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Journal of NeuroVirology

, Volume 12, Issue 3, pp 178–189 | Cite as

Cerebrospinal and peripheral human immunodeficiency virus type 1 load in a multisite, randomized, double-blind, placebo-controlled trial of d-Ala1-peptide T-amide for HIV-1-associated cognitive-motor impairment

  • Karl Goodkin
  • Benedetto Vitiello
  • William D. Lyman
  • Deshratn Asthana
  • J. Hampton Atkinson
  • Peter N. R. Heseltine
  • Rebeca Molina
  • Wenli Zheng
  • Imad Khamis
  • Frances L. Wilkie
  • Paul Shapshak
Article

Abstract

d-Ala1-peptide T-amide (DAPTA) has shown neuroprotection in vitro against gp120-induced loss of dendritic arborization and is promulgated as a CCR5 antagonist. A multisite, randomized, double-blind clinical trial of DAPTA versus placebo prior to combination antiretroviral therapy conducted with human immunodeficiency virus (HIV)-1 seropositive participants having cognitive impairment showed no overall cognitive effect, though subgroups with greater impairment and CD4 cell counts of 201 to 500 cells/mm3 at baseline showed significant improvement. The objective of this study was to examine whether intranasal administration of DAPTA at a dose of 2 mg three times per day (tid) was associated with a reduction of cerebrospinal fluid (CSF) and peripheral (plasma and serum) viral load among a subgroup of participants completing 6 months of treatment. Baseline and 6-month CSF (n = 92) and peripheral (plasma n = 33; serum n = 24) viral load were measured by the Roche Ultrasensitive assay, version 1.5, with reflexive use of the AMPLICOR assay and preservation of the blind. A DAPTA treatment indicator variable was tested using generalized linear models on change in viral load. Peripheral load (combined plasma and serum) was significantly reduced in the DAPTA-treated group. No group differences in CSF viral load were found. This retrospective study on a limited subgroup of the original trial sample indicated that DAPTA treatment may reduce peripheral viral load without concomitant CSF effects. Future studies should be undertaken to confirm the existence of this result and the CSF-periphery dissociation observed with respect to HIV-1-associated cognitive-motor impairment.

Keywords

CSF clinical trial cognition DAPTA HIV peptide T viral load 

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References

  1. Antinori A, Giancola ML, Grisetti S, Soldani F, Alba L, Liuzzi G, Amendola A, Capobianchi M, Tozzi V, Perno CF (2002). Factors influencing virological response to antiretroviral drugs in cerebrospinal fluid of advanced HIV-1-infected patients. AIDS 16: 1867–1876.CrossRefPubMedGoogle Scholar
  2. Benton AL (1974). Revised Visual Retention Test: clinical and experimental applications, 4th ed. New York: Psychological Corp.Google Scholar
  3. Brambilla DJ, Jennings C, Morack R, Granger S, Bremer JW (2004). Comparison of the sensitivities of the version 1.5 and version 1.0 ultrasensitive Roche AMPLICOR HIV-1 MONITOR kits at low concentrations of human immunodeficiency virus RNA. J Clin Micro 42: 2819–2820.CrossRefGoogle Scholar
  4. Brenneman DE, Hauser J, Spong CY, Phillips TM, Pert CB, Ruff M (1999). VIP and D-ala-peptide T-amide release chemokines which prevent HIV-1 gp120-induced neuronal death. Brain Res 838: 27–36.CrossRefPubMedGoogle Scholar
  5. Brew BJ, Pemberton L, Ray J (2004). Can the peripheral blood monocyte count be used as a marker of CSF resistance to antiretroviral drugs? J NeuroVirol. 10(Suppl 1): 38–43.PubMedGoogle Scholar
  6. Centers for Disease Control and Prevention (1992). 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mort Weekly Rep 41(No. RR-17): 1–19.Google Scholar
  7. Escobar I, Campo M, Martin J, Fernandez-Shaw C, Pulido F, Rubio R (2003). Factors affecting patient adherence to highly active antiretroviral therapy. Ann Pharmacother 37: 775–781.CrossRefPubMedGoogle Scholar
  8. Erali M, Hillyard DR (1999). Evaluation of the ultrasensitive Roche Amplicor HIV-1 Monitor assay for quantitation of human immunodeficiency type 1 RNA. J clin Micro 37: 792–795.Google Scholar
  9. Gartner S (2000). HIV infection and dementia. Science 287: 602–604.CrossRefPubMedGoogle Scholar
  10. Gisslen M, Fuchs D, Svennerholm B, Hagberg L (1999). Cerebrospinal fluid viral load, intrathecal immunoactivation, and cerebrospinal fluid monocytic cell count in HIV-1 infection. J Acquir Immune Defic Syndr Hum Retrovirol 21: 271–276.Google Scholar
  11. Goodkin K, Shapshak P, Asthana D, Zheng W, Concha M, Wilkie FL, Molina R, Lee D, Suarez P, Symes S, Khamis I (2004). Older age and plasma viral load in HIV-1 infection. AIDS 18(Supp 1): S87-S98.PubMedGoogle Scholar
  12. Goodkin K, Shapshak P, Fujimura RK, Tuttle RS, Bradley WG, Yoshioka M, Nagano I, Xin K, Kumar A, Kumar M, Maher KJ, Asthana D, Fletcher MA (2000). Immune function, brain, and HIV-1 infection. In: Psychoneuroimmunology: stress, mental disorders and health. Goodkin K, Visser APH (eds). Washington, DC: American Psychiatric Press, pp 243–316.Google Scholar
  13. Grober E, Silwinski M, Korey SR (1991). Development and validation of a model for estimating premorbid verbal intelligence in the elderly. J clin Exp Neuropsychol 13: 933–949.CrossRefPubMedGoogle Scholar
  14. Gronwall DMA (1977). Paced Auditory Serial Addition Task: a measure of recovery from concussion. Percept Mot Skills 44: 367–373.PubMedGoogle Scholar
  15. He J, Chen Y, Farzan M, Choe H, Ohagen A, Gartner S, Busciglio J, Yang X, Hofmann W, Newman W, Mackay CR, Sodroski J, Gabuzda D (1997). CCR3 and CCR5 are co-receptors for HIV-1 infection of microglia. Nature 385: 645–649.CrossRefPubMedGoogle Scholar
  16. Heseltine PN, Goodkin K, Atkinson JH, Vitiello B, Rochon J, Heaton RK, Eaton EM, Wilkie FL, Sobel E, Brown SJ, Feaster D, Schneider L, Goldschmidts WL, Stover ES (1998). Randomized double-blind placebo-controlled trial of peptide T for HIV-associated cognitive impairment. Arch Neurol 55: 41–51.CrossRefPubMedGoogle Scholar
  17. Heyes MP, Saito K, Markey SP (1992). Human macrophages convert L-tryptophan into the neurotoxin quinolinic acid. J Biochem 83: 633–635.Google Scholar
  18. Hill JM, Mervis RF, Avidor R, Moody TW, Brenneman DE (1993). HIV envelope protein-induced neuronal damage and retardation of behavioral development in rat neonates. Brain Res 603: 222–233.CrossRefPubMedGoogle Scholar
  19. Hirschhorn L, Beattie A, Davidson D, Agins B (2005). The role of viral load as a measure of the quality of care for people with HIV: the expert meeting report. September 9, 2005. Available from: URL: http://www.hivguidelines.org/public_html/center/quality-of-care/viral-load-report.docGoogle Scholar
  20. Klove H (1963). Clinical neuropsychology. Med Clin No Amer 47: 1647–1658.Google Scholar
  21. Jackson JB, Piwowar-Manning E, Johnson-Lewis L, Bassett R, Demeter LM, Brambilla D (2004). Comparison of versions 1.0 and 1.5 of the ultrasensitive AMPLICOR HIV-1 MONITOR test for subjects with low viral load. J Clin Micro 42: 2774–2776.CrossRefGoogle Scholar
  22. McCullagh P, Nelder JA (1989). Generalized linear models. New York: Chapman & Hall.Google Scholar
  23. Operskalski EA, Mosley JW, Busch MP, Stram DO (1997). Influences of age, viral load and CD4+ count on the rate of progression of HIV-1 infection to AIDS. J AIDS Hum Retrovirol 15: 243–244.Google Scholar
  24. Parker ES, Eaton EM, Whipple SC, Heseltine PNR, Bridge TP (1995). The University of Southern California Repeatable Episodic Memory Test. J Clin Exp Neuropsychol 17: 926–936.CrossRefPubMedGoogle Scholar
  25. Pert CB, Hill JM, Ruff MR, Berman RM, Robey WG, Arthur LO, Ruscetti FW, Farrar WL (1986). Octapeptides deduced from the neuropeptide receptor-like pattern of antigen T4 in brain potently inhibit human immunodeficiency virus receptor binding and T-cell infectivity. Proc Natl Acad Sci U S A 83: 9254–9258.CrossRefPubMedGoogle Scholar
  26. Phipps DJ, MacFadden DK (1996). Inhibition of tumour necrosis factor-alpha explains inhibition of HIV replication by peptide T. AIDS 10: 919–920.CrossRefPubMedGoogle Scholar
  27. Ramsdale TE, Andrews PR, Nice EC (1993). Verification of the interaction between peptide T and CD4 using surface plasmon resonance. FEBS Lett 333: 217–222.CrossRefPubMedGoogle Scholar
  28. Raychaudhuri SP, Farber EM, Raychaudhuri SK (1999). Immunomodulatory effects of peptide T in Th1/Th2 cytokines. Int J Immunopharmacol 21: 609–615.CrossRefPubMedGoogle Scholar
  29. Raychaudhuri SK, Raychaudhuri SP, Farber EM (1998). Anti-chemotactic activities of peptide-T: a possible mechanism of actions for its therapeutic effects on psoriasis. Int J Immunopharmacol. 20: 661–667.CrossRefPubMedGoogle Scholar
  30. Redwine LS, Pert CB, Rone JD, Nixon R, Vance M, Sandler B, Lumpkin MD, Dieter DJ, Ruff MR (1999). Peptide T blocks gp120/CCR5 chemokine receptor-mediated chemotaxis. Clin Immunol 93: 124–131.CrossRefPubMedGoogle Scholar
  31. Reitan RM, Wolfson D. (1985). The Halstead-Reitan Neuropsychological Test Battery: theory and clinical interpretation. Tucson: Neuropsychology Press.Google Scholar
  32. Ruff MR, Melendez-Guerrero LM, Yang QE, Ho WZ, Mikovits JW, Pert CB, Ruscetti FA (2001). Peptide T inhibits HIV-1 infection mediated by the chemokine receptor-5 (CCR5). Antiviral Res 52: 63–75.CrossRefPubMedGoogle Scholar
  33. Ruff MR, Polianova M, Yang QE, Leoung GS, Ruscetti FW, Pert CB (2003). Update on D-ala-peptide T-amide (DAPTA): a viral entry inhibitor that blocks CCR5 chemokine receptors. Curr HIV Res 1: 51–67.CrossRefPubMedGoogle Scholar
  34. Saag MS, Holodniy M, Kuritzkes DR, O’Brien WA, Coombs R, Poscher ME, Jacobsen DM, Shaw GM, Richman DD, Volberding PA (1996). HIV viral load markers in clinical practice. Nature Med 2: 625–629.CrossRefPubMedGoogle Scholar
  35. Sacktor N, Tarwater PM, Skolasky RL, McArthur JC, Selnes OA, Becker J, Cohen B, Miller EN (2001). CSF antiretroviral drug penetrance and the treatment of HIV-associated psychomotor slowing. Neurology 57: 542–544.PubMedGoogle Scholar
  36. Shapshak P, Duncan R, Minagar A, Rodriguez de la Vega P, Stewart RV, Goodkin K (2004). Elevated expression of IFN-gamma in the HIV-1 infected brain. Front Biosci 9: 1073–1081.CrossRefPubMedGoogle Scholar
  37. Singer E, Aronow HA, Lee S-Y, Hinkin CH, Lazarus T (2002). Stability of human immunodeficiency virus type 1 RNA in cerebrospinal fluid determined with the AMPLICOR HIV-1 MONITOR test, version 1.5 (ultrasensitive). J Clin Micro 40: 3863–3864.CrossRefGoogle Scholar
  38. Sodroski J, Kowalski M, Dorfman T, Basiripour L, Rosen C, Haseltine W (1987). HIV envelope-CD4 interaction not inhibited by synthetic octapeptides. Lancet 1: 1428–1429.CrossRefPubMedGoogle Scholar
  39. Sternberg S (1966). High speed scanning in human memory. Science 153: 652–654.CrossRefPubMedGoogle Scholar
  40. Stroop J (1935). Studies of interference in serial verbal reactions. J Exp Psychol 18: 643–662.CrossRefGoogle Scholar
  41. Vandamme A-M, Van Dooren S, Kok W, Goubau P, Fransen K, Kievits T, Schmit J-C, De Clercq E, Desmyter J (1995). Detection of HIV-1 RNA in plasma and serum samples using the NASBA amplification system compared to RNA-PCR. J Virol Methods 52: 121–132.CrossRefPubMedGoogle Scholar
  42. Walczak M, Imielska D, Mackiewicz Z, Kupryszewski G, Dzierzanowska-Madalinska D, Madalinski K (1991). The influence of D-Ala1-peptide T amide, an analogue of HIV glycoprotein 120 fragment, on the CD4—anti CD4 lymphocyte interaction. Arch Immunol Ther Exp 39: 27–31.Google Scholar
  43. Wilkie F (1988). Computer tests for the measurement of speed of information processing. Miami: University of Miami School of Medicine.Google Scholar
  44. Wilkie FL, Eisdorfer C, Morgan R, Loewenstein DA, Szapocznik J (1990). Cognition in early human immunodeficiency virus infection. Arch Neurol 47: 433–440.PubMedGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2006

Authors and Affiliations

  • Karl Goodkin
    • 1
    • 2
  • Benedetto Vitiello
    • 3
  • William D. Lyman
    • 4
    • 5
  • Deshratn Asthana
    • 1
  • J. Hampton Atkinson
    • 6
  • Peter N. R. Heseltine
    • 7
  • Rebeca Molina
    • 1
  • Wenli Zheng
    • 1
  • Imad Khamis
    • 1
  • Frances L. Wilkie
    • 1
  • Paul Shapshak
    • 1
    • 8
  1. 1.Departments of Psychiatry and Behavioral Sciences and of Neurology (M836)University of Miami School of MedicineMiamiUSA
  2. 2.Department of NeurologyUniversity of Miami School of MedicineMiamiUSA
  3. 3.Child and Adolescent Treatment and Preventive Intervention Research BranchNational Institute of Mental HealthBethesdaUSA
  4. 4.Children’s Research Center of MichiganChildren’s Hospital of MichiganDetroitUSA
  5. 5.Department of PediatricsWayne State UniversityDetroitUSA
  6. 6.HIV Neurobehavioral Research Center, Department of PsychiatryUniversity of California at San DiegoSan DiegoUSA
  7. 7.Infectious Diseases DivisionQuest Diagnostics Nichols InstituteSan Juan CapistranoUSA
  8. 8.Department of PathologyUniversity of Miami School of MedicineMiamiUSA

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