AIDSWEEKLY Plus, 11 November 1996
Daniel J. DeNoon, Senior Editor

The HIV transcriptional activation (Tat) protein is essential for high-level HIV replication. But the protein has a non-transcriptional role as well: Tat released by HIV infected cells readily enters and activates uninfected cells, rendering them susceptible to HIV infection.

Now New York University researcher Gideon Goldstein suggests that individuals immunized against Tat would be protected against HIV disease in much the same way that toxoid vaccines protect against tetanus and diphtheria.

"Immunologic interdiction of extracellular Tat protein by prophylactic active immunization should critically reduce explosive replication of the [HIV] virus and permit effective immune control," Goldstein wrote ("HIV-1 Tat Protein as a Potential AIDS Vaccine," Nature Medicine, 1(9):960-4.)

Goldstein based his hypothesis on the observation that the magnitude of HIV replication during the initial phase of HIV infection determines HIV disease progression and outcome.

He suggested that in this regard HIV infection is analogous to lymphocytic choriomeningitis virus (LCMV). Small inocula of LCMV lead to infection that is easily controlled by the immune system; large inocula do not evoke an effective immune response. Intermediate LCMV inoculation leads to a long-term, HIV-like balance between viral replication and ongoing immune surveillance.

"Thus clinical and experimental observations imply that control of viral expansion during the initial acute viral infection is a key point for intervention to negate chronic viremia and clinical progression," Goldstein wrote.

The Tat protein is a tempting target for such control.

"Prior specific vaccination against Tat protein is designed to abolish the intercellular traffic of this transactivator, thereby removing the evidently essential basis for the massive multiplication of virus, which fosters uncontrollable production of viral variants surviving and eventually destroying immune defenses," Goldstein noted.

The central problem in developing an HIV vaccine is the extraordinary variability of the virus. A Tat vaccine would not suffer from this limitation:

• The two immunodominant domains in the essential portion of the tat gene (amino acids 5-22 and 44-62) are relatively well conserved.
• Anti-Tat antibodies act on extracellular protein, thereby affecting all HIV quasispecies indiscriminately and providing no basis for selection of escape mutations.

Goldstein noted that monoclonal or polyclonal antibodies to Tat not only attenuate HIV infectivity, but also reduce HIV replication in infected cells. This latter observation (Re et al., JAIDS, 1995;10:408-16) suggests that a Tat vaccine could be used to treat HIV infected patients early in the course of infection.

Moreover, Goldstein noted, several researchers have found that progression to AIDS is associated with low or no natural anti-Tat antibodies.

The NYU researcher listed a number of practical considerations in the creation of a Tat-based HIV vaccine:

• Undesired cellular activation by the Tat vaccine antigen could be avoided by substituting other amino acids for cysteine in the non-immunogenic cysteine-rich domain of the Tat protein.
• The antibodies raised by a Tat-based vaccine are not those detected by serologic tests for HIV infection. Vaccine recipients would therefore avoid the trauma and stigma of a false-positive HIV test; moreover, breakthrough HIV infection could be detected easily.
• To protect against HIV-2 as well as HIV-1, an HIV-2 Tat antigen would have to be included in the vaccine.
• While a Tat-based HIV vaccine is designed to prevent HIV infection, it could also be therapeutic for people with asymptomatic HIV infection.

Goldstein announced that animal studies of Tat-based vaccination are already underway in primates.

"There is a need for a novel strategy ... to find a sufficiently early target of vulnerability other than the [HIV] virion itself," he concluded. "These terms of reference appear to be met by specific vaccination against the Tat transcriptional activator, a free protein product of the virus that passes from cell to cell and is responsible for the massive replication and output of virus. Without this protein, chronic infection, leading to immune failure and progression to AIDS, should be contained."

The corresponding author for this study is Gideon Goldstein, 30 Dorison Drive, Short Hills, New Jersey 07078- 1701.

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