Transmissible gene therapy treatment proposed for HIV to curb epidemic

Engineered, virus-like particles that would latch onto HIV, exploit its genes, stop it from replicating and then get transmitted in the same way as HIV are being proposed as a new way of stopping the epidemic.

Biochemist Leor Weinberger and colleagues at the University of California, San Diego and UCLA, estimate that what they call `Therapeutic Interfering Particles` have the potential to reduce HIV prevalence 30-fold over 50 years in the worst epidemics in sub-Saharan Africa, compared with a halving of prevalence in the most optimistic alternative scenarios of antiretroviral use or use of a successful vaccine.

The findings are published in theMarch 17 issue of PLoS Computational Biology.

"TIPs are molecular parasites that 'piggyback' on HIV to spread between individuals," Weinberger said.

TIPs are a form of gene therapy, in that they would incorporate into human cells and use human cells, together with HIV’s genes, in order to reproduce. Other forms of gene therapy also being explored include CD4 cells that have been genetically altered in order to eliminate a target protein on the cell surface that is used by HIV in order to enter the CD4 cell.

In the case of TIPs, the engineered particles use the same outer envelope as HIV but lack the genes for components of this structure and the enzymes needed to assemble it. They can only replicate, infect additional cells and transmit to new individuals by stealing these elements from HIV. Until the host cell is infected with HIV, TIPs remain dormant.

When the cell is infected the TIP is activated, and it begins to replicate. Because the TIP genome is shorter than the HIV genome, it would replicate faster and would be able to hijack any HIV capsid or envelope products generated within an infected cell in order to spread to other cells. (The capsid is a conical structure that packages other HIV genes inside the envelope).

These TIPs, once produced, could be passed onto another person by the same transmission routes as HIV. However, once they had infected another person, the TIPs would lie dormant and could not replicate further – or be passed on to others – unless that person was exposed to HIV and subsequently began producing TIPs.

Thus the primary mechanism by which TIPs would limit the growth of the epidemic is by limiting viral load, rather than acting as a form of freely transmissible vaccine. Indeed, say the researchers, TIPs can also be considered as an adjunct to treatment.

However their effectiveness in limiting viral load would be much greater than treatment at a population level because only one injection – or one infection – would be needed to introduce the antiretroviral effect of the TIP.

In contrast conventional antiretroviral treatment must be taken every day, must be delivered through a functional health system, and must be funded consistently. In all these respects African countries are likely to continue to face huge challenges in using treatment as a means of bringing down the number of new infections.

Two of the major challenges for `treatment as prevention` approaches will be how to reach those who are hardest to reach with treatment before they infect others, and how to reach people soon after infection when they are most likely to pass on the virus.

In both respects, say the authors, TIPs would prove superior.

Their transmissible nature means that they would follow sexual and drug-injecting networks rather than relying on the intervention of the health system to reach all those at risk of infection. In addition they would not require regular mass testing in order to identify people with HIV: the virus will trigger the TIP to start replicating, and the particle will do the rest.

Also, because the TIP would respond immediately after infection, this approach ought to limit viral load during the early weeks after infection, even if infection is not prevented entirely. This would minimise the risk of passing on HIV during the time of peak infectiousness.

TIPs wouldn't replace other therapies, Weinberger said, "In part, we are arguing that TIPs could be used in conjunction with current antiretroviral drug therapy or vaccine campaigns, and could enhance the efficacy of these campaigns at the population level."

For the time being the research group’s findings are based on a mathematical model, and the only evidence that the idea might work comes from animal studies that show that a lentiviral vector similar to a TIP is taken up by HIV and subsequently inhibits HIV replication.

Weinberger acknowledges that an infectious treatment raises ethical concerns and is working with bioethicists to explore the unique issues associated with any use of TIPs in more detail.

The researchers say that any research into the human use of this potential technology will have to proceed cautiously, both to examine the genetic safety of a lentiviral vector that can insert itself into human cells, and also to test how the TIP would evolve, whether it would be cleared by `carriers` and whether the TIP might have unexpected interactions with the human immune system.

In particular, animal studies will need to test whether TIPs might paradoxically drive up HIV replication, or cause mutations in human cells.

This work was funded by a grant from the Bill and Melinda Gates Foundation and an NIH Director's Innovators Award to Leor Weinberger.

Metzger VT, Lloyd-Smith JO, Weinberger LS. Autonomous targeting of infectious superspreaders using engineered transmissable therapies. PLoS Computational Biology, March 17, 2011.