Recent Advances in the Development of HIV-1 Tat-Based Vaccines

Abstract

Over the last two decades most of the efforts in HIV vaccine development have been based on the use of the HIV Env with the goal to induce sterilizing immunity. However, as a result of Env variability disappointing results have been obtained in preclinical and phase III clinical trials. Although the objective of a preventive immunity still remains a priority, secondary endpoints (e.g. block of virus replication and disease onset) are being considered at the present as more achievable end-points in HIV vaccine development. This is based on accumulating evidence indicating that low viral load correlates with maintenance of immune functions and slow progression to disease, and that cell-mediated immunity plays a major protective role in the absence of sterilizing immunity. The promising results obtained in non-human primates with a vaccine based on a native Tat protein (B-clade), which is an early regulatory protein key for HIV replication and AIDS pathogenesis, highlights the importance of targeting the virus very early after infection. In particular, the immune response against Tat appears to modify the virus-host interactions at the very beginning of infection, thus containing the depletion of critical immune cells and the progression of infection. Moreover, since Tat targets and induces maturation of dendritic cells, has immunomodulatory activities and drives Th-1 and CTL responses, immunization with Tat may drive or increase these immune responses also against other HIV antigens to support an effective, long-lasting and hopefully even sterilizing antiviral immunity. Finally, Tat B-clade is similarly recognized by sera from individuals infected by different virus clades (A, B, C, D) supporting the concept of a cross-clade vaccine. Therefore, the Tat-vaccine should contain virus replication protecting from disease progression (non-sterilizing immunity) or even favoring an abortive infection. Although only a phase III clinical trial will establish the efficacy of this vaccine strategy, the Tat-vaccine has recently entered preventive and therapeutic phase I clinical testing in Italy to establish safety (primary-end-point) and immunogenicity (secondary end-point) and phase II studies are being prepared.

HIV-1 Tat-Based Vaccines: An Overview and Perspectives in the Field of HIV/AIDS Vaccine Development

“…4,63,67,84,85] and 46% of anti-Tat seropositive individuals were reported when anti-Tat ELISA were carried out with Tat variants specific for the subtype infecting patients [119]. High antibody titers directed against a broad spectrum of Tat functional domains neutralize the effects of extracellular Tat on virus replication and cell functions and play an important role in the control of the HIV infection and disease progression [105,[119][120][121][122][123][124][125][126][127][128][129][130].…”

“…Hence, in a fashion similar to different vaccine antigens, the use of a biologically active Tat protein as a vaccine antigen represents a critical issue since the preservation of the native conformation permits the induction of an effective Th1-type cellular immune response, the induction of antibodies directed against conformational epitopes, and allows to retain its adjuvant properties. As Tat contains a basic domain rich in arginine and lysine, novel anionic biocompatible core-shell nano-and micro-spheres were developed consisting of a poly(methylmethacrylate) (PMMA) core and an expanded hydrophilic shell made of a functional poly(methacrylic acid-st-ethyl acrylate) copolymer, whose commercial name is Eudragit L100-55 [63,192]. These particles are able to bind, deliver, and release the HIV-1 Tat protein, both in vitro and in vivo, while protecting it from oxidation and preserving its biological activity.…”

“…The main goal of these approaches is generation of CTLs against epitopes that are conserved among different HIV clades capable of limiting virus replication or aborting HIV infection, providing protection from disease progression, and reducing virus transmission to healthy individuals (non-sterilizing immunity) [recently reviewed in refs. [63][64][65][66][67]. These strategies based on recombinant proteins, DNA plasmids, or expression vectors have proven to be effective in controlling viremia and progression to AIDS in non-human primates [68][69][70][71][72][73][74][75].…”

A Replication-Competent Adenovirus-Human Immunodeficiency Virus (Ad-HIV)tatand Ad-HIVenvPriming/Tat and Envelope Protein Boosting Regimen Elicits Enhanced Protective Efficacy against Simian/Human Immunodeficiency Virus SHIV89.6PChallenge in Rhesus Macaques

“…Similarly, vaccination with Tat peptides resulted in only one of seven rhesus macaques being protected against intrarectal SHIV BX08 challenge (3), and a replication-defective adenovirus (Ad) type 5 (Ad5)-HIV tat vaccine was ineffective in protecting rhesus macaques against intravenously administered SHIV 89.6P (30). However, the combination of Tat with other regulatory and/or structural gene products in multigenic vaccines has improved protective efficacy against both SHIV and SIV challenges in the rhesus macaque system (10,21). The contribution of each vaccine component has yet to be clarified.…”

Antigen Expression Kinetics and Immune Responses of Mice Immunized with Noninfectious Simian-Human Immunodeficiency Virus DNA

“…Two potential problems with current DNA approaches are that (i) it is still not known which of the viral proteins are essential for inducing optimum protection, since claims of efficacy using gag (8,15), env (19,25,43), and tat (11,21,22) have been raised, and (ii) viral strategies that plan for the use of vectors expressing viral proteins will be cumbersome to apply in underdeveloped countries. To overcome the necessity for using a protein boost and yet achieve efficacy with a DNA vaccine, we adopted a new approach by using the DNA of the simian-human immunodeficiency virus SHIV KU2 , which expresses all of the viral proteins with high efficiency but from which we deleted the rt gene to render the DNA noninfectious.…”