Summary of Invention This invention relates to a specific molecular complex formed between the HIV Tat protein and the HIV envelope protein gp120, which is generated upon the interaction of the cysteine rich and basic regions of Tat protein and the gp120 V3 loop. In particular the invention relates to said molecular complex obtained using the whole Tat protein, its mutants, fragments or derivatives thereof, and the HIV envelope protein gp120, fragments or derivatives thereof, and to its use as a novel antigen for preventive or therapeutic vaccination against HIV/AIDS. Solution to which problem (s) HIV-1 has evolved mechanisms to prevent the uncontrolled fusion of the virus envelope and the cell membrane. This, in fact, would divert HIV from its natural cell targets exposing the infected host to unpredictable hazard. Indeed, the HIV-1 envelope surface protein gp120 is assembled on the HIV envelope in such a way to mask the gp41 fusion determinants. Upon interaction with CD4, sequential conformational changes in gp120 lead to V3 loop exposure, allowing it to interact with the HIV coreceptors (CCR5, CXCR4). These processes induce further conformational changes culminating in the exposure of gp41 fusion peptides. Thus, fusion of the virus envelope with the cell membrane can occur only on cells expressing both CD4 and HIV coreceptors. At the same time, however, this stepwise conformational program also prevents recognition by B cells of crucial gp120 and gp41 epitopes that are exposed only transiently upon virus adsorption and entry. Efficient induction of antibodies directed against these epitopes is, therefore, crucial for achieving a sterilizing immunity against HIV infection and represents a long sought goal of the HIV vaccine research. At present, this is pursued through immunization with gp120-CD4 complexes, modified gp120 molecules exposing cryptic epitopes, or molecular vectors expressing recognized neutralizing epitopes. In this context, our unpublished data indicate that the HIV-1 Tat protein, released by acutely infected cells, mediates HIV entry in CD4-posistive CCR5-negative cells by a molecular mimicry of the CCR5 coreceptor. This is dependent upon the formation of a complex between the cystein rich and basic regions of Tat and the gp120 V3 loop, which acts by mimicking the complex formed between the CCR5 coreceptor and the gp120 V3 loop. These data indicate, therefore, that antibodies directed against the Tat-V3 loop complex are also required for a complete blockade of virus spread in exposed individuals or to induce an effective sterilizing immunity upon vaccination. The present invention envisages a new antigen based on the molecular complex formed between the HIV Tat protein and the V3 loop as a mean to obtain a sterilizing immunity against HIV infection or to produce antibodies for passive immunization to block vertical or horizontal HIV transmission among HIV-exposed individuals. Key applications Most vaccine approaches aimed at preventing or controlling HIV infection and AIDS have so far failed due to the poor immunogenicity and/or the high variability of the HIV antigens used as immunogens. Furthermore, crucial HIV epitopes capable of inducing neutralizing antibodies or targeted by neutralizing antibodies are exposed to the immune system only transiently upon virus adsorption and penetration. This has impaired the induction and or the effectiveness of both cell-mediated and humoral responses. In this context, our recent work has shown that the HIV Tat protein is highly immunogenic as it acts both as an antigen and as an adjuvant capable of polarizing the immune response toward a Th1-type response. Furthermore, we have unexpectedly found that Tat mimics the HIV co-receptor CCR5 and, therefore, it forms a molecular complex with HIV-1 gp120 V3 loop. This confers to HIV-1 CCR5-tropic strains the capability of infecting CCR5- negative T cells. Thus, the invention can be used in the following key applications:

PCT stage, to be published in August 2005

Developmental Partnership, Outlicense, Sale