Login Register Cart 0
Generic placeholder image

Current HIV Research

Editor-in-Chief

ISSN (Print): 1570-162X
ISSN (Online): 1873-4251

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Drug Use is Associated with Anti-CD4 IgG-mediated CD4+ T Cell Death and Poor CD4+ T Cell Recovery in Viral-suppressive HIV-infected Individuals Under Antiretroviral Therapy

Author(s): Wei Jiang*, Zhenwu Luo, Lisa Martin, Zhuang Wan, Pingfu Fu, Amanda Wagner, Binhua Ling, Sonya L. Heath, Azizul Haque and Aimee McRae-Clark

Volume 16, Issue 2, 2018

Page: [143 - 150] Pages: 8

DOI: 10.2174/1570162X16666180703151208

Price: $65

Abstract

Background: The role and mechanism of drug use or abuse in Antiretroviral Therapy (ART)-treated HIV disease are not completely known.

Methods: To investigate the impact of drug use on HIV pathogenesis without confounding by HIV replication and ART adherence, we first analyzed the data from our clinical database in 103 HIV+ subjects with viral-suppressed ART treatment by a multiple regression test.

Results: We found that HIV+ drug users had lower CD4+ T cell counts but higher CD8+ T cell counts compared to HIV+ non-drug users, and both drug use and nadir CD4+ T cell counts was independently associated with CD4+ T cell recovery after controlling for sex and age. Next, we enrolled individuals from four study groups, HIV-negative and HIV+ subjects without any substance use, HIV-negative and HIV+ subjects with current illicit drug use (either non-injection cocaine or cannabis). All HIV+ subjects were viral-suppressed with ART treatment (≥ 2 years). Notably, HIV+ drug users had increased plasma anti-CD4 IgG levels compared to the other three study groups which were inversely correlated with decreased CD4+ T cell counts only in HIV+ drug users. There was a significant increase in CD4+ T cell recovery following ART in HIV+ non-drug users but not in HIV+ drug users. Anti-CD4 IgGs purified from plasma of HIV+ drug users induced CD4+ T cell death in vitro through Antibody-Dependent Cytotoxicity (ADCC).

Conclusion: These results suggest that drug use prevents immune reconstitution in HIV-infected individuals despite long-term ART treatment and viral suppression.

Keywords: HIV, drug use, antiretroviral therapy, anti-CD4 IgG, CD4+ T cell recovery, antibody-dependent cytotoxicity.

« Previous Next »
Graphical Abstract

[1]
Donnell D, Baeten JM, Kiarie J, et al. Heterosexual HIV-1 transmission after initiation of antiretroviral therapy: A prospective cohort analysis. The Lancet 2010; 375(9731): 2092-8.
[2]
Mocroft A, Phillips AN, Gatell J, et al. Normalisation of CD4 counts in patients with HIV-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study. The Lancet 2007; 370(9585): 407-13.
[3]
Battegay M, Nüesch R, Hirschel B, Kaufmann GR. Immunological recovery and antiretroviral therapy in HIV-1 infection. The Lancet Infect Dis 2006; 6(5): 280-7.
[4]
Kaufmann GR, Furrer H, Ledergerber B, et al. Characteristics, Determinants, and clinical relevance of CD4 T cell recovery to< 500 cells/µL in HIV type 1—infected individuals receiving potent antiretroviral therapy. Clin Infect Dis 2005; 41(3): 361-72.
[5]
Guihot A, Bourgarit A, Carcelain G, Autran B. Immune reconsti-tution after a decade of combined antiretroviral therapies for human immunodeficiency virus. Trends Immunol 2011; 32(3): 131-7.
[6]
Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS (London, England) 2008; 22(7): 841.
[7]
El-Sadr W, Lundgren JD, Neaton J, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006; 355(22): 2283-96.
[8]
Silverberg MJ, Neuhaus J, Bower M, et al. Risk of cancers during interrupted antiretroviral therapy in the SMART study. AIDS 2007; 21(14): 1957-63.
[9]
Lapadula G, Cozzi-Lepri A, Marchetti G, et al. Risk of clinical progression among patients with immunological nonresponse despite virological suppression after combination antiretroviral treatment. AIDS 2013; 27(5): 769-79.
[10]
Monforte Ad, Abrams D, Pradier C, et al. HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies. AIDS 2008; 22(16): 2143-53.
[11]
Lederman MM, Calabrese L, Funderburg NT, et al. Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells. J Infect Dis 2011; 204(8): 1217-26.
[12]
Hunt PW, Brenchley J, Sinclair E, et al. Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis 2008; 197(1): 126-33.
[13]
Doitsh G, Cavrois M, Lassen KG, et al. Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue. Cell 2010; 143(5): 789-801.
[14]
Grossman Z, Meier-Schellersheim M, Paul WE, Picker LJ. Pathogenesis of HIV infection: what the virus spares is as important as what it destroys. Nat Med 2006; 12(3): 289-95.
[15]
Day CL, Kaufmann DE, Kiepiela P, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006; 443(7109): 350-4.
[16]
Doitsh G, Galloway NL, Geng X, et al. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection. Nature 2014; 505(7484): 509-14.
[17]
Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin M, Roederer M. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 2005; 434(7037): 1093-7.
[18]
Okoy AA, Picker LJ. CD4(+) T-cell depletion in HIV infection: mechanisms of immunological failure. Immunol Rev 2013; 254(1): 54-64.
[19]
Kuwata T, Nishimura Y, Whitted S, et al. Association of progressive CD4(+) T cell decline in SIV infection with the induction of autoreactive antibodies. PLoS Pathog 2009; 5(4): e1000372.
[20]
Brenchley JM, Price DA, Schacker TW. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006; 12(12): 1365-71.
[21]
Meng J, Yu H, Ma J, et al. Morphine induces bacterial translocation in mice by compromising intestinal barrier function in a TLR-dependent manner. PLoS One 2013; 8(1): e54040.
[22]
Banerjee S, Sindberg G, Wang F, et al. Opioid-induced gut microbial disruption and bile dysregulation leads to gut barrier compromise and sustained systemic inflammation. Mucosal Immunol 2016; 9(6): 1418-28.
[23]
Anthony IC, Arango JC, Stephens B, Simmonds P, Bell JE. The effects of illicit drugs on the HIV infected brain. Front Biosci 2008; 13: 1294-307.
[24]
Bell JE, Brettle RP, Chiswick A, Simmonds P. HIV encephalitis, proviral load and dementia in drug users and homosexuals with AIDS. Effect of neocortical involvement. Brain 1998; 121: 2043-52.
[25]
Silverstein PS, Shah A, Gupte R. Methamphetamine toxicity and its implications during HIV-1 infection. J Neurovirol 2011; 17(5): 401-15.
[26]
Gaskill PJ, Calderon TM, Coley JS, Berman JW. Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND. J Neuroimmune Pharmacol 2013; 8(3): 621-42.
[27]
Meyer VJ, Little DM, Fitzgerald DA, et al. Crack cocaine use impairs anterior cingulate and prefrontal cortex function in women with HIV infection. J Neurovirol 2014; 20(4): 352-61.
[28]
Baum MK, Campa A, Page JB, et al. Recruitment, follow-up and characteristics of HIV infected adults who use illicit drugs in Southern Africa. J Drug Abuse 2015; 1: 1.
[29]
Tyagi M, Weber J, Bukrinsky M, Simon GL. The effects of cocaine on HIV transcription. J Neurovirol 2016; 22(3): 261-74.
[30]
Ellis RJ, Childers ME, Cherner M, Lazzaretto D, Letendre S, Grant I. HIV Neurobehavioral Research Center Group. Increased human immunodeficiency virus loads in active methamphetamine users are explained by reduced effectiveness of antiretroviral therapy. J Infect Dis 2003; 188(12): 1820-6.
[31]
Fairbairn N, Kerr T, Milloy MJ, Zhang R, Montaner J, Wood E. Crystal methamphetamine injection predicts slower HIV RNA suppression among injection drug users. Addict Behav 2011; 36(7): 762-3.
[32]
Cook JA, Grey DD, Burke-Miller JK, et al. Illicit drug use, depression and their association with highly active antiretroviral therapy in HIV-positive women. Drug Alcohol Depend 2007; 89(1): 74-81.
[33]
Passaro RC, Pandhare J, Qian HZ, Dash C. The complex interaction between methamphetamine abuse and HIV-1 pathogenesis. J Neuroimmune Pharmacol 2015; 10(3): 477-86.
[34]
Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998; 59(20): 22-33.
[35]
First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV-TR Axis I disorders, research version, patient edition (SCID-I/P). New York: Biometrics Research, New York State Psychiatric Institute 2002.
[36]
Toneatto A, Sobell LC, Sobell MB. Gender issues in the treatment of abusers of alcohol, nicotine, and other drugs. J Subst Abuse 1992; 4(2): 209-18.
[37]
Skinner HA. The drug abuse screening test. Addict Behav 1982; 7(4): 363-71.
[38]
Gavin DR, Ross HE, Skinner HA. Diagnostic validity of the drug abuse screening test in the assessment of DSM-III drug disorders. Br J Addict 1989; 84(3): 301-7.
[39]
Luo ZW, Li Z, Martin L, et al. Pathological role of anti-CD4 antibodies in HIV-infected immunologic non-responders under viral suppressive antiretroviral therapy. J Infect Dis 2017; 216(1): 82-91.
[40]
Rothman KJ. No adjustments are needed for multiple comparisons. Epidemiology 1990; 1(1): 43-6.
[41]
Meier A, Chang JJ, Chan ES, et al. Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1. Nat Med 2009; 15(8): 955-9.
[42]
Means AR, Risher KA, Ujeneza EL, Maposa I, Nondi J, Bellan SE. Impact of age and sex on CD4+ cell count trajectories following treatment initiation: An analysis of the tanzanian HIV treatment database. PLoS One 2016; 11(10): e0164148.
[43]
Negredo E, Massanella M, Puig J, et al. Nadir CD4 T cell count as predictor and high CD4 T cell intrinsic apoptosis as final mechanism of poor CD4 T cell recovery in virologically suppressed HIV-infected patients: clinical implications. Clinical infectious diseases: An official publication of the Infectious Diseases Society of America 2010; 50(9): 1300-8.
[44]
Baker JV, Peng G, Rapkin J, et al. Community Programs for Clinical Research on, A., CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS 2008; 22(7): 841-8.
[45]
Lewden C, Chene G, Morlat P, et al. Agence nationale de recherches sur le Sida et les hepatites virales, C.O.A.-C.S.G.; agence nationale de recherches sur le Sida et les hepatites virales, C.O.A.S.G., HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr 2007; 46(1): 72-7.
[46]
Gutierrez F, Padilla S, Masia M, et al. Patients’ characteristics and clinical implications of suboptimal CD4 T-cell gains after 1 year of successful antiretroviral therapy. Curr HIV Res 2008; 6(2): 100-7.
[47]
Parsons JT, Kowalczyk WJ, Botsko M, Tomassilli J, Golub SA. Aggregate versus day level association between methamphetamine use and HIV medication non-adherence among gay and bisexual men. AIDS Behav 2013; 17(4): 1478-87.
[48]
Marquez C, Mitchell SJ, Hare CB, John M, Klausner JD. Methamphetamine use, sexual activity, patient-provider communication, and medication adherence among HIV-infected patients in care, San Francisco 2004-2006. AIDS Care 2009; 21(5): 575-82.
[49]
Valdez H, Connick E, Smith KY, et al. Limited immune restoration after 3 years’ suppression of HIV-1 replication in patients with moderately advanced disease. AIDS 2002; 16(14): 1859-66.
[50]
Hunt PW, Martin JN, Sinclair E, et al. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis 2003; 187(10): 1534-43.
[51]
Landay A, Benning L, Bremer J, et al. Correlates of immune activation marker changes in human immunodeficiency virus (HIV)-seropositive and high-risk HIV-seronegative women who use illicit drugs. J Infect Dis 2003; 188(2): 209-18.
[52]
Cescon A, Chan K, Raboud JM, et al. Significant differences in clinical outcomes between HIV-hepatitis C virus coinfected individuals with and without injection drug use history. AIDS 2014; 28(1): 121-7.
[53]
Engsig FN, Zangerle R, Katsarou O, et al. Long-term mortality in HIV-positive individuals virally suppressed for >3 years with incomplete CD4 recovery. Clin Infect Dis 2014; 58(9): 1312-21.
[54]
Wang X, Ho WZ. Drugs of abuse and HIV infection/replication: implications for mother-fetus transmission. Life Sci 2011; 88(21-22): 972-9.
[55]
Mantri CK, Mantri JV, Pandhare J, Dash C. Methamphetamine inhibits HIV-1 replication in CD4+ T cells by modulating anti-HIV-1 miRNA expression. Am J Pathol 2014; 184(1): 92-100.
[56]
Suzuki S, Carlos MP, Chuang LF, Torres JV, Doi RH, Chuang RY. Methadone induces CCR5 and promotes AIDS virus infection. FEBS Lett 2002; 519(1-3): 173-7.
[57]
Pandhare J, Addai AB, Mantri CK, et al. Cocaine enhances HIV-1-induced CD4(+) T-cell apoptosis: implications in disease progression in cocaine-abusing HIV-1 patients. Am J Pathol 2014; 184(4): 927-36.
[58]
Mahajan SD, Aalinkeel R, Sykes DE. Methamphetamine alters blood brain barrier permeability via the modulation of tight junction expression: Implication for HIV-1 neuropathogenesis in the context of drug abuse. Brain Res 2008; 1203: 133-48.
[59]
Ahmed SH, Lutjens R, van der Stap LD. Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction. Proc Natl Acad Sci USA 2005; 102(32): 11533-8.
[60]
Piechota M, Korostynski M. Solecki, The dissection of transcriptional modules regulated by various drugs of abuse in the mouse striatum. Genome Biol 2010; 11(5): R48.
[61]
Dalvi P, Wang K, Mermis J, et al. HIV-1/cocaine induced oxidative stress disrupts tight junction protein-1 in human pulmonary microvascular endothelial cells: role of Ras/ERK1/2 pathway. PLoS One 2014; 9(1): e85246.
[62]
Poon HF, Abdullah L, Mullan MA, Mullan MJ, Crawford FC. Cocaine-induced oxidative stress precedes cell death in human neuronal progenitor cells. Neurochem Int 2007; 50(1): 69-73.
[63]
Sindberg GM, Sharma U, Banerjee S, et al. An infectious murine model for studying the systemic effects of opioids on early HIV pathogenesis in the gut. J Neuroimmune Pharmacol 2015; 10(1): 74-87.
[64]
Meng J, Sindberg GM, Roy S. Disruption of gut homeostasis by opioids accelerates HIV disease progression. Front Microbiol 2015; 6: 643.
[65]
Funderburg N, Luciano AA, Jiang W, Rodriguez B, Sieg SF, Lederman MM. Toll-like receptor ligands induce human T cell activation and death, a model for HIV pathogenesis. PLoS One 2008; 3(4): e1915.
[66]
Jiang W, Lederman MM, Hunt P, et al. Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis 2009; 199(8): 1177-85.
[67]
Jiang W, Younes SA, Funderburg NT, et al. Cycling memory CD4+ T cells in HIV disease have a diverse T cell receptor repertoire and a phenotype consistent with bystander activation. J Virol 2014; 88(10): 5369-80.
[68]
Bai L, Zhang Z, Zhang H, et al. HIV-1 Tat protein alter the tight junction integrity and function of retinal pigment epithelium: an in vitro study. BMC Infect Dis 2008; 8: 77.
[69]
Nazli A, Chan O, Dobson-Belaire WN, et al. Exposure to HIV-1 directly impairs mucosal epithelial barrier integrity allowing microbial translocation. PLoS Pathog 2010; 6(4): e1000852.

Rights & Permissions Print Cite
Article Metrics
23
5
© 2024 Bentham Science Publishers | Privacy Policy