Immunomodulation Induced by Tucaresol in HIV Infection: Results of a 16 Week Pilot Phase I/II Trial

Objective Immune reconstitution in highly active anti-retroviral therapy (HAART)-treated individuals is incomplete and immunomodulatory compounds are needed to improve the outcome of HIV therapy. In a Phase I/II clinical trial performed on HIV-positive patients we analysed the safety and immunomodulating effects of tucaresol, a novel compound that has previously been described to enhance cell-mediated immune responses. Patients and methods Sixteen weeks pulse dose escalation protocol. Four groups of HIV-positive patients were enrolled: group A (n=6): HAART, CD4+ 300–500 cells/μl, HIV RNA <80 copies/ml; group B (n=6): HAART-naive, CD4+ <500 cells/μl, HIV RNA >10 000 copies/ml; group C (n=3): HAART-naive, CD4+ >500 cells/μl, HIV RNA <10 000 copies/ml; and group D (n=6): HAART, CD4+ <200 cells/μl, HIV RNA <80 copies/ml. Tucaresol was added to HAART in group A and D patients; group B patients started tucaresol with HAART, group C patients received tucaresol alone. Clinical and immunological analyses were performed at different time points. Results Tucaresol-related serious adverse events were observed in the first week of therapy in 2/21 patients who were viraemic when commencing treatment, but did not occur in patients on stable HAART. Tucaresol did not affect HIV viraemia whereas increases in CD4+ percentages, mainly supported by naive CD4+ cells, were observed. CD8+/28-/45RA+ cells and HIV-specific CD8+ IFNγ- and perforin-producing cells improved whereas IL-10 mRNA diminished in tucaresol-treated patients. The effects were greater with 25 mg given every other day for 1 week. Conclusion In HAART-receiving patients with proper virus suppression, tucaresol was not associated with serious adverse events and resulted in qualitative and quantitative stimulation of HIV-specific cytotoxic T lymphocyte activity and generation of naive T cells. These data may support further exploration of tucaresol use in reconstitution of immune system parameters in HIV patients with proper virus suppression while on HAART.

[1]  A. Frey,et al.  CD8+ Tumor-Infiltrating T Cells Are Deficient in Perforin-Mediated Cytolytic Activity Due to Defective Microtubule-Organizing Center Mobilization and Lytic Granule Exocytosis , 2001, The Journal of Immunology.

[2]  C. Harding,et al.  Processing of Exogenous Antigens for Presentation by Class I MHC Molecules Involves Post-Golgi Peptide Exchange Influenced by Peptide-MHC Complex Stability and Acidic pH1 , 2001, The Journal of Immunology.

[3]  J. Lifson,et al.  MHC-I–restricted presentation of HIV-1 virion antigens without viral replication , 2001, Nature Medicine.

[4]  M. Clerici,et al.  In vitro immunomodulatory properties of tucaresol in HIV infection. , 2000, Clinical immunology.

[5]  A. Masci,et al.  Mucosal and systemic immune activation is present in human immunodeficiency virus-exposed seronegative women. , 2000, The Journal of infectious diseases.

[6]  Douglas D. Richman,et al.  HIV-Specific Cd8+ T Cells Produce Antiviral Cytokines but Are Impaired in Cytolytic Function , 2000, The Journal of experimental medicine.

[7]  R. Maserati,et al.  Different immunologic profiles characterize HIV infection in highly active antiretroviral therapy-treated and antiretroviral-naïve patients with undetectable viraemia , 2000, AIDS.

[8]  J. Reimann,et al.  Alternative pathways for processing exogenous and endogenous antigens that can generate peptides for MHC class I‐restricted presentation , 1999, Immunological reviews.

[9]  D. Nixon,et al.  Changes in frequency of HIV-1-specific cytotoxic T cell precursors and circulating effectors after combination antiretroviral therapy in children. , 1999, The Journal of infectious diseases.

[10]  J. Lieberman,et al.  Perforin is not co-expressed with granzyme A within cytotoxic granules in CD8 T lymphocytes present in lymphoid tissue during chronic HIV infection. , 1999, AIDS.

[11]  J. Phair.  Determinants of the natural history of human immunodeficiency virus type 1 infection. , 1999, The Journal of infectious diseases.

[12]  D. Montefiori,et al.  Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. , 1999, Science.

[13]  T. Merigan,et al.  Frequency of class I HLA-restricted anti-HIV CD8+ T cells in individuals receiving highly active antiretroviral therapy (HAART). , 1999, Journal of immunology.

[14]  R. Reichman,et al.  Highly active antiretroviral therapy results in a decrease in CD8+ T cell activation and preferential reconstitution of the peripheral CD4+ T cell population with memory rather than naive cells. , 1998, Antiviral research.

[15]  R. Detels,et al.  Immunologic effects of combined protease inhibitor and reverse transcriptase inhibitor therapy in previously treated chronic HIV‐1 infection , 1998, AIDS.

[16]  J. Leonard,et al.  Improvement in cell-mediated immune function during potent anti-human immunodeficiency virus therapy with ritonavir plus saquinavir. , 1998, The Journal of infectious diseases.

[17]  M A Nowak,et al.  Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. , 1998, Science.

[18]  E. Rosenberg,et al.  Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. , 1997, Science.

[19]  M. McElrath,et al.  Cytotoxic-T-cell responses, viral load, and disease progression in early human immunodeficiency virus type 1 infection. , 1997, The New England journal of medicine.

[20]  J Leibowitch,et al.  Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. , 1997, Science.

[21]  J. Rhodes,et al.  Schiff base forming drugs: mechanisms of immune potentiation and therapeutic potential , 1996, Journal of Molecular Medicine.

[22]  D. Cooper,et al.  Alterations in the immune response of human immunodeficiency virus (HIV)-infected subjects treated with an HIV-specific protease inhibitor, ritonavir. , 1996, The Journal of infectious diseases.

[23]  B. Zheng,et al.  Therapeutic potentiation of the immune system by costimulatory Schiff-base-forming drugs , 1995, Nature.

[24]  C. Rinaldo,et al.  High levels of anti-human immunodeficiency virus type 1 (HIV-1) memory cytotoxic T-lymphocyte activity and low viral load are associated with lack of disease in HIV-1-infected long-term nonprogressors , 1995, Journal of virology.

[25]  P. Rolan,et al.  Pharmacokinetics and pharmacodynamics of tucaresol, an antisickling agent, in healthy volunteers. , 1995, British journal of clinical pharmacology.

[26]  G. Shaw,et al.  Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection , 1994, Journal of virology.

[27]  D. Ho,et al.  Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome , 1994, Journal of virology.

[28]  J. Berzofsky,et al.  Detection of cytotoxic T lymphocytes specific for synthetic peptides of gp160 in HIV-seropositive individuals. , 1991, Journal of immunology.

[29]  J. Rhodes.  Erythrocyte rosettes provide an analogue for Schiff base formation in specific T cell activation. , 1990, Journal of immunology.

[30]  X M Gao,et al.  An essential role for constitutive Schiff base-forming ligands in antigen presentation to murine T cell clones. , 1990, Journal of immunology.

[31]  M. Clerici,et al.  Detection of three distinct patterns of T helper cell dysfunction in asymptomatic, human immunodeficiency virus-seropositive patients. Independence of CD4+ cell numbers and clinical staging. , 1989, The Journal of clinical investigation.

[32]  J. Rhodes.  Evidence for an intercellular covalent reaction essential in antigen-specific T cell activation. , 1989, Journal of immunology.

[33]  Jaap,et al.  Immunological abnormalities in human immunodeficiency virus (HIV)-infected asymptomatic homosexual men. HIV affects the immune system before CD4+ T helper cell depletion occurs. , 1988, The Journal of clinical investigation.

[34]  R. Zinkernagel,et al.  Molecular mechanisms of lymphocyte-mediated cytotoxicity and their role in immunological protection and pathogenesis in vivo. , 1996, Annual review of immunology.