We’re used to combination therapy against
HIV and have more recently started talking about combination prevention. A cure
for HIV is also unlikely to involve one ‘magic bullet’. Any cure is likely to
involve several different approaches, used together or sequentially.
For instance, we don’t yet know if there is
a threshold number of infected cells below which active HIV replication is very
unlikely to restart. It’s like cancer: can we tolerate a few infected cells in
the body, or will the presence of even one eventually lead to the return of
HIV?
We could therefore use HDAC and NFκB
inhibitors to flush out the majority of infected cells, use engineered CCR5-negative
cells to try and replace them, and use a therapeutic vaccine to mount continued
surveillance against whatever small minority of HIV-infected cells might still
remain. Or – since one of the problems with therapeutic vaccination is that it
depends on enhancing an immune response, which may lead to more infection – use
an immune-suppressant drug to ‘lock down’ the infected remainder.
There have been a number of attempts already
to deliver several HIV eliminators in one package. For instance, the Australian
biotech company Benitec has devised a combination consisting of an enzyme that
snips out CCR5 from CD4 cells, combined with sections of ‘interfering’ RNA that
delete HIV’s reverse transcriptase enzyme and its Tat protein, the viral toxin
that over-excites CD4 cells into an HIV-receptive state in the first place.
This is all wrapped up in a vector, the shell of an HIV-like virus that infects
cells with the genetic products and gets them to start making them. Zaia’s team
at the City of Hope Hospital in Duarte,
California, has already done a Phase
I proof-of-concept trial in lymphoma patients in which the genetically modified
cells produced the HIV-disabling products for over two years, though only at
low levels.18
We are only as yet on the first steps of a
journey towards making a cure practicable for all, though in researching this
article I sensed a new confidence amongst researchers that it might be
possible. Many refused to guess at timelines, but Steven Deeks told me that a
usable cure strategy would take “at least ten years”.
Sharon Lewin of Monash
University in Melbourne,
Australia, made a keynote address
at the opening of the International AIDS Conference in Vienna last year,19 and, with
Nobel Laureate and co-discoverer of HIV, Françoise Barré-Sinoussi, was
instrumental in pulling together a pre-conference two-day workshop on strategies
towards a cure.20
In her keynote address she said she was
encouraged by two major cure-research initiatives now underway: amfAR’s ARCHE
initiative, which had a budget of $1m, and the Martin Delaney Collaboratory, a
public/private partnership of research labs funded to the tune of $8.5 million
by the US National Institutes of Health and named after the late AIDS activist
who founded Project Inform. However, she pointed out that less than 10% of the
current funding for an HIV preventive vaccine is currently devoted to curing
HIV.
“Cure research doesn’t have to be hugely
expensive,” she told HTU. “You don’t
need the big trials with tens of thousands of people you need for vaccine and
biomedical prevention studies. The initial discoveries can be made with studies
of 100 people. But we do need large, multidisciplinary consortia like the
Martin Delaney project to ensure that research is co-ordinated and not
wasteful.”
The final question, though, is one only
Deeks addressed, among the researchers I talked to. We can control HIV and the
illness caused by it, but it’s becoming apparent we may never be able to treat
everyone because of the massive levels of funding, human resources and healthcare
provision needed. Will the same be true of a cure?
“A cure is going to be expensive,” he said.
“If we were going to do it with aspirin we’d have done it by now. It may also
carry with it a degree of risk, and researchers and patients may have to ask
themselves how much risk they are prepared to tolerate if the result is going
to be elimination of HIV.
“But it’s going to be a lot more affordable
than lifelong antiretrovirals in resource-rich countries. As to whether it
would be scalable for poor countries, though – ah, that’s a very different
question.”