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  HIV-1 TAT VACCINES: A NOVEL APPROACH TO VACCINATION
HIV-1 Tat protein
Among the HIV regulatory genes, tat has a fundamental function in HIV pathogenesis and disease. In the absence of Tat, the virus is still able to infect the cell, however it does not replicate. Tat is produced very early after HIV infection, even before the virus integrates with (becomes part of) the host cell's genetic machinery. Moreover, Tat is necessary for the virus to replicate within the host cells and to infect new cells. Finally, Tat is released by acutely infected cells and helps to recruit and activate uninfected cells. This provides new cells for the virus to infect, helping to spread the HIV infection throughout the body.
Focusing on the Tat protein represents a radically different approach to creating a vaccine against HIV-1. The rationale for this approach is based upon the following scientific evidence:
  1. The presence of anti-Tat antibodies seems to protect infected individuals from progressing to AIDS. In fact, anti-Tat antibodies are more frequently found in the early stage of the disease than during the symptomatic stages. Finally, in studies conducted over long period of times (longitudinal studies), anti-Tat antibodies have been associated with a slower disease progression.

  2. Anti-Tat cytotoxic (CD8+) T lymphocytes (CTLs), a type of white blood cells also called Killer T cells because they kill cells that are infected with pathogens or damaged cells, are frequently found in individuals who are infected naturally by HIV. CD8+T cell responses correlate with early virus control in both humans and experimental animals.

  3. The immunogenic regions (those capable of producing an immune response) of Tat are conserved among the different HIV-1 clades , different evolutionary forms of the HIV-1 virus that have originated over the years. In fact, cross-clade recognition of the Tat B clade has been observed with sera from Ugandan, South African and Italian patients with infections of different subtypes. In addition, key regions of the Tat protein are well conserved among the circulating virus clades. The data from these studies suggests that a Tat vaccine may be useful in different geographic areas of the world.

  4. In addition to representing a valuable antigen for an HIV/AIDS vaccine, biologically active Tat has immunomodulatory features that make it an attractive adjuvant (substance that increases the immune response) for other antigens. Recent data shows that monocyte-derived dendritic cells (MDDC) and macrophages efficiently and rapidly take up native Tat, i.e. the biologically active form of Tat. After uptake, native Tat promotes MDDC maturation and activation. Activation includes increased expression of major histocompatibility complex (MHC) antigens and co-stimulatory molecules, as well as increased production of cytokines and chemokines in Th-1 (helper T cells). Increased activation of MDDC leads to a more efficient presentation of both allogenic (genetically different but from the same species) and exogenous soluble antigens. All these events are key to obtain a successful iummunogenic response to vaccination.
This growing body of scientific evidence has implications for a Tat-based vaccine. The data suggest that vaccination with Tat may modify the virus-host dynamics and control HIV-1 replication both in primary infection (preventive strategy) and in infected individuals (therapeutic strategy). Moreover, Tat can function as both an antigen and a potent adjuvant. Together, these features make Tat an optimal candidate for an HIV vaccine, alone or in combination with other antigens.
Used in a therapeutic strategy, vaccinating seropositive (HIV-positive) patients with Tat should reduce HIV-1 replication and slow disease progression. Used in a preventive strategy, a Tat-based vaccine could modify the virus-host dynamics at the very beginning of HIV infection, should it occur. As a result, critical immune cells would not be depleted, and progression of the infection would be interrupted. This scenario is based on accumulating evidence suggesting that the viral load at the beginning of the infection is a strong indicator of progression to disease.
Finally, another advantage of a Tat-based vaccine approach is that it would allow to discriminate vaccinated from unvaccinated individuals. This is possible because a Tat-based vaccine does not contain structural HIV proteins on which current blood tests are based, and therefore the Tat-vaccinated volunteer will not seroconvert (false positives).

 

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