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Live attenuated HIV
One of the most powerful ways to create vaccines is by weakening or 'attenuating' the pathogen against which protection is sought. This normally involves deletions of genes which normally protect the virus against the immune system, but which are not essential for its reproduction in other animals or in cell or tissue cultures. Vaccines based on this principle include the original smallpox vaccine and the live attenuated polio vaccines that are given to millions of children on sugar lumps.
In 1992, researchers from the laboratory of Ronald Desrosiers of the New England Primate Center in the United States demonstrated that a live attenuated vaccine, made by deleting a gene of HIV known as nef, protected monkeys against SIV (Daniel 1992). Researchers in the United Kingdom and France replicated these results. Hopes for a nef-deleted vaccine were further boosted by reports of human 'long-term non-progressors' identified in the United States and in Australia who were naturally infected with nef-deficient strains of HIV.
In their attempt to develop a live attenuated vaccine, Desrosiers and colleagues tried to delete as many genes as possible from the virus, while still preserving its immunogenicity. The basic strategy was to knock out those HIV genes which did not seem to be essential for the virus to reproduce in cell cultures. However, these studies showed that protection depends on having continued viral replication, i.e. a low-level infection, with the attenuated virus. They also showed that the more the virus is attenuated, the weaker the protection becomes.
Further complicating this picture, animal studies and human cohorts have shown that even these weakened strains of SIV may still cause immune deficiency. For example, Dr Ruth Ruprecht and colleagues reported in 1995 that a virus that had so many deletions that it was not fully protective against the SIV on which it was based still induced an AIDS-like disease in newborn rhesus monkeys. Follow-up of adult monkeys infected with the same strain suggested that the effect of the deletions was to increase the incubation period for SIV-related disease by a factor of three or more, but not to make the virus safe.
Enthusiasm for a live attenuated virus has been further dampened by the news that several of the 'non-progressors' infected with nef-deleted virus have experienced slow damage to their immune systems. These individuals have been reported as the Sydney Blood Bank Cohort - a group of eight transfusion recipients and a blood donor who have been infected with a nef-deleted strain of HIV for between 15 and 19 years. Of the six surviving members of the cohort, three have detectable viral loads and declining CD4 cell counts (between 16 and 73 cells/mm3 per year). The donor commenced antiretroviral therapy in February 1999 after developing an opportunistic condition at a CD4 cell count of 160 cells/mm3. The other three members of the cohort, who all have undetectable viral load, have not experienced significant declines in their CD4 cell counts (Rhodes 1999).
As things stand, an attenuated HIV vaccine will not be acceptable for human use until the mechanisms by which the virus causes disease are much better understood and can be disabled. However, this approach has not been a complete failure. Some of the ideas which were first tested in live attenuated vaccines may be included in other kinds of vaccines. For example, the use of genes for cytokines to generate specific immune responses is being tested in current vaccine trials.
The nearest and best alternative to a live attenuated form of HIV itself would probably be to take a live attenuated virus that is widely used as a vaccine against another disease, and include carefully chosen elements of HIV within it.