AIDS TREATMENT NEWS - October 16, 2005
John S. James

Summary: We use this well-publicized research finding as a starting point for discussion of different kinds of immune-based therapy.

A laboratory study comparing recent (2002-2003) vs. early (1986-1989) untreated HIV found that the recent virus reproduced somewhat less well, and appeared more sensitive to two antiretrovirals tested (3TC and TAK-779, a CCR5 antagonist no longer being developed as a drug). The authors suggested that "this 'attenuation' could be the consequence of serial bottlenecks during transmission and result in adaptation of HIV-1 to the human host." [1]

Comment

It is common for infectious diseases to become less severe after they have been in a population for a long time. One mechanism is that bacteria or viruses that kill people or animals too quickly have less time to spread, so greater virulence is a selective disadvantage. At the same time, the individuals more resistant to the disease are more likely to survive and reproduce. The new study [1] shows the first evidence that such attenuation of HIV (with the virus becoming less able to reproduce, and also less able to be transmitted) appears to have occurred.

The "bottlenecks" quoted above refer to the fact that HIV loses its genetic diversity when transmitted from person to person -- perhaps because only one virus or very few succeed in getting established in the newly infected person. Unfortunately genetic diversity then develops again, separately within each infected person, since HIV makes many mistakes in replication. This diversity is important in disease progression, as viruses can become less susceptible to control by parts of the immune system, much as they become resistant to drugs. The authors note that the transmission bottlenecks could result in overall reduction in viral fitness if more fitness is lost during each transmission than is gained as viral diversity develops again in the person infected [1] -- one possible mechanism for attenuation of HIV over time.

Other evidence suggests that when an animal population has long been infected by a retrovirus, the virus may be present with a high viral load, but the animal does not get sick -- while the same virus kills animals in other species where it is not native. [2] This seems to be how populations adopt to retroviruses (there are no human examples, as HIV was the first retrovirus found to infect humans). Of course no one wants to wait centuries for the HIV epidemic to control itself this way.

This animal observation supports the belief that there could be two very different kinds of immune-based treatment -- helping the immune system suppress HIV and reduce viral load (much like antiretroviral drugs do), vs. preventing human responses to the virus that cause the symptomatic illness (this kind of treatment might not suppress viral load, and might even allow it to increase). There has long been some interest in "immune suppressive therapy," reducing immune responses to HIV infection that may do more harm than good in some patients.

The problem today is that little research has been done on immune-based treatment of any sort. We do not have a good understanding of what immune responses are needed to control HIV -- and while a handful of people have used immune-suppressive drugs like prednisone to treat HIV infection, these drugs were not developed or formally tested for that purpose, and little is known about whether, when, or how to do this safely. (Note: immune-based therapy was not discussed in [1].)

The immune system includes many different mechanisms; it should not be thought of as just more or less (as the phrase "boosting" the immune system wrongly implies). The practical importance of getting this picture right is that immune-based therapy that acts against HIV is not the opposite of immune-suppressive therapy. In the future, both kinds might be used -- even together in the same patient at the same time.

References

1. Arien KK, Troyer RM, Gali Y, Colebunders RL, Arts EJ, and Vanham G. Replicative fitness of historical and recent HIV-1 isolates suggests HIV-1 attenuation over time. AIDS. 2005 Oct 14;19(15):1555-64.

[2] Rey-Cuille MA, Berthier JL, Bornsel-Demontoy MC, Chaduc Y, Montagnier L, Hovanessian AG, and others. Simian immunodeficiency virus replicates to high levels in sooty mangabeys without inducing diseases. J Virol. 1998 May;72(5):3872-86.

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