Could Tat be the right HIV Vaccine Target?

A red ribbon for AIDS

From a small clustering of men with Karposi’s sarcoma and Pneumocystis pneumonia in the early 1980s, HIV/AIDS has quickly become a pandemic that has killed more than 25 million people to date.

Despite relatively inefficient mode of transmission, HIV continues to spread throughout the world, and is projected to infect at least another 50 million people.

Because of its rapid emergence, lack of cure, and continuous spread and annual death tole of several million, HIV is arguably the worst prevalent infectious disease on Earth today.

Based off experience combating other diseases such as smallpox, measles and polio, hope was high – at first – that developing an HIV vaccine would happen reasonably quickly. Research to date has focused on similar targets as those that worked for those diseases, such as viral envelope proteins (env), as well as the pol gene, and the nef accessory gene.

Those are promising targets because they are essential to viral replication and infection.

Env because it codes proteins coat the virus before it enters target cells, and an immune response to it could potentially prevent infection.

Pol because it codes for products like reverse transcriptase, integrase and protease, all of which are essential at different stages of the HIV lifecycle, regulating its transformation into DNA, its incorporation into the host genome, and processing of the genetic products, respectively.

Nef because it plays a role in maintaining a host cell environment conducive to infection, such as reducing expression of immune signaling molecule MHC-I.

Results have so far been almost uniformly negative, barring one moderately positive trial that, interestingly enough, was a combination of two vaccines that had both failed independently. Why? The main explanation focuses on the hypervariable nature of the virus. Due to the lack of error checking at certain phases of viral replication, mutations accumulate at a significant rate. These mutations cause immunological changes that make existing immune responses ineffective.

Critically, the high mutation rate also means that there are a significant variety of HIV strains on the earth, many of which are significantly different from each other, and which may each require their own vaccine, based off existing approaches. Another key factor is the shielding of the virus as it leaves cells by heavy glycoslyation that shields its native proteins from the immune system, as well as adopting host proteins as a sort of “cloaking” device.

Vaccine research has shifted from the outright goal of sterilizing immunity – of preventing disease outright – to other goals such as reducing transmission and the seriousness of infection. One target that has become the subject of increasing interest and research is tat.

Tat is a gene in HIV that is essential to viral replication. It is one of the first genes expressed, possibly even before viral integration, and is essential to transcription of viral mRNA, as it stabilizes the transcription complex. Initial research into developing a mouse model of HIV, for instance, failed to support HIV infection in mice as their cells do not allow proper use of tat. Without tat, the virus is non-pathogenic.

Beyond the role it plays in viral replication, tat is a secreted product that has significant impact on the body of the host, much of which we still don’t understand. Crucially, the secreted tat product seems to cause a shift towards an environment conducive to viral replication. Tat, for instance, causes apoptosis of certain immunological cells, and promotes expression of receptors such as CXCR4 and CCR5 that are typically essential for HIV to attach to in infecting cells. Additionally, it induces costimulatory molecules CD40, 80, 86.

The native tat protein has also been shown to induce a shift from a B-cell, antibody mediated Th2 response to a T-cell mediated Th1. This is important because this shift in immunological response may help promote progression to AIDS. Tat is capable of cross the blood brain barrier with “toxic consequences” to the brain. As such, it may play a role in HIV associated dementia.

Because of the critical role tat plays in viral infection, it is not surprising that immunological response to tat is correlated with long-term non-progression of HIV infection to AIDS. Additionally, a mutation in an important tat receptor may be associated with reduced CNS damage in certain populations in India.

A very hopeful aspect about tat is that it may be conserved. That is, some research has shown that an immunological response against the A, C and D subtypes of HIV can also protect against the B subtype. This is crucial, as an effective vaccine would need to work against multiple subtypes.

Unfortunately, that tat is conserved is not an accepted scientific belief. Other research has shown the opposite: that a response to B type tat does not protect against A or C. Additionally, tat may be able to experience up to 40% sequence variation and maintain functional integrity, meaning that mutations in it are likely to arise, dulling the impact of an immune response. Finally, some have argued that only region IV of the six region molecule are conserved, and it is precisely this region that is protected against immune response by similarity to host sequences.

Initial clinical studies into the safety of tat vaccines have begun in Humans, with positive results. No significant toxicity or adverse events such as increased risk of viral progression have been witnessed, always a concern in vaccine development to a disease that preys on immune response. Before research progresses, however, it may be essential to further investigate the utility of a tat vaccine in protecting against multiple strains of HIV.

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Pharmaceutical analyst who loves blogging about health and medical issues. Has written more than 150 articles and a book on attention deficit disorder. Correctly predicted delayed approval of Bydureon, approval of Provenge by FDA, and the non-approval of Acthar on June 11.

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