Live attenuated HIV vaccines: pitfalls and prospects

Purpose of review When simian immunodeficiency virus (SIV) deleted in the nef gene caused no disease in macaques and provided protection against wild-type SIV challenge, hopes were high that the removal of nef would convert a pathogenic immunodeficiency virus into a live attenuated vaccine. We seek to highlight recent studies focused on several major issues regarding live attenuated AIDS viruses as vaccine candidates: (1) safety, (2) efficacy, (3) the correlates of immune protection, and (4) the molecular determinants for lentiviral virulence or attenuation. Recent findings Nef-deletion mutants have retained virulence; compared with wild-type SIV, disease progression was slowed but not abrogated. After long-term observation, all adult macaques given SIVmac239Δ3 exhibited immune dysfunction; over 50% had T-cell depletion, and 18% developed AIDS. Vaccine efficacy has been disappointing, with limited or no cross-protection and no protection against homologous virus challenge years after initial vaccination. To date, the correlates of protective immunity have defied precise definition; no dominant mechanism has yet emerged. Data from passive serum transfer and CD8+ T-cell depletion studies have raised the possibility that alternate mechanism of protection may be operative. Due to relentless viral replication and continuous selective pressure, initially benign viruses can generate virulent progeny with unpredictable genotypes. Summary Neither safety nor efficacy of the current live attenuated primate immunodeficiency virus vaccines has withstood the test of time. However, such viruses are invaluable tools to address two key questions: (1) what are the correlates of protection, and (2) what are the molecular determinants of viral immunopathogenesis?

[1]  J. Adelsberger,et al.  High Attenuation and Immunogenicity of a Simian Immunodeficiency Virus Expressing a Proteolysis-resistant Inhibitor of NF-κB* , 2004, Journal of Biological Chemistry.

[2]  Christopher Baum,et al.  Gene Therapy--New Challenges Ahead , 2003, Science.

[3]  Cameron S. Osborne,et al.  LMO2-Associated Clonal T Cell Proliferation in Two Patients after Gene Therapy for SCID-X1 , 2003, Science.

[4]  J. Heeney,et al.  Single-cycle immunodeficiency viruses provide strategies for uncoupling in vivo expression levels from viral replicative capacity and for mimicking live-attenuated SIV vaccines. , 2003, Virology.

[5]  A. McMichael,et al.  HIV vaccines 1983–2003 , 2003, Nature Medicine.

[6]  R. Means,et al.  Determinants of Increased Replicative Capacity of Serially Passaged Simian Immunodeficiency Virus with nef Deleted in Rhesus Monkeys , 2003, Journal of Virology.

[7]  R. Koup,et al.  Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. , 2003, Immunity.

[8]  D. Montefiori,et al.  Simian-Human Immunodeficiency Virus SHIV89.6-Induced Protection against Intravaginal Challenge with Pathogenic SIVmac239 Is Independent of the Route of Immunization and Is Associated with a Combination of Cytotoxic T-Lymphocyte and Alpha Interferon Responses , 2003, Journal of Virology.

[9]  H. McClure,et al.  Live attenuated, nef-deleted SIV is pathogenic in most adult macaques after prolonged observation , 2003, AIDS.

[10]  J. Heeney,et al.  Replication, immunogenicity, and protective properties of live-attenuated simian immunodeficiency viruses expressing interleukin-4 or interferon-gamma. , 2003, Virology.

[11]  C. Cheng‐Mayer,et al.  A Truncated Form of Nef Selected during Pathogenic Reversion of Simian Immunodeficiency Virus SIVmac239Δnef Increases Viral Replication , 2003, Journal of Virology.

[12]  G. Hubbard,et al.  Expression of IL-18 by SIV does not modify the outcome of the antiviral immune response. , 2002, Virology.

[13]  D. Montefiori,et al.  Live, Attenuated Simian Immunodeficiency Virus SIVmac-M4, with Point Mutations in the Env Transmembrane Protein Intracytoplasmic Domain, Provides Partial Protection from Mucosal Challenge with Pathogenic SIVmac251 , 2002, Journal of Virology.

[14]  R. Ahmed,et al.  Spontaneous production of RANTES and antigen‐specific IFN‐γ production in macaques vaccinated with SHIV‐4 correlates with protection against SIVsm challenge , 2002, Clinical and experimental immunology.

[15]  D. Montefiori,et al.  Molecular Evolution of Human Immunodeficiency Virus env in Humans and Monkeys: Similar Patterns Occur during Natural Disease Progression or Rapid Virus Passage , 2002, Journal of Virology.

[16]  A. Wade-Evans,et al.  Mechanisms of protection induced by attenuated simian immunodeficiency virus. , 2002, Virology.

[17]  G. Nabel.  HIV vaccine strategies. , 2002, Vaccine.

[18]  D. Montefiori,et al.  Rev-Independent Simian Immunodeficiency Virus Strains Are Nonpathogenic in Neonatal Macaques , 2002, Journal of Virology.

[19]  K. Jeang,et al.  Constitutively Dead, Conditionally Live HIV-1 Genomes , 2001, The Journal of Biological Chemistry.

[20]  B. Berkhout,et al.  In vitro evolution of a highly replicating, doxycycline-dependent HIV for applications in vaccine studies , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Y. Nagai,et al.  Quintuple Deglycosylation Mutant of Simian Immunodeficiency Virus SIVmac239 in Rhesus Macaques: Robust Primary Replication, Tightly Contained Chronic Infection, and Elicitation of Potent Immunity against the Parental Wild-Type Strain , 2001, Journal of Virology.

[22]  M. Wainberg,et al.  Construction and In Vitro Properties of a Series of Attenuated Simian Immunodeficiency Viruses with All Accessory Genes Deleted , 2001, Journal of Virology.

[23]  M. Wainberg,et al.  Novel, Live Attenuated Simian Immunodeficiency Virus Constructs Containing Major Deletions in Leader RNA Sequences , 2001, Journal of Virology.

[24]  W. Blattner,et al.  Reversal of Human Immunodeficiency Virus Type 1 IIIB to a Neutralization-Resistant Phenotype in an Accidentally Infected Laboratory Worker with a Progressive Clinical Course , 2001, Journal of Virology.

[25]  S. Staprans,et al.  Simian Immunodeficiency Virus Replicates to High Levels in Naturally Infected African Green Monkeys without Inducing Immunologic or Neurologic Disease , 2001, Journal of Virology.

[26]  B. Berkhout,et al.  Strict Control of Human Immunodeficiency Virus Type 1 Replication by a Genetic Switch: Tet for Tat , 2001, Journal of Virology.

[27]  S. Mboup,et al.  In vitro correlates of HIV-2-mediated HIV-1 protection. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[28]  J. Sodroski,et al.  Evidence for Recombination of Live, Attenuated Immunodeficiency Virus Vaccine with Challenge Virus to a More Virulent Strain , 2000, Journal of Virology.

[29]  B. Dodet.  Retroviruses of Human AIDS and Related Animal Diseases , 2000 .

[30]  T. Miura,et al.  Construction of chimeric simian and human immunodeficiency viruses that produce interleukin 12. , 2000, AIDS research and human retroviruses.

[31]  P. Luciw,et al.  Pathogenic Conversion of Live Attenuated Simian Immunodeficiency Virus Vaccines Is Associated with Expression of Truncated Nef , 2000, Journal of Virology.

[32]  D. Ho,et al.  Normal T-Cell Turnover in Sooty Mangabeys Harboring Active Simian Immunodeficiency Virus Infection , 2000, Journal of Virology.

[33]  D. Montefiori,et al.  Protection by Live, Attenuated Simian Immunodeficiency Virus against Heterologous Challenge , 1999, Journal of Virology.

[34]  R. Ruprecht.  Live attenuated AIDS viruses as vaccines: promise or peril? , 1999, Immunological reviews.

[35]  J. Mills,et al.  Immunologic and virologic status after 14 to 18 years of infection with an attenuated strain of HIV-1. A report from the Sydney Blood Bank Cohort. , 1999, The New England journal of medicine.

[36]  Robert M. Grant,et al.  Simian Immunodeficiency Virus Disease Course Is Predicted by the Extent of Virus Replication during Primary Infection , 1999, Journal of Virology.

[37]  D. Montefiori,et al.  Highly Attenuated Vaccine Strains of Simian Immunodeficiency Virus Protect against Vaginal Challenge: Inverse Relationship of Degree of Protection with Level of Attenuation , 1999, Journal of Virology.

[38]  P. Ghys,et al.  Lack of protection against HIV-1 infection among women with HIV-2 infection. , 1999, AIDS.

[39]  F. Dias,et al.  Trends and interaction of HIV-1 and HIV-2 in Guinea-Bissau, west Africa: no protection of HIV-2 against HIV-1 infection. , 1999, AIDS.

[40]  L. Foresman,et al.  Characterization of a neutralization-escape variant of SHIVKU-1, a virus that causes acquired immune deficiency syndrome in pig-tailed macaques. , 1999, Virology.

[41]  H. McClure,et al.  Live attenuated, multiply deleted simian immunodeficiency virus causes AIDS in infant and adult macaques , 1999, Nature Medicine.

[42]  B. Berkhout,et al.  Genetic Instability of Live, Attenuated Human Immunodeficiency Virus Type 1 Vaccine Strains , 1999, Journal of Virology.

[43]  T. Greenough,et al.  Declining CD4 T-cell counts in a person infected with nef-deleted HIV-1. , 1999, The New England journal of medicine.

[44]  P. Luciw,et al.  Importance of the intracytoplasmic domain of the simian immunodeficiency virus (SIV) envelope glycoprotein for pathogenesis. , 1998, Virology.

[45]  L. Montagnier,et al.  Simian Immunodeficiency Virus Replicates to High Levels in Sooty Mangabeys without Inducing Disease , 1998, Journal of Virology.

[46]  J. Zuniga.  Setting the record straight: IAPAC's HIV vaccine initiative. International Association of Physicians in AIDS Care. , 1997, Journal of the International Association of Physicians in AIDS Care.

[47]  J. Cohen.  Novel Campaign to Test Live HIV Vaccine , 1997, Science.

[48]  R. Stebbings,et al.  Mechanisms of protection induced by attenuated simian immunodeficiency virus. I. Protection cannot be transferred with immune serum. , 1997, The Journal of general virology.

[49]  J. Smith,et al.  Macaques infected with live attenuated SIVmac are protected against superinfection via the rectal mucosa. , 1997, Virology.

[50]  D. Fuchs,et al.  Construction, replication, and immunogenic properties of a simian immunodeficiency virus expressing interleukin-2 , 1997, Journal of virology.

[51]  N. Almond,et al.  Mechanisms of protection induced by attenuated simian immunodeficiency virus. IV. Protection against challenge with virus grown in autologous simian cells , 1997, Journal of medical primatology.

[52]  T. Greenough,et al.  High frequency of defective nef alleles in a long-term survivor with nonprogressive human immunodeficiency virus type 1 infection , 1996, Journal of virology.

[53]  J. Sodroski,et al.  A chimeric simian/human immunodeficiency virus expressing a primary patient human immunodeficiency virus type 1 isolate env causes an AIDS-like disease after in vivo passage in rhesus monkeys , 1996, Journal of virology.

[54]  D. Fuchs,et al.  Attenuated SIV imparts immunity to challenge with pathogenic spleen-derived SIV but cannot prevent repair of the nef deletion. , 1996, Immunology letters.

[55]  D. Montefiori,et al.  Vaccine protection by a triple deletion mutant of simian immunodeficiency virus , 1996, Journal of virology.

[56]  M. Clerici,et al.  Attenuated Retrovirus Vaccines and AIDS , 1995, Science.

[57]  J. S. Sullivan,et al.  Genomic Structure of an Attenuated Quasi Species of HIV-1 from a Blood Transfusion Donor and Recipients , 1995, Science.

[58]  H. Petry,et al.  Cellular immune response of rhesus monkeys infected with a partially attenuated nef deletion mutant of the simian immunodeficiency virus. , 1995, Virology.

[59]  A. Hendrickx,et al.  Effects of viral virulence on intrauterine growth in SIV-infected fetal rhesus macaques (Macaca mulatta). , 1995, Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association.

[60]  A. Whatmore,et al.  Repair and evolution of nef in vivo modulates simian immunodeficiency virus virulence , 1995, Journal of virology.

[61]  N. Pedersen,et al.  Viral factors determine progression to AIDS in simian immunodeficiency virus-infected newborn rhesus macaques , 1995, Journal of virology.

[62]  I. Thior,et al.  Natural protection against HIV-1 infection provided by HIV-2. , 1995, Science.

[63]  N. Almond,et al.  Protection by attenuated simian immunodeficiency virus in macaques against challenge with virus-infected cells , 1995, The Lancet.

[64]  R. Bronson,et al.  Pathogenicity of live, attenuated SIV after mucosal infection of neonatal macaques. , 1995, Science.

[65]  John L. Sullivan,et al.  Absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection , 1995 .

[66]  N. Pedersen,et al.  A partially attenuated simian immunodeficiency virus induces host immunity that correlates with resistance to pathogenic virus challenge , 1994, Journal of virology.

[67]  R. Desrosiers,et al.  Construction and in vitro properties of SIVmac mutants with deletions in "nonessential" genes. , 1994, AIDS research and human retroviruses.

[68]  B. Clarke,et al.  Molecular and biological characterization of simian immunodeficiency virus macaque strain 32H proviral clones containing nef size variants. , 1994, The Journal of general virology.

[69]  R. Desrosiers,et al.  Upstream U3 sequences in simian immunodeficiency virus are selectively deleted in vivo in the absence of an intact nef gene , 1994, Journal of virology.

[70]  N. Pedersen,et al.  Viral determinants of simian immunodeficiency virus (SIV) virulence in rhesus macaques assessed by using attenuated and pathogenic molecular clones of SIVmac , 1993, Journal of virology.

[71]  R. Desrosiers,et al.  Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene. , 1992, Science.

[72]  J. Kaldor,et al.  Long-term symptomless HIV-1 infection in recipients of blood products from a single donor , 1992, The Lancet.

[73]  R. Desrosiers,et al.  Importance of the nef gene for maintenance of high virus loads and for development of AIDS , 1991, Cell.

[74]  N. Pedersen,et al.  Immunization with a live, attenuated simian immunodeficiency virus (SIV) prevents early disease but not infection in rhesus macaques challenged with pathogenic SIV , 1990, Journal of virology.

[75]  L. Hwang,et al.  PREVENTION OF PERINATALLY TRANSMITTED HEPATITIS B VIRUS INFECTIONS WITH HEPATITIS B IMMUNE GLOBULIN AND HEPATITIS B VACCINE , 1983, The Lancet.

[76]  R. Newcombe,et al.  MATERNAL DEATHS , 1975, The Lancet.

[77]  C. Pauza,et al.  Simian/human immunodeficiency virus(89.6) expressing the chemokine genes MIP-1alpha, RANTES, or lymphotactin. , 2003, Viral immunology.

[78]  R. Desrosiers,et al.  Resistance of neonatal monkeys to live attenuated vaccine strains of simian immunodeficiency virus , 1997, Nature Medicine.

[79]  J L Sullivan,et al.  Brief report: absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection. , 1995, The New England journal of medicine.

[80]  N. Pedersen,et al.  Rhesus Macaques Inoculated With Molecularly Cloned Simian Immunodeficiency Virus , 1989, Journal of medical primatology.