Opinion
News Analysis
The Year Ahead
Business
and Finance
Science, Technology,
and Medicine
The Biology of Hope
AIDS Research
Old drugs, new indications
Obesity
Immune Modulators
Hospitalists
Plastic Surgery
Drug delivery: the Biopump
Xenotransplantation
DNA replication
Genomics
Biofilm
Junk DNA
The polypill
Molecular pathology
People:
Tom Cech
People:
Stanley Falkow
People:
Heino von Prondzynski
The Bibliome
Future Trend
Policy, Society,
and Ethics
Reviews
Metrics
Common Sense
Editor's Letter




spacer

The Best Defense

Protective strategies that focus on viral infectivity factor may be more effective than direct combat in fighting HIV.

When fighting HIV, “almost” is not good enough. Expensive drugs with inconvenient dosing schedules and unpleasant side effects can reduce the amount of virus in infected people to undetectable levels, but they donít finish it off. As soon as a patient stops highly active antiretroviral therapy, commonly called HAART, the virus, quiescent in a small reservoir of inactive immune cells, returns to dangerous levels. Clinicians once thought patients needed simply to stay on HAART long enough for the last cells harboring the virus to die off, but the approach failed in human trials, and calculations now put the time required at 50 years or more.1

Lately, the possibility that infected patients could come off HAART and stay that way is within reach, according to the National Institutes of Healthís head of basic aids research, Carl Dieffenbach.

“A year ago, I would have said I canít conceive of a way that people could stay off,” Dr. Dieffenbach says. “I would have been a lot more pessimistic, but in the intervening year, all these studies of Vif have come out.”

The viral infectivity factor that Dr. Dieffenbach is referring to is a protein that serves as HIVís defense against the bodyís virus-fighting system. One defense mechanism, a human protein called APOBEC3G, causes HIV to “hypermutate,” which renders the virus inactive; infected cells in which APOBEC3G has done its work make less than 2% of the normal number of viruses, and those that emerge are much less infectious.2 But if Vif is around, APOBEC3G is in for a difficult time. Vif grabs APOBEC3G and dumps it into a cellular shredder known as the proteasome, destroying it within minutes.3,4

Mutant HIV that lacks the Vif gene is unable to infect cells in culture; a Vif-less version of SIV, the monkey equivalent of HIV, is less able to infect lab animals. The reason simians donít get AIDS is probably that Vif is powerless against nonhuman versions of APOBEC3G.5 With Vif stopped, says Dr. Dieffenbach, “the virus has the potential to mutate itself to death.” David Kabat, a professor at Oregon Health and Science University whose lab helped determine Vifís function, agrees. “If there were a lot of mutant HIV floating around in a person, the chances of active HIV surviving would be very small,” he says, especially given all the other current HIV drugs that could be thrown at it.

spacer
spacer
spacer

1  Siliciano, J.D. et al. (June 2003) Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nature Medicine 9:727Ė8.

spacer

2  Apoliprotein B MRNa-editing enzyme, catalytic polypeptide-like 3G, also known as CEM15.

3  Marin, M. et al. (October 2003) HIV-1 Vif protein binds the editing enzyme APOBEC3G and induces its degradation. Nature Medicine. Published online.

4  Sheehy, A.M. (October 2003) The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif. Nature Medicine. Published online.

5  Mariani, R. et al. (July 11, 2003) Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif. Cell 114:21Ė31.

spacer