A cure for HIV infection is scientifically
feasible and increasingly necessary, but the goal requires focus and funding, said
Sharon Lewin of Monash University in Melbourne,
in a keynote address at the opening session of the AIDS 2010 conference and at a
preceding workshop organised by the International AIDS Society (IAS).
Antiretroviral therapy has dramatically
reduced illness and increased survival, but people with HIV still do not
achieve normal life expectancy relative to the general population, Lewin said.
In addition, a growing body of evidence indicates that even very low-level
virus contributes to a number of health problems.
The most sensitive tests can find residual
HIV in almost everyone infected, including people on effective combination
therapy and elite controllers who suppress the virus naturally. "There is
no such thing as an undetectable viral load," Lewin added.
As Steven Deeks from the University of
California, San Francisco explained at an IAS pre-conference meeting on HIV
reservoirs and eradication, these problems
– which range from cardiovascular and liver disease to neurocognitive
impairment and bone loss
increasingly linked to chronic immune activation and inflammation triggered by
"There's some sort of HIV-related
problem that's causing people to get sick earlier than they otherwise would
have," he said.
What's more, long-term antiretroviral
therapy for everyone is not sustainable. Lewin noted that even treating the
current 40% of HIV-positive people in low- and middle-income countries starting at the
old World Health Organization CD4 threshold of 200 cells/mm3 would
cost $25 billion by 2030, whilst increasing coverage to 80% would raise that
figure to $35 billion.
The main barriers to curing HIV, according
to Lewin, are latently infected T-cells, residual viral replication, and
anatomical reservoirs (such as the brain, gut and genital tract) that harbour
Most T-cells in the body are resting, she explained.
HIV mostly infects active CD4 T-cells, which produce new virus but then soon
die. In resting cells, by contrast, HIV genetic material is integrated into the
host cell's genome where it can remain dormant for a long time, but can
"wake up" at any point and reignite viral replication.
The IAS workshop devoted considerable
attention to the ongoing debate about whether problems in people on suppressive
antiretroviral therapy are attributable to residual low-level viral
replication, re-emergence of latent virus from reactivated T-cells, or a
combination of the two.
Scientists do not fully understand how HIV
evades the immune response and establishes latency in resting cells, but a
variety of signalling molecules and transcription factors appear to play a
role, and thus offer potential targets for intervention.
Intensification of antiretroviral therapy
by adding more drugs has not been able to eradicate HIV in multiple studies to
date. A more promising approach uses agents such as interleukin 7 (IL-7) to
activate resting cells and flush HIV out of hiding. Another strategy uses
compounds called histone deacetylase (HDAC) inhibitors to turn on HIV genes.
Some two dozen HDAC inhibitors are under
study as cancer treatments and one, known as vorinostat or SAHA, is already
licensed for T-cell lymphoma. These agents, along with IL-7, appear safe and
well-tolerated and should quickly move into clinical trials, Lewin said. She
predicted that a combination approach would be most effective.
Daria Hazuda from Merck Research Labs,
speaking at the IAS pre-conference meeting, said her company has screened
millions of compounds, including numerous HDAC inhibitors, and found several
dozen that warrant further study.
Whilst such agents might achieve a 'functional cure' or long-term remission, future approaches could
potentially protect cells completely from HIV infection and thereby achieve a 'sterilising cure'.
The international conference in Vienna will not be the conference
where we announce a cure, but it will mark the
beginning of a future where we seriously prioritise finding a cure. Professor Sharon Lewin, Monash University
The experience of one man in Germany, dubbed the 'Berlin patient', offers
proof-of-concept that this may be possible. Gero Hütter, who treated the
patient, described the case at the IAS pre-conference meeting.
The man underwent chemotherapy for
leukaemia that destroyed his own immune cells and received bone marrow stem
cell transplants from a donor who carried the protective CCR5-delta32 mutation,
which makes cells resistance to HIV infection. Within two months after his
first transplant the man showed no measurable HIV, despite stopping
antiretroviral therapy. Three years later, he still shows no signs of
While widespread bone marrow transplants
are not realistic, Lewin acknowledged, this patient tells us that getting rid
of latently infected cells and living without antiretroviral treatment is
possible, and we need to learn why. Researchers are now pursuing a related
approach, using gene therapy to make cells HIV-resistant.
Lewin urged greater resources for an HIV
cure and a collaborative effort of basic scientists, clinicians, pharmaceutical
companies and funders, as exists for HIV vaccine research. In recent months,
amfAR and the US National Institutes of Health have announced funding for
cure research, though advocates
argue that it is not sufficient.
"The international conference in Vienna will not be the conference
where we announce a cure," Lewin concluded, "but it will mark the
beginning of a future where we seriously prioritise finding a cure."
Watch the keynote address from Sharon Lewin on the Kaiser Family Foundation website.