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
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.
findings are published in theMarch
17 issue of PLoS Computational Biology.
are molecular parasites that 'piggyback' on HIV to spread between
individuals," Weinberger said.
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.
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.
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).
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
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
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.
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
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.
both respects, say the authors, TIPs would prove superior.
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.
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.
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."
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.
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.
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.
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.