I see the body through a crack in the autopsy room door, lying on
the stainless-steel bier, half covered by a faded blue sheet. His
face -- once vibrant -- is now still, the eyes in an intense stare
as if transfixed by something on the ceiling. Bulging from the door
rack is his chart, with an autopsy permit and hastily scribbled note
clipped to its worn manila cover: "Forty-year-old white male
landscaper. History of colds and mild weight loss attributed to long
work days in damp weather until hospitalized for pneumocystis
carinii pneumonia (PCP) in 1994. CD4 160, severe hypertension.
Placed on AZT and antihypertensives. Improved. Added Epivir in 1995,
Crixivan in 1996. Counts increased, viral load dropped. Developed
acute-onset renal failure. Also memory problems. Possible early
HIV-1 dementia. What about the brain?"
That's a good question, not just for this late landscaper, but
for anybody with HIV -- including me. What about the brain?
As expected, treatment failures are beginning to dampen exuberance
over protease inhibitors, and bigger problems may loom. What will
happen if multidrug therapy prolongs life but fails to stop virus
lurking in the shadows of the brain? Will the miracle of longevity
-- a seemingly hopeless fantasy for people with HIV not so long ago
-- be rendered meaningless by an increase in late-onset dementia?
After donning layers of protective garb, I approach the corpse's
head. And with a slash of the scalpel, ear to ear, I cut through the
once-admired hair and peel the scalp forward, draping it to shield
myself from his staring eyes. Invading the skull -- peering into the
temple of the brain -- always leaves me in awe. For within its
fleshy folds lies the very mystery of our souls. But there is
something unnerving about entering this particular temple. Perhaps
it's the memory of an AIDS autopsy that I performed years ago, when
the slip of a scalpel exposed my blood to the virus, and, in an
instant, shoved me from the ivory-tower life of a neuropathologist
into the perilous underworld of an HIV patient. Or maybe I'm fearing
the future. This man's fate might someday be mine: If the virus
slips into my brain and silently begins its destruction, it could
take years to discover.
It has long been apparent that HIV can invade the brain early.
During the weeks immediately following infection, about five percent
of patients develop meningitis -- inflammation of the brain's
coverings -- and traces of HIV can sometimes be found in their
cerebrospinal fluid before it shows up in their blood. Recent
studies have also found the virus (or its antibodies) in the brain
and cerebrospinal fluid of the asymptomatic.
Though the route of entry is uncertain, many researchers support
the "Trojan Horse" theory: As a stowaway in circulating monocytes
(patrolmen of the immune system), HIV is able to sneak past
checkpoints in the blood-brain barrier -- a cellular fence around
the brain's blood vessels that keeps large blood-borne molecules
from entering. Once inside, HIV begins a slow sabotage of cells,
perhaps triggering the release of neuron-damaging toxins. As with
Alzheimer's disease, symptoms from minuscule nerve-cell loss develop
slowly over the years, masked by the brain's reserve capacity, as
well as its impressive ability to compensate for minor indignities.
In the pre-protease days, AIDS patients died from opportunistic
infections before their intellectual decline became noticeable.
Others developed subtle memory loss. And about 20 percent developed
HIV-associated dementia as a late complication.
Perhaps that's the case with the man whose skull I'm about to saw
open, in search of clues that his brain may hold about the course of
his HIV infection and; by implication, the course that may await the
rest of us. I recall the note: placed on AZT. Added Epivir in
1995, Crixivan in 1996. Cautiously, I cut the brain stem,
releasing the brain from the quiet safety of its sanctuary; I wonder
if his drugs ever infiltrated it. I marvel at the irony that while
HIV has no trouble sneaking past the border patrol of the
blood-brain barrier, the drugs that supposedly fight the virus have
failed to build their own Trojan Horse.
Most HIV medications, including DDC, DDI, 3TC, Saquinavir and
Ritonavir, don't cross the blood-brain barrier reliably. d4t crosses
sluggishly and AZT's track record is only slightly better, with
approximately 20 percent to 25 percent penetration. Thus, it's not
surprising that many studies have shown that standard doses of AZT
do not protect against dementia, even though early research reported
that treatment with high doses of AZT improved cognitive function in
Even more disturbing are recent findings from the NIH and Johns
Hopkins University that patients with undetectable viral loads after
a year on a protease inhibitor (as part of highly active
antiretroviral therapy -- "HAART") still have apparently replicating
HIV in memory CD4 cells. And this may be worse in the brain: In
another study, HAART was administered to a patient with
HIV-associated spinal chord damage, and while it reduced the plasma
viral load below detection limits, it failed to reduce it in the
central nervous system -- which, of course, includes the brain.
Troubling? Very much so, since it suggests that even if HAART has
reduced your viral load to undetectable levels, you could still have
HIV-related damage in the brain that might emerge unexpectedly years
The good news is that HIV in the brain doesn't necessarily mean
the worst -- the virus eventually enters the brains of most
patients, but only a fraction develop dementia. And many patients
with significant HIV in their brains or cerebrospinal fluid exhibit
no signs of dementia.
Other factors are clearly involved, most likely certain proteins
made and released by immune cells in response to HIV infection. In
addition, viruses like CMV and herpes have also been found in the
brains of demented patients. All of this indicates that prevention
of dementia may require drugs that stop not only HIV but also
co-conspirators and toxins unwittingly produced by our own cells.
Fortunately, such drugs are already available, and others are in
But promised help comes too late for the man who lies before me.
I carefully lift the brain from the skull and lower it into a bucket
filled with formaldehyde, where it will pickle for two weeks. Then,
I'll section the brain, turn on the microscope and search the
labyrinth of his mind for HIV. The findings -- an epilogue -- will
perhaps bring closure to the final chapter of his life. And, in a
sense, they will become part of our life story -- at least, those of
us with HIV. What we learn from his brain may help us protect our
own. For there is hope. Recently approved drugs like nevirapine
(Viramune) -- and others currently in clinical trials, such as 1592
(abacavir) and 141W94 -- manage to make it past the brain's
sentries, and promise better control of HIV there. A new study
suggests that more Crixivan enters the brain than previously
thought. Most important, research into the multifaceted causes of
HIV-associated dementia continues.
The word autopsy means "to see for oneself." With HIV, I
guess I have -- from a vantage point much closer than I'd intended.
The neuropathologist in me, exploring the hidden recesses of the
brain, sees the ravages of AIDS; the patient in me sees the urgent
need to stop it; the pharmacology PhD in me, cautious about new
developments and concerned about the blood-brain barrier, sees the
difficulty in delivering drugs that will. But maybe now, in this new
era, we are starting to ask -- and are on our way to answering --
the ultimate question: "What about the brain?"