna,et al.  Host determinants of HIV-1 control in African Americans. , 2010, The Journal of infectious diseases.

[11]  G. Wray,et al.  Multiple Functional Variants in cis Modulate PDYN Expression. , 2010, Molecular biology and evolution.

[12]  T. Isowa,et al.  Association of polymorphism in the human μ-opioid receptor OPRM1 gene with proinflammatory cytokine levels and health perception , 2009, Brain, Behavior, and Immunity.

[13]  Tao Li,et al.  GENETIC STUDY: An association of prodynorphin polymorphisms and opioid dependence in females in a Chinese population , 2009, Addiction biology.

[14]  Mardge H. Cohen,et al.  CYP1A1 genotype modifies the impact of smoking on effectiveness of HAART among women. , 2009, AIDS education and prevention : official publication of the International Society for AIDS Education.

[15]  Michael Wagner,et al.  Gene polymorphisms in prodynorphin (PDYN) are associated with episodic memory in the elderly , 2009, Journal of neural transmission.

[16]  M. Finley,et al.  Bi-directional heterologous desensitization between the major HIV-1 co-receptor CXCR4 and the κ-opioid receptor , 2008, Journal of Neuroimmunology.

[17]  Mardge H. Cohen,et al.  Crack cocaine, disease progression, and mortality in a multicenter cohort of HIV-1 positive women , 2008, AIDS.

[18]  J. Gelernter,et al.  The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk , 2008, Molecular Psychiatry.

[19]  G. Gerra,et al.  Human Kappa opioid receptor gene (OPRK1) polymorphism is associated with opiate addiction , 2007, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[20]  J. Ott,et al.  GENETIC STUDY: Prodynorphin gene promoter repeat associated with cocaine/alcohol codependence , 2007, Addiction biology.

[21]  Jacques Fellay,et al.  A Whole-Genome Association Study of Major Determinants for Host Control of HIV-1 , 2007, Science.

[22]  L. Bierut,et al.  Association of the κ-opioid system with alcohol dependence , 2006, Molecular Psychiatry.

[23]  J. Oppenheim,et al.  Crosstalk between chemokines and neuronal receptors bridges immune and nervous systems , 2005, Journal of leukocyte biology.

[24]  D. Oslin,et al.  Confirmation of the association between a polymorphism in the promoter region of the prodynorphin gene and cocaine dependence , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[25]  David Vlahov,et al.  The role of substance abuse in HIV disease progression: reconciling differences from laboratory and epidemiologic investigations. , 2005, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[26]  D. Vlahov,et al.  The relationship between non-injection drug use behaviors on progression to AIDS and death in a cohort of HIV seropositive women in the era of highly active antiretroviral therapy use. , 2005, Addiction.

[27]  J. Ott,et al.  Redefinition of the human kappa opioid receptor gene (OPRK1) structure and association of haplotypes with opiate addiction. , 2004, Pharmacogenetics.

[28]  J. Bidlack,et al.  κ-Opioid Receptor Ligands Inhibit Cocaine-Induced HIV-1 Expression in Microglial Cells , 2004, Journal of Pharmacology and Experimental Therapeutics.

[29]  G. Rogers,et al.  Depressive disorders and unprotected casual anal sex among Australian homosexually active men in primary care , 2003, HIV medicine.

[30]  T. Rogers,et al.  μ-opioid modulation of HIV-1 coreceptor expressionand HIV-1 replication , 2003 .

[31]  T. Rogers,et al.  Ca2+-independent Protein Kinase Cs Mediate Heterologous Desensitization of Leukocyte Chemokine Receptors by Opioid Receptors* , 2003, The Journal of Biological Chemistry.

[32]  P. Peterson,et al.  Opioid G protein-coupled receptors: signals at the crossroads of inflammation. , 2003, Trends in immunology.

[33]  M. Adler,et al.  Heterologous desensitization of opioid receptors by chemokines inhibits chemotaxis and enhances the perception of pain , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[34]  P. Peterson,et al.  Kappa-opioid receptor agonist inhibition of HIV-1 envelope glycoprotein-mediated membrane fusion and CXCR4 expression on CD4(+) lymphocytes. , 2002, Biochemical pharmacology.

[35]  P. Portoghese,et al.  Kappa-opioid receptor agonist suppression of HIV-1 expression in CD4+ lymphocytes. , 2001, Biochemical pharmacology.

[36]  E Rauch,et al.  An Allelic Variation in the Human Prodynorphin Gene Promoter Alters Stimulus‐Induced Expression , 2000, Journal of neurochemistry.

[37]  T. Rogers,et al.  Bidirectional Heterologous Desensitization of Opioid and Chemokine Receptors , 2000, Annals of the New York Academy of Sciences.

[38]  J J Goedert,et al.  Consistent associations of HLA class I and II and transporter gene products with progression of human immunodeficiency virus type 1 infection in homosexual men. , 1999, The Journal of infectious diseases.

[39]  D. Taub,et al.  Opiates transdeactivate chemokine receptors: delta and mu opiate receptor-mediated heterologous desensitization. , 1998 .

[40]  P. O’Connell,et al.  Genealogy of the CCR5 locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression , 1998, Nature Medicine.

[41]  J J Goedert,et al.  Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study. , 1997, Science.

[42]  J W Mulder,et al.  Virologic and immunologic benefits of initial combination therapy with zidovudine and zalcitabine or didanosine compared with zidovudine monotherapy. Wellcome Resistance Study Collaborative Group. , 1996, The Journal of infectious diseases.

[43]  J. Goedert,et al.  Influence of combinations of human major histocompatibility complex genes on the course of HIV–1 infection , 1996, Nature Medicine.

[44]  R. Gelber,et al.  Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. , 1994, The New England journal of medicine.

[45]  A. Abdul-Quader,et al.  Contrasting prevalence of delta hepatitis markers in parenteral drug abusers with and without AIDS. , 1990, The Journal of infectious diseases.

[46]  D. Vlahov,et al.  Cocaine injection and ethnicity in parenteral drug users during the early years of the human immunodeficiency virus (hiv) epidemic in new york city , 1989, Journal of medical virology.

[47]  M. Kreek,et al.  HIV-1 infection among intravenous drug users in Manhattan, New York City, from 1977 through 1987 , 1989 .

[48]  L. Bierut,et al.  Association of the kappa-opioid system with alcohol dependence. , 2006, Molecular psychiatry.

[49]  T. Rogers,et al.  Mu-opioid modulation of HIV-1 coreceptor expression and HIV-1 replication. , 2003, Virology.

[50]  R. Harrigan.  Measuring viral load in the clinical setting. , 1995, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[51]  H. Bessler,et al.  Beta-endorphin modulation of IL-1-induced IL-2 production. , 1990, Immunopharmacology.

[52]  M. Kreek,et al.  Antibody to LAV, the putative agent of AIDS, in parenteral drug abusers and methadone-maintained patients: therapeutic, historical, and ethical aspects. , 1986, NIDA research monograph.