Therapeutic strategies for immune reconstitution in acquired immunodeficiency syndrome

Transcription

1 30 1, 1, 2, 3 1. ( ), ; 2., ; 3., : ( AIDS) ( HIV) 20 90,,,,,, AIDS, CD4 + T ( CTL), HIV, : ; ; Therapeutic strategies for immune reconstitution in acquired immunodeficiency syndrome SUN Fu-Yan 1, LU Hong-Zhou 1, 2, 3 1. Department of Infectious Disease, Shanghai Public Health Clinical Center Affiliated to Fudan University, Shanghai , China; 2. Department of Infectious Disease, Huashan Hospital, Fudan University, Shanghai , China; 3. Department of Medical Science, Shanghai Medical College, Fudan University, Shanghai , China Abstract: Acquired immunodeficiency syndrome ( AIDS) is caused by the human immunodeficiency virus ( HIV), an infection that destroys the body s immune system. It was thought that the immunodeficiency observed in this disease was irreversible, despite antiretroviral therapy. Since the 1990s, however, highly active antiretroviral therapy ( HAART) has been used for clinical treatment. It has since been realized that HAART not only suppresses HIV replication but also reconstitutes the immune function in AIDS patients. Recent research has asked how to effectively reconstitute the immune function in AIDS patients, which involves facilitating the ability of the immune system to normal or near normal levels through anti-viral strategies and adoptive immunotherapy among other approaches. The goal of immune reconstitution is dissipation of the clinical symptoms of AIDS, as evidenced by a decrease in the incidence of AIDS-related opportunistic infections and tumors and a decline in rates of mortality. Through technological developments and better understanding of the immunopathogenesis and mechanisms of immune reconstitution, it is possible to improve the level and function of CD4 + T cells and to enhance HIV-specific cytotoxic T lymphocyte( CTL) immune responses. At present, a number of new therapies and strategies are entering clinical studies, including the use of various cytokines and therapeutic HIV vaccines. Key words: Acquired immunodeficiency syndrome; Therapeutic vaccine; Immune reconstitution ( acquired immunodeficiency syndrome, AIDS), ( human immunodeficiency virus, HIV) : ( 2008ZX ) :, luhongzhou@ fudan. edu. cn Corresponding author: LU Hong-Zhou, luhongzhou@ fudan. edu. cn AIDS, HIV RNA, CD4 + ( CD4 + T ), ( ),, 20 90, ( highly active antiretroviral therapy, HAART),

2 Journal of Microbes and Infection, March 2009, Vol. 4, No HAART HIV, AIDS, AIDS,, AIDS 1 AIDS HAART, AIDS, AIDS AIDS, HIV, : CD4 + T ; CD4 + T ;,, AIDS HAART AIDS T HAART, CD4 + T HAART, 2 ( nucleoside reverse transcriptase inhibitor, NRTI) 1 ( non-nrti, NNRTI), 2 NRTI 1 ( protease inhibitor, PI) HAART T 3 [ 1] : T,,,, ; T CD4 + T ; CD4 + T CD8 + T,, T, CD4 + T T, T T, T HAART, T,, T ; 2 ( interleukin-2, IL-2) [ 2] HAART HIV,, AIDS, T [ 3] HAART HIV / AIDS : HAART,, HIV, T [ 2],, CD4 + HIV [ 4 ], HIV, CD8 + T HIV [ 4] HAART 2. 2 T IL-2 IL-7 IL-15 IL-12, IL-2 IL-2 T, T, HIV IL-2, HAART IL-2 CD4 + T T, HAART IL-2 CD4 +,, : T T ; T, T T ;,

3 32 T IL-7 / CD127 ( IL-7R) IL-2 1, CD4 + T, IL-2 CD38 CD8 + T, HIV [ 5 ] IL-7 IL-15 T, HIV IL-7 T, T [ 6] HIV T CD127, CD8 + T, CD127 IL-7 T [ 7 ], HIV CD8 + T CD127, CD8 + T, CD4 + T T, CD127 - T CD38, CD127 T HAART CD127 CD4 + T ( T ), CD8 + T ; CD38 CD4 + T CD8 + T, CD127, CD4 + T CD127 IL-7, HAART CD4 + T, IL-7 /CD127 [ 8 ], CD25( IL- 2R) CD127( IL-7R) CD4 + T 3 : CD127 + CD25 low / - CD127 - CD25 - CD127 low CD25 high, HIV CD4 + CD127 - CD25 - T CD127 + T, CD127 -, CD127 - T T IL-7, IL-7 / CD127 [ 9 ] IL-15 ( antigen presenting cell, APC), CD8 + T [ 10] T ( CD38 CTLA-4 ), HIV HIV AIDS, AIDS,, HIV HIV, CD8 + T HIV ; B, HIV, HIV HIV AIDS DNA,, DNA, Megati, RNA HIV-1 env gp160 DNA env, env env HIV [ 11] IL-7 IL-15 HIV-1 DermaVir Gag T, IL-15, DermaVir Gag CD8 + T, [ 12 ] Merck s ,,, CD4 + T ( structured treatment interruption, STI),,,, Dianzani ( interferon, IFN), IFN, 4, IFN 3 /4 2 [ 1 3] IL-2,,, STI

4 Journal of Microbes and Infection, March 2009, Vol. 4, No CD8 + T HIV, HAART HIV CD8 + T, HIV CD8 + T, CD8 + T CD8 + T CD38, CD8 + T, CD38 [ 14] Mollet [ 15 ], HAART, HIV HIV CD8 + T CD8 + T,, IFN- HIV CD8 + T,, CD8 + CD27 - CD11a high, HIV CD8 + T CD8 + T 2, CD8 + T, CD8 + T, CD8 + T HIV CD8 + T, ( cytomegalovirus, CMV), CMV CD8 + T STI STI, HIV CD4 + T CCR5, CD4 + T CCR5 HIV AIDS HIV [ 1 6], CCR5 PRO40 HIV,, 4 d 1 /10, 3 [ 1 7] ( ), HIV AIDS [ 1] Li TS, Tubiana R, Katlama C, et al. Long-lasting recovery in CD4 + T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease[ J]. Lancet, 1998, 351( 9117) : [ 2] Ye P, Kirschner DE, Kourtis AP, et al. The thymus during HIV disease: role in pathogenesis and in immune recovery[ J]. Curr HIV Res, 2004, 2( 2) : [ 3] Cheimi J, Azzoni L, Farabaugh M, et al. Baseline viral load and immune activation determine the extent of reconstitution of innate immune effectors in HIV-1- infected subjects undergoing antiretroviral treatment[ J]. J Immunol, 2007, 179( 4) : [ 4] Kalams SA, Goulder PJ, Shea AK, et al. Levels of human immunodeficiency virus type-1 specific cytotoxic T- lymphocyte effector and memory response decline after suppression of viremia with highly active antiretroviral therapy[ J]. J Virol, 1999, 73( 8) : [ 5] Marchetti G, Franzetti F, Gori A. Partial immune reconstitution following highly active antiretroviral therapy: can adjuvant interleukin-2 fill the gap[ J]? J Antimicrob Chemother, 2005, 55( 4) : [ 6] Fry TJ, Mackall CL. The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance [ J]. J Immunol, 2005, 174( 11) : [ 7] Colle JL, Moreau JL, Fontanet A, et al. The correlation between levels of IL-7R [ alpha ] expression and responsiveness to IL-7 is lost in CD4 lymphocytes from HIV-infected patients[ J]. AIDS, 2007, 21( 1) : [ 8] Benito JM, Lopez M, Lozano S, et al. Down-regulation of interleukin-7 receptor ( CD127 ) in HIV infection is associated with T cell activation and is a main factor influencing restoration of CD4 + cells after antiretroviral therapy[ J]. J Infect Dis, 2008, 198( 10) : [ 9] Dunham RM, Cervasi B, Brenchley JM, et al. CD127 and CD25 expression defines CD4 + T cell subsets: That are differentially depleted during HIV infection [ J]. J Immunol, 2008, 180( 8) : [ 10] Lodolce JP, Burkett PR, Koka RM, et al. Regulation of lymphoid homeostasis by interleukin-15 [ J]. Cytok Growth Fac Rev, 2002, 13( 6) : [ 11] Megati S, Garcia-Handa D, Cappelloa S, et al. Modifying the HIV-1 env gp160 gene to improve pdna vaccineelicited cell-mediated immune responses[ J]. Vaccine, 2008, 26( 40) : [ 12] Calarotaa AS, Dai A, Trocio NJ, et al. IL-15 as memory T-cell adjuvant for topical HIV-1 DermaVir vaccine[ J]. Vaccine, 2008, 26( 40) : [ 13] Dianzni F, Rozera G, Abbate I, et al. Interferon may prevent HIV viral rebound after HAART interruption in HIV patients[ J]. J Interf Cytok Res, 2008, 28( 1) : 1-3 [ 14] Kalams AS, Goulder JP, Shea KA, et al. Levels of human

5 34 immunodeficiency virus type 1-specific cytotoxic T- lymphocyte effector and memory responses decline after suppression of viremia with highly active antiretroviral therapy[ J]. J Virol, 1999, 73( 8) : [ 15] Mollet L, Li TS, Samri A, et al. Dynamics of HIVspecific CD8 + T lymphocytes with changes in viral load [ J]. J Immunol, 2000, 165( 3) : [ 16] Nazari R, Joshi S. CCR5 as target for HIV-1 gene therapy[ J]. Curr Gene Ther, 2008, 8( 4) : [ 17] Jacobson JM, Saag MS, Thompson MA, et al. Antiviral activity of single-dose PRO 140, a CCR5 monoclonal antibody, in HIV-infected adults[ J]. J Infect Dis, 2008, 198( 9) : ( : )