So we can’t do for everyone as we did for
Brown. Rowena Johnston is vice-president and director of research for amfAR,
the American Foundation for AIDS Research, which last year launched ARCHE – the
Research Consortium on HIV Eradication,5 a network of
researchers investigating a cure (see www.amfar.org/cure).
“With Brown they used a more intense and
toxic regimen to prepare him for the transplant than is ever used in the United States,” says Johnston. “But even if all the procedural
details were worked out, you’d never find enough donors with the delta-32
Something along the lines of Brown’s cure has
been discussed since the dawn of the epidemic. One research paper6
documented 32 attempts between 1982 and 1996 to eradicate HIV using bone marrow
transplantation. In one in 1989,7 doctors succeeded in wiping out
HIV from the T-cells of a man dying of non-Hodgkin’s lymphoma within a month of
a bone marrow transplant from a negative donor. He died two weeks later of the
cancer, but autopsy specimens from brain, bone marrow, gut and other organs
could find no HIV.
The reason HIV is so hard to eradicate is
twofold. Firstly, a tiny proportion of cells infected with HIV become ‘resting
memory’ cells. These are cells whose job it is to stay secreted away in tissues
like the brain, lymph nodes and gut, like sleeper cells in a resistance
organisation, until a new infection comes along that resembles the one in which
they were originally created.
Secondly, ARVs seem to block most, but not
all, virus replication so there are still very low levels of virus replication
in patients on treatment – although its significance is an area of hot debate.
The problem with HIV is that one in every
thousand to every million resting memory cells is a double agent. Instead of
being equipped to fight HIV, it actually contains within its DNA, HIV’s genetic
code. As soon as you relax the police state enforced by ARVs, these cells set
off a whole new wave of infection.
Cells that produce virus soon die, but
putting people on ARVs means that the memory cells may never be activated. They
can lurk in the body life-long, as a ‘reservoir’ of HIV.
If you take someone off ARVs for a short
while, some reservoir cells die but other memory cells are infected, so you
just replenish the reservoir. This is why structured treatment interruptions
(‘drug holidays’) didn’t work.
Steven Deeks is professor of medicine at the
University of California. He puts it this way: “The
fundamental problem is that you’re trying to stimulate the output of part of
the immune system while dampening down another part.”
What we need is some fiendishly clever way
to get the HIV-infected lurking cells to come out of hiding and blow themselves
up, while at the same time protecting uninfected cells from infection.
They managed this with Brown – but only by replacing his immune system with
Several other attempts to cure HIV didn’t
work either – although they may in the end contribute to a cure.
early treatment. If you know someone has acute HIV,
within the first three weeks of infection, and give them ARVs right away, the
number of infected resting memory cells (the ‘reservoir’) is 10 to 100 times
less than in patients treated during chronic infection. In a few patients
treated like this, after stopping ARVs the viral load stayed low.8
In another study, however, HIV returned 50 days after therapy in a patient
treated early who only had one in every 1.7 billion resting memory cells
infected.9 In any case, this strategy would only work for the small
minority of people who test for HIV when they have acute infection.
intensification. If you added more drugs to someone’s
ARV regimen, would it drive their viral load down to a point below which there
was too little HIV left for it to come back? A tall order if it requires fewer
than one in two billion cells to be infected, but there were high hopes when
the integrase inhibitor drug raltegravir (Isentress) came along, as it lowers
viral load faster than other drugs. A trial found, however, that it had no
significant effect on the residual replicating virus in the body.10
Similarly, maraviroc, the first drug of the CCR5 inhibitor class, failed to
drive viral load down to any useful extent when added to a regimen11
even though, as we have seen, CCR5 may hold the key to a cure.
stimulation. You can use cytokines (naturally occurring
immune modulators like IL-2 or IL-7) to activate resting cells to produce HIV
and destroy themselves. But IL-2 had no effect on the number of resting
infected cells,12 and the type of cells it stimulated do not replace
HIV-infected cells as a bone marrow transplant does. Also, IL-2 and IL-7 may
cause resting infected cells to divide and replenish the reservoir.13
Immune stimulant drugs can be very toxic: many patients found IL-2 hard to
tolerate and a previous study using IL-2 and another immune modifier called
OKT-3 left some in intensive care.14
vaccine. Studies show that most of the minority of
people who control HIV without drugs have CD8 cells (the ones that kill
HIV-infected cells) with unusually high activity against HIV. You could try to
enhance CD8 cell responses with a therapeutic vaccine made from
immune-stimulating bits of HIV. But therapeutic vaccines by themselves have no
great record of success. They do seem to stimulate the anti-HIV activity of CD8
cells, but are ineffective at controlling HIV replication, probably because the
virus can mutate to evade the surveillance of the CD8 cells.15 If it
does, it can come back stronger than ever.16
And yet…the point about Timothy Ray Brown’s
cure is that, as Steven Deeks says, “For the first time ever, something worked.”
Rowena Johnston adds: “What’s important is
that it focused attention that an HIV cure is possible and realistic and that
this is a worthy research area to fund.”
So how might we cure HIV infection in ways
that are safer and less toxic than what happened to Brown? Clearly, if we knew,
we’d be doing it. But researchers are engaged in the early stages of a number
of promising strategies.
To find out what they are, you’ll have to
read part two next month…