Focus On...

Scientific obstacles to an effective HIV vaccine
8 December, 2008

Reprinted with permission from Pfizer Pipeline.

"HIV has an uncanny ability to avoid immune responses and replicate continuously," says Ronald Desrosiers, professor in the Dept. of Microbiology and Molecular Genetics at Harvard Medical School. "The virus has only nine genes, and three are devoted to evading immunity. At the beginning of this epidemic, did anyone think its defeat would be so difficult?"

Desrosiers cited four scientific reasons to explain the lack of an effective vaccine more than two decades after HIV was identified as the cause of AIDS. First, the natural immune response to HIV does not control the virus. The body seems incapable of clearing HIV and immune responses to natural infection do not routinely protect against re-infection. Consequently, vaccine developers cannot identify, analyze or mimic a natural, protective immune response.

Explosive replication commences shortly after infection, and a subsequent decline in viral load to a setpoint still represents a dynamic state of persistent viral replication. The half-life of an HIV-infected cell is only one day. In addition, retroviruses such as HIV produce numerous genetic mutants due to the high error rate of reverse transcriptase. During chronic HIV infections, single mutations at any position of the viral genome could conceivably arise thousands of time a day. "Mixing and matching" of mutations during genomic recombination furnishes large numbers of mutant viruses equipped to escape the humoral and cellular immune responses of the infected person.

A second scientific challenge is that a person's natural immune response to HIV infection does not protect against superinfection, i.e., simultaneous infection with another strain. Thus, even robust antibody responses to a single HIV strain would offer no protection against different strains.

Third, the enormous genetic sequence variability in the virus complicates the selection of immune-stimulating portions that could be used in a vaccine. Among currently circulating HIV subtypes, for example, gene products diverge by 15% to 30% at the amino acid level. With the influenza virus, amino acid divergence of only 2% between a vaccine and the circulating strain requires a change in the vaccine strain. Finally, no one yet knows what constitutes a protective immune response to HIV.

Disappointing results in three human efficacy trials underscore the need to return to basic discovery research, according to Desrosiers. "The classical vaccine approach—to deliver HIV immunogens that stimulate a protective immune response—clearly isn't working," he says. "We need to look at non-classical approaches. How do you deliver potent, broadly neutralizing antibodies to HIV?"

To answer that question, Desrosiers and his colleagues at Harvard are exploring the possibility of using persistent viral vectors to deliver antibodies that will create a permanent protective barrier to HIV. Their experimental model is the simian immunodeficiency virus (SIV), which Desrosiers isolated and identified in 1984. The team created a live, attenuated SIV vaccine so they could study immune responses, although an attenuated vaccine would never be considered for human use for safety reasons.

The team has also engineered a rhesus monkey rhadinovirus (RRV) to act as a viral vector in an SIV vaccine. To date they have achieved SIV-specific CD8+ responses of high magnitude and persistence. The vaccine also produced a 62-fold reduction in viral load. Six of nine monkeys vaccinated with the vectored vaccine developed sterilizing immunity, proof that a vectored SIV vaccine could work.

"What we really need is an economic stimulus package to foster basic HIV research," says Desrosiers. "The government sponsored the Manhattan Project, and it succeeded because all of the theoretical underpinnings for an atom bomb were in place. That's not the case with an HIV vaccine right now. We still need to learn what genetic and molecular factors allow this virus to evade the immune system so successfully."

Desrosiers' call for a return to basic HIV research doesn't eliminate creativity. Administration of the recombinant RRV vaccine, for example, produced several gene-expressed products in vaccinated monkeys. But researchers found no anti-SIV envelope antibodies. "That's still a mystery," says Desrosiers. "Of course, the surprising results are the important ones. In science, you come up with the creative idea and then embark on a series of experiments. In discovering the fundamental principles, you lay the foundation for a breakthrough."