Candidate HIV-1 Tat vaccine development: from basic science to clinical trials.

Over the past 20 years most of the efforts in HIV vaccinedevelopment have focused on sterilizing immunity bytargeting the Envelope protein (Env). However, resultsfrom preclinical and clinical trials have been largelydisappointing [1–11]. Therefore, current vaccine strat-egies are not only aimed at preventing virus infection butalso at blocking virus replication and disease onset. Inparticular, the control of virus replication should provideprotection from disease development and reduce virustransmission, halting the HIV epidemic. This objectivemay be achieved by targeting virus regulatory genes,which are expressed early after infection, are essential forvirus replication and pathogenesis, and are moreconserved among HIV clades. This approach may beeffective for both preventive and therapeutic vaccinestrategies [12–68]. In this article we review thecharacteristics of Tat and why it was selected for use in avaccine.Wealsocitethelessonlearnedinthedevelopmentof this anti-Tat vaccine for use in human clinical trials.

[1]  D. Montefiori,et al.  An Adenovirus-Based HIV Subtype B Prime/Boost Vaccine Regimen Elicits Antibodies Mediating Broad Antibody-Dependent Cellular Cytotoxicity Against Non-Subtype B HIV Strains , 2006, Journal of acquired immune deficiency syndromes.

[2]  R. König,et al.  Retroviral vectors for vaccine development: induction of HIV-1-specific humoral and cellular immune responses in rhesus macaques using a novel MLV(HIV-1) pseudotype vector. , 2006, Journal of biotechnology.

[3]  Giuseppe Altavilla,et al.  DNA prime and protein boost immunization with innovative polymeric cationic core-shell nanoparticles elicits broad immune responses and strongly enhance cellular responses of HIV-1 tat DNA vaccination. , 2006, Vaccine.

[4]  Giulia Marsili,et al.  Intracellular HIV-1 Tat protein represses constitutive LMP2 transcription increasing proteasome activity by interfering with the binding of IRF-1 to STAT1. , 2006, The Biochemical journal.

[5]  R. Mumper,et al.  HIV-1 Tat-coated nanoparticles result in enhanced humoral immune responses and neutralizing antibodies compared to alum adjuvant. , 2006, Vaccine.

[6]  J. Berzofsky,et al.  Systemic Immunization with an ALVAC-HIV-1/Protein Boost Vaccine Strategy Protects Rhesus Macaques from CD4+ T-Cell Loss and Reduces both Systemic and Mucosal Simian-Human Immunodeficiency Virus SHIVKU2 RNA Levels , 2006, Journal of Virology.

[7]  M. Humbert,et al.  The role of neutralizing antibodies in HIV infection. , 2006, AIDS reviews.

[8]  B. Ensoli,et al.  Efficient systemic and mucosal responses against the HIV-1 Tat protein by prime/boost vaccination using the lipopeptide MALP-2 as adjuvant. , 2006, Vaccine.

[9]  Eddy Pasquier,et al.  The C Terminus of HIV-1 Tat Modulates the Extent of CD178-mediated Apoptosis of T Cells* , 2005, Journal of Biological Chemistry.

[10]  B. Ensoli.  Introduction: rational vaccine strategies against AIDS , 2005 .

[11]  G. Zauli,et al.  HIV‐1 Tat protein concomitantly down‐regulates apical caspase‐10 and up‐regulates c‐FLIP in lymphoid T cells: A potential molecular mechanism to escape TRAIL cytotoxicity , 2005, Journal of cellular physiology.

[12]  Scott A. Brown,et al.  HIV vaccines: brief review and discussion of future directions , 2005, Expert review of vaccines.

[13]  M. Ciccozzi,et al.  The presence of anti-Tat antibodies is predictive of long-term nonprogression to AIDS or severe immunodeficiency: findings in a cohort of HIV-1 seroconverters. , 2005, The Journal of infectious diseases.

[14]  M. Giacca,et al.  Cell surface-associated Tat modulates HIV-1 infection and spreading through a specific interaction with gp120 viral envelope protein. , 2005, Blood.

[15]  Kenneth H Mayer,et al.  Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. , 2005, The Journal of infectious diseases.

[16]  J. Mascola,et al.  Lessons from failure--preparing for future HIV-1 vaccine efficacy trials. , 2005, The Journal of infectious diseases.

[17]  D. Montefiori,et al.  Efficacy of DNA and Fowlpox Virus Priming/Boosting Vaccines for Simian/Human Immunodeficiency Virus , 2004, Journal of Virology.

[18]  S. Muller,et al.  A synthetic HIV‐1 Tat protein breaches the skin barrier and elicits Tat‐neutralizing antibodies and cellular immunity , 2004, European journal of immunology.

[19]  B. Ensoli,et al.  Nonstructural HIV proteins as targets for prophylactic or therapeutic vaccines. , 2004, Current opinion in biotechnology.

[20]  M. Nowak,et al.  Determinants of Human Immunodeficiency Virus Type 1 Escape from the Primary CD8+ Cytotoxic T Lymphocyte Response , 2004, The Journal of experimental medicine.

[21]  R. Gavioli,et al.  Recent advances in the development of HIV-1 Tat-based vaccines. , 2004, Current HIV research.

[22]  J. Heeney,et al.  Long-term protection against SHIV89.6P replication in HIV-1 Tat vaccinated cynomolgus monkeys. , 2004, Vaccine.

[23]  K. M. Mohankumar,et al.  Codon Optimization of the Tat Antigen of Human Immunodeficiency Virus Type 1 Generates Strong Immune Responses in Mice following Genetic Immunization , 2004, Journal of Virology.

[24]  E. Sandström,et al.  DNA immunization with HIV early genes in HIV type 1-infected patients on highly active antiretroviral therapy. , 2004, AIDS research and human retroviruses.

[25]  P. Kaleebu,et al.  Full-length HIV-1 Tat protein necessary for a vaccine. , 2004, Vaccine.

[26]  J. Ulmer,et al.  Neutralizing antibody responses to HIV: role in protective immunity and challenges for vaccine design , 2004, Expert review of vaccines.

[27]  J. Heeney,et al.  Enhanced cellular immunity and systemic control of SHIV infection by combined parenteral and mucosal administration of a DNA prime MVA boost vaccine regimen. , 2004, The Journal of general virology.

[28]  Frances Gotch,et al.  Support for the RV144 HIV Vaccine Trial , 2004, Science.

[29]  N. Letvin,et al.  Evaluation of combination DNA/replication-competent Ad-SIV recombinant immunization regimens in rhesus macaques. , 2004, AIDS research and human retroviruses.

[30]  Russell J Mumper,et al.  Strong T cell type-1 immune responses to HIV-1 Tat (1-72) protein-coated nanoparticles. , 2004, Vaccine.

[31]  J. Heeney,et al.  Protective efficacy of a multicomponent vector vaccine in cynomolgus monkeys after intrarectal simian immunodeficiency virus challenge. , 2004, The Journal of general virology.

[32]  S. Rowland-Jones,et al.  A human immunodeficiency virus 1 (HIV-1) clade A vaccine in clinical trials: stimulation of HIV-specific T-cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans. , 2004, The Journal of general virology.

[33]  R. Doms,et al.  Qualitative T-Helper Responses to Multiple Viral Antigens Correlate with Vaccine-Induced Immunity to Simian/Human Immunodeficiency Virus Infection , 2004, Journal of Virology.

[34]  Wayne C Koff,et al.  HIV vaccine design and the neutralizing antibody problem , 2004, Nature Immunology.

[35]  Susan Zolla-Pazner,et al.  Identifying epitopes of HIV-1 that induce protective antibodies , 2004, Nature Reviews Immunology.

[36]  Charal Trinvuthipong.  Thailand's Prime-Boost HIV Vaccine Phase III , 2004, Science.

[37]  D. Birx,et al.  HIV Vaccine Trial Justified , 2004, Science.

[38]  J. Lieberman,et al.  A Sound Rationale Needed for Phase III HIV-1 Vaccine Trials , 2004, Science.

[39]  M. Huigen,et al.  Multiple effects of HIV‐1 trans‐activator protein on the pathogenesis of HIV‐1 infection , 2004, European journal of clinical investigation.

[40]  Jorma Hinkula,et al.  Therapeutic vaccination with MVA-HIV-1 nef elicits Nef-specific T-helper cell responses in chronically HIV-1 infected individuals. , 2003, Vaccine.

[41]  M. Colvin,et al.  Sequence conservation and antibody cross-recognition of clade B human immunodeficiency virus (HIV) type 1 Tat protein in HIV-1-infected Italians, Ugandans, and South Africans. , 2003, The Journal of infectious diseases.

[42]  Jianhong Cao,et al.  Evolution of CD8+ T Cell Immunity and Viral Escape Following Acute HIV-1 Infection1 , 2003, The Journal of Immunology.

[43]  M. Marinaro,et al.  Mucosal delivery of the human immunodeficiency virus-1 Tat protein in mice elicits systemic neutralizing antibodies, cytotoxic T lymphocytes and mucosal IgA. , 2003, Vaccine.

[44]  Yi-da Yang,et al.  Monocytes Treated with Human Immunodeficiency Virus Tat Kill Uninfected CD4+ Cells by a Tumor Necrosis Factor-Related Apoptosis-Induced Ligand-Mediated Mechanism , 2003, Journal of Virology.

[45]  Lawrence Corey,et al.  Comprehensive Analysis of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific Gamma Interferon-Secreting CD8+ T Cells in Primary HIV-1 Infection , 2003, Journal of Virology.

[46]  A. Scoglio,et al.  Efficient mucosal delivery of the HIV‐1 Tat protein using the synthetic lipopeptide MALP‐2 as adjuvant , 2003, European journal of immunology.

[47]  M. Magnani,et al.  Red blood cell-mediated delivery of recombinant HIV-1 Tat protein in mice induces anti-Tat neutralizing antibodies and CTL. , 2003, Vaccine.

[48]  G. Altavilla,et al.  Immunization with low doses of HIV-1 tat DNA delivered by novel cationic block copolymers induces CTL responses against Tat. , 2003, Vaccine.

[49]  Glen S. Hatfield,et al.  Tat-Neutralizing Antibodies in Vaccinated Macaques , 2003, Journal of Virology.

[50]  N. Larke,et al.  Construction and immunogenicity in a prime-boost regimen of a Semliki Forest virus-vectored experimental HIV clade A vaccine. , 2003, The Journal of general virology.

[51]  D. Watkins,et al.  Prevention of Disease Induced by a Partially Heterologous AIDS Virus in Rhesus Monkeys by Using an Adjuvanted Multicomponent Protein Vaccine , 2003, Journal of Virology.

[52]  Qiang Zhou,et al.  HIV‐1 Tat targets microtubules to induce apoptosis, a process promoted by the pro‐apoptotic Bcl‐2 relative Bim , 2002, The EMBO journal.

[53]  D. Weiner,et al.  T-cell responses induced in normal volunteers immunized with a DNA-based vaccine containing HIV-1 env and rev , 2002, AIDS.

[54]  D. Montefiori,et al.  Containment of Simian Immunodeficiency Virus Infection in Vaccinated Macaques: Correlation with the Magnitude of Virus-Specific Pre- and Postchallenge CD4+ and CD8+ T Cell Responses1 , 2002, The Journal of Immunology.

[55]  T. Ndung’u,et al.  Magnitude and Frequency of Cytotoxic T-Lymphocyte Responses: Identification of Immunodominant Regions of Human Immunodeficiency Virus Type 1 Subtype C , 2002, Journal of Virology.

[56]  E. Bouveret,et al.  Tat HIV-1 Primary and Tertiary Structures Critical to Immune Response Against Non-homologous Variants* , 2002, The Journal of Biological Chemistry.

[57]  M. Robert-Guroff,et al.  Potent, persistent cellular immune responses elicited by sequential immunization of rhesus macaques with Ad5 host range mutant recombinants encoding SIV Rev and SIV Nef. , 2002, DNA and cell biology.

[58]  J. Altman,et al.  Design and in vivo immunogenicity of a polyvalent vaccine based on SIVmac regulatory genes. , 2002, DNA and cell biology.

[59]  G. Sutter,et al.  Evaluation in rhesus macaques of Tat and rev-targeted immunization as a preventive vaccine against mucosal challenge with SHIV-BX08. , 2002, DNA and cell biology.

[60]  J. Kim,et al.  Inclusion of Vpr accessory gene in a plasmid vaccine cocktail markedly reduces Nef vaccine effectiveness in vivo resulting in CD4 cell loss and increased viral loads in rhesus macaques , 2002, Journal of medical primatology.

[61]  A. Osterhaus,et al.  Comparison of the efficacy of early versus late viral proteins in vaccination against SIV. , 2002, Vaccine.

[62]  P. Earl,et al.  Critical Role for Env as well as Gag-Pol in Control of a Simian-Human Immunodeficiency Virus 89.6P Challenge by a DNA Prime/Recombinant Modified Vaccinia Virus Ankara Vaccine , 2002, Journal of Virology.

[63]  G. Altavilla,et al.  Micellar-type complexes of tailor-made synthetic block copolymers containing the HIV-1 tat DNA for vaccine application. , 2002, Vaccine.

[64]  P. Earl,et al.  Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. , 2002, Vaccine.

[65]  Austin L. Hughes,et al.  Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection , 2002, Nature Medicine.

[66]  Todd M. Allen,et al.  Tat-Vaccinated Macaques Do Not Control Simian Immunodeficiency Virus SIVmac239 Replication , 2002, Journal of Virology.

[67]  S. Moretti,et al.  Native HIV-1 Tat Protein Targets Monocyte-Derived Dendritic Cells and Enhances Their Maturation, Function, and Antigen-Specific T Cell Responses1 , 2002, The Journal of Immunology.

[68]  B. Ensoli,et al.  HIV-1 Tat vaccines. , 2001, Virus research.

[69]  J. Clements,et al.  Identification of a peptide capable of inducing an HIV-1 Tat-specific CTL response. , 2001, Vaccine.

[70]  F. Vannberg,et al.  Identification of Human Immunodeficiency Virus Type 1 Subtype C Gag-, Tat-, Rev-, and Nef-Specific Elispot-Based Cytotoxic T-Lymphocyte Responses for AIDS Vaccine Design , 2001 .

[71]  Yuntao Wu,et al.  Selective Transcription and Modulation of Resting T Cell Activity by Preintegrated HIV DNA , 2001, Science.

[72]  J. Kim,et al.  Protection from immunodeficiency virus challenges in rhesus macaques by multicomponent DNA immunization. , 2001, Virology.

[73]  B. Wahrén,et al.  Interactions of single and combined human immunodeficiency virus type 1 (HIV-1) DNA vaccines. , 2001, Virology.

[74]  J. Heeney,et al.  Enhanced simian immunodeficiency virus-specific immune responses in macaques induced by priming with recombinant Semliki Forest virus and boosting with modified vaccinia virus Ankara. , 2001, Vaccine.

[75]  M. Marchisio,et al.  Characterization of HIV-1 Tat proteins mutated in the transactivation domain for prophylactic and therapeutic application. , 2001, Vaccine.

[76]  A. Borsetti,et al.  Vaccination with DNA containing tat coding sequences and unmethylated CpG motifs protects cynomolgus monkeys upon infection with simian/human immunodeficiency virus (SHIV89.6P). , 2001, Vaccine.

[77]  M. Re,et al.  Antibodies against full-length Tat protein and some low-molecular-weight Tat-peptides correlate with low or undetectable viral load in HIV-1 seropositive patients. , 2001, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[78]  E. Rosenberg,et al.  The HIV-1 regulatory proteins Tat and Rev are frequently targeted by cytotoxic T lymphocytes derived from HIV-1-infected individuals. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[79]  Kenneth M. Yamada,et al.  Immunization with a novel HIV-1-Tat multiple-peptide conjugate induces effective immune response in mice , 2000, Peptides.

[80]  Alessandro Sette,et al.  Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia , 2000, Nature.

[81]  G. Tribbick,et al.  Minimization of chronic plasma viremia in rhesus macaques immunized with synthetic HIV-1 Tat peptides and infected with a chimeric simian/human immunodeficiency virus (SHIV33). , 2000, Vaccine.

[82]  F. Mueller,et al.  Antibody spectrum against the viral transactivator protein in patients with human immunodeficiency virus type 1 infection and Kaposi's sarcoma. , 2000, Journal of human virology.

[83]  M. Ramanathan,et al.  Immunogenicity of a novel DNA vaccine cassette expressing multiple human immunodeficiency virus (HIV-1) accessory genes , 2000, AIDS.

[84]  D. Soll,et al.  HIV-induced T-cell syncytia release a two component T-helper cell chemoattractant composed of Nef and Tat. , 1999, Journal of cell science.

[85]  Todd M. Allen,et al.  Effective Induction of Simian Immunodeficiency Virus-Specific Cytotoxic T Lymphocytes in Macaques by Using a Multiepitope Gene and DNA Prime-Modified Vaccinia Virus Ankara Boost Vaccination Regimen , 1999, Journal of Virology.

[86]  E. Sandström,et al.  Immune responses in asymptomatic HIV-1-infected patients after HIV-DNA immunization followed by highly active antiretroviral treatment. , 1999, Journal of immunology.

[87]  H. Pfister,et al.  HIV type 1 Nef protein is a viral factor for leukocyte recruitment into the central nervous system. , 1999, Journal of immunology.

[88]  R. Gallo.  Tat as one key to HIV-induced immune pathogenesis and Pat toxoid as an important component of a vaccine , 1999 .

[89]  A. Osterhaus,et al.  Vaccination with Rev and Tat against AIDS. , 1999, Vaccine.

[90]  J. Heeney,et al.  Control of SHIV-89.6P-infection of cynomolgus monkeys by HIV-1 Tat protein vaccine , 1999, Nature Medicine.

[91]  C. Rossi,et al.  DNA immunization with HIV-1 tat mutated in the trans activation domain induces humoral and cellular immune responses against wild-type Tat. , 1999, Journal of immunology.

[92]  S. Bartz,et al.  Human Immunodeficiency Virus Type 1 Tat Induces Apoptosis and Increases Sensitivity to Apoptotic Signals by Up-Regulating FLICE/Caspase-8 , 1999, Journal of Virology.

[93]  M. Schutten,et al.  Kinetics of Antiviral Activity by Human Immunodeficiency Virus Type 1-Specific Cytotoxic T Lymphocytes (CTL) and Rapid Selection of CTL Escape Virus In Vitro , 1998, Journal of Virology.

[94]  E. Sandström,et al.  Cellular cytotoxic response induced by DNA vaccination in HIV-1-infected patients , 1998, The Lancet.

[95]  W. Blattner,et al.  Antibodies to the HIV-1 Tat protein correlated with nonprogression to AIDS: a rationale for the use of Tat toxoid as an HIV-1 vaccine. , 1998, Journal of human virology.

[96]  W. Blattner,et al.  Safety and immunogenicity of HIV-1 Tat toxoid in immunocompromised HIV-1-infected patients. , 1998, Journal of human virology.

[97]  A. McMichael,et al.  DNA multi-CTL epitope vaccines for HIV and Plasmodium falciparum: immunogenicity in mice. , 1998, Vaccine.

[98]  W. Koff,et al.  Cationic liposomes are a strong adjuvant for a DNA vaccine of human immunodeficiency virus type 1. , 1997, AIDS research and human retroviruses.

[99]  Luigi Buonaguro,et al.  HIV‐1 Tat protein exits from cells via a leaderless secretory pathway and binds to extracellular matrix‐associated heparan sulfate proteoglycans through its basic region , 1997, AIDS.

[100]  B. Wahrén,et al.  Induction of HIV‐1 Specific Mucosal Immune Responses by DNA Vaccination , 1997, Scandinavian journal of immunology.

[101]  A. Pardee,et al.  Tat protein induces self-perpetuating permissivity for productive HIV-1 infection. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[102]  K. Okuda,et al.  Recognition of prominent viral epitopes induced by immunization with human immunodeficiency virus type 1 regulatory genes , 1997, Journal of virology.

[103]  W. Koff,et al.  DNA vaccination followed by macromolecular multicomponent peptide vaccination against HIV-1 induces strong antigen-specific immunity. , 1997, Vaccine.

[104]  B. Wahrén,et al.  Nucleic acid vaccination with HIV regulatory genes: a combination of HIV-1 genes in separate plasmids induces strong immune responses. , 1997, Vaccine.

[105]  D. Weiner,et al.  Protection of chimpanzees from high-dose heterologous HIV-1 challenge by DNA vaccination , 1997, Nature Medicine.

[106]  C. Van Lint,et al.  Immune Hyperactivation of HIV-1-Infected T Cells Mediated by Tat and the CD28 Pathway , 1997, Science.

[107]  E. Verdin,et al.  Dual role of HIV Tat in regulation of apoptosis in T cells. , 1997, Journal of immunology.

[108]  J. Kim,et al.  In vivo engineering of a cellular immune response by coadministration of IL-12 expression vector with a DNA immunogen. , 1997, Journal of immunology.

[109]  H. Mohri,et al.  Induction of HIV‐1 Nef‐specific cytotoxic T lymphocytes by Nef‐expressing DNA vaccine , 1996, American journal of hematology.

[110]  G. Goldstein.  HIV–1 Tat protein as a potential AIDS vaccine , 1996, Nature Medicine.

[111]  V. De Rosa,et al.  Effect of antibody to HIV-1 Tat protein on viral replication in vitro and progression of HIV-1 disease in vivo. , 1995, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[112]  H. Bukawa,et al.  Induction of potent humoral and cell-mediated immune responses following direct injection of DNA encoding the HIV type 1 env and rev gene products. , 1995, AIDS research and human retroviruses.

[113]  R. Gallo,et al.  Regulation of Cellular Gene Expression and Function by the Human Immunodeficiency Virus Type 1 Tat Protein. , 1995, Journal of biomedical science.

[114]  P. Krammer,et al.  Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120 , 1995, Nature.

[115]  V. Metelev,et al.  Induction of apoptosis in uninfected lymphocytes by HIV-1 Tat protein. , 1995, Science.

[116]  R. Gallo,et al.  Inflammatory cytokines induce AIDS-Kaposi's sarcoma-derived spindle cells to produce and release basic fibroblast growth factor and enhance Kaposi's sarcoma-like lesion formation in nude mice. , 1995, Journal of immunology.

[117]  M. Raffeld,et al.  Synergy between basic fibroblast growth factor and HIV-1 Tat protein in induction of Kaposi's sarcoma , 1994, Nature.

[118]  R. F. Smith,et al.  Human Retroviruses and AIDS. A compilation and analysis of nucleic acid and amino acid sequences: I--II; III--V , 1993 .

[119]  R. Gallo,et al.  The Tat protein of human immunodeficiency virus type 1, a growth factor for AIDS Kaposi sarcoma and cytokine-activated vascular cells, induces adhesion of the same cell types by using integrin receptors recognizing the RGD amino acid sequence. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[120]  K. Manchester,et al.  Epitopes for natural antibodies of human immunodeficiency virus (HIV)-negative (normal) and HIV-positive sera are coincident with two key functional sequences of HIV Tat protein. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[121]  P. Wingfield,et al.  Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation , 1993, Journal of virology.

[122]  S. Salahuddin,et al.  Tat protein of HIV-1 stimulates growth of cells derived from Kaposi's sarcoma lesions of AIDS patients , 1990, Nature.

[123]  C. Debouck,et al.  Speed of progression to AIDS and degree of antibody response to accessory gene products of HIV‐1 , 1990, Journal of medical virology.

[124]  Carl O. Pabo,et al.  Cellular uptake of the tat protein from human immunodeficiency virus , 1988, Cell.

[125]  C. Debouck,et al.  Natural antibodies to HIV‐tat epitopes and expression of HIV‐1 genes in vivo , 1988, Journal of medical virology.

[126]  S. Arya,et al.  Trans-activator gene of human T-lymphotropic virus type III (HTLV-III). , 1985, Science.

[127]  廷冕 李,et al.  応用 (Application) について , 1981 .

[128]  F. Peruzzi.  The multiple functions of HIV-1 Tat: proliferation versus apoptosis. , 2006, Frontiers in bioscience : a journal and virtual library.

[129]  D. Birx,et al.  Policy rebuttal. HIV vaccine trial justified. , 2004, Science.

[130]  K. Khalili,et al.  Antibodies to Tat and Vpr in the GRIV cohort: differential association with maintenance of long-term non-progression status in HIV-1 infection. , 2003, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[131]  R. Gallo.  Tat as one key to HIV-induced immune pathogenesis and Tat (correction of Pat) toxoid as an important component of a vaccine. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[132]  M. Gonda,et al.  The trans-activator gene of HTLV-III is essential for virus replication , 1986, Nature.