HIV/Ebola comparison could spur new treatments
HIV/Ebola comparison could spur new treatments
Aaron Diamond researcher answers questions
(Editor’s note: Paul Bieniasz, PhD, a staff investigator at the Aaron Diamond AIDS Research Center and an assistant professor at Rockefeller University, both in New York City, has discovered a similarity between the HIV and Ebola viruses: Both use the same method to spread through the human body. Bieniasz, who has worked primarily on the virus host-cell interactions that occur during HIV-1 entry, transcription, and particle assembly, discusses his recent findings with AIDS Alert.)
AIDS Alert: How did your research team decide to compare HIV to Ebola virus, and how long have you been working on this particular investigation?
Bieniasz: My team has been working on the mechanisms of HIV-1 particle assembly in general for a little under two years. We initiated studies specifically on late budding events, i.e., the final stages of particle assembly, earlier this year. By that time, significant evidence had accumulated in the scientific literature to suggest that host-cell factors play an important role in the budding of retroviruses as well as other enveloped viruses. We were also struck by the fact that a small sequence that is critical for the budding of HIV-1 occurs in some other viruses, including Ebola virus.
AIDS Alert: Please explain your findings about how both viruses utilize the Tsg101 protein.
Bieniasz: HIV and Ebola virus make proteins, called Gag in the case of HIV and Vp40 in the case of Ebola virus, that drive the formation of virus particles. Both of these proteins bind to the inner surface of the cell membrane, where they coalesce to form a budding structure. Ultimately, the bud pinches off a piece of the cell membrane, which then forms the envelope of the new virus particle. Our work indicates that a host cell protein, called Tsg101, is required for the completion of this budding event.
We found that a small sequence that is conserved in HIV Gag and Ebola Vp40 is both necessary and sufficient to interact with Tsg101. By genetically manipulating HIV Gag and Ebola Vp40, we made a variety of mutants, and we found that any mutants that were unable to bind to Tsg101 were also unable to bud efficiently from cells. This perfect correlation between Tsg101 binding and efficient budding strongly suggested that the two events are functionally linked. In addition, we found that both HIV-1 Gag and Ebola Vp40 recruit Tsg101 to sites of particle assembly at the outer membrane of the cell. Finally, a mutant HIV strain that is unable to bind to Tsg101 and therefore cannot bud into the surrounding medium can be rescued by artificially tethering Tsg101 to the site of particle assembly.
Taken together, these findings make an extremely compelling case that Tsg101 participates in the budding process of both HIV-1 and Ebola virus. What makes this especially interesting to us is that Tsg101 is thought to participate in the physiological budding of membranes within cells. Thus it appears that these two viruses (and possibly others) have parasitized this normal cellular process in order to facilitate their own replication.
AIDS Alert: In light of the similarities between the two viruses, what are the key differences that make HIV a much slower virus than Ebola?
Bieniasz: It is likely that Ebola virus and HIV-1, as well as many enveloped viruses, use broadly similar mechanisms to get into and out of cells. However, once inside cells where virus multiplication occurs, the two viruses use very different strategies. While this in itself does not explain why Ebola virus causes acute infections and HIV-1 causes chronic infections, it is likely to be contributory. Many factors contribute to defining whether a given virus is "slow" or "fast," such as the kinetics or speed with which the virus can complete its life cycle, how many different tissues it can infect, the amount of progeny virus produced by a single infected cell, how quickly the infected cell dies, how effectively the host mounts an immune response, and whether the virus is capable of remaining latent within a sub-population of infected cells. Each of these properties can, in principle, contribute to the overall characteristics of the infection.
Ebola virus replicates rapidly in many cell types, makes very large quantities of progeny, and does not appear to be capable of latently infecting cells. In contrast, HIV-1 replicates at a more modest but still significant speed in a more restricted cell population and is clearly capable of establishing latency.
AIDS Alert: These days, when the world’s mindset is focused on terrorism, it seems natural to ask whether it is possible for scientists to manipulate either HIV or the Ebola virus to create a fast-acting, more easily transmitted virus that could be used in a bioterrorism scenario.
Bieniasz: I think that this is an extremely remote possibility. While HIV is rather easy to genetically manipulate and we know a great deal about its biology, we do not know how to easily make it "faster" and more easily transmitted. Perhaps such an HIV-based virus could be engineered, but it would take a sophisticated research program many years to accomplish, if it is possible at all. Ebola virus already causes a rather frightening, rapid infection, but its poor transmissibility limits its potential as a biological weapon. Ebola virus is much more difficult to manipulate in the laboratory, and we do not know enough about its biology to rationally engineer increased transmissibility.
AIDS Alert: How might your discovery lead to a more potent treatment for HIV and Ebola virus?
Bieniasz: The identification of essential virus-host cell interactions presents possibilities for the discovery of new classes of agents that can inhibit virus replication by blocking these interactions. In the case of Tsg101, the binding site on viral proteins is small, and it might be possible to mimic this structure with a small molecule inhibitor. Such compounds would be predicted to exhibit significant antiviral activity. We do not yet know if these agents would also interfere with important interactions between Tsg101 and other host cell proteins, and, as such, be toxic. However, this is a promising avenue of research and one that we are currently pursuing.
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