Being Alive 1998 Mar 5: 3
How and why some individuals, long infected with HIV, manage to
elude the devastation of the disease has been a medical and
scientific mystery for some time now. Despite the presence of
HIV in their blood, these "long-term non-progressors" possess
ostensibly healthy immune systems, maintaining high levels of
CD4 cells and low or undetectable viral loads, without the help
of any anti-retroviral therapy. Clearly some as-yet-unknown
mechanism is at work in these peoples' immune systems, the
exact nature and operation of which might prove invaluable in
developing new ways to fight HIV infection.
On Day 2 of the Conference Dr. Bruce Walker of Massachusetts
General Hospital gave a fascinating presentation which, while
not solving the mystery of long-term non-progression,
nonetheless used it as a stepping-off point for developing a
"unifying hypothesis for HIV pathogenesis"-how HIV interferes
with the workings of the immune system, and how the immune
system responds to HIV infection.
Hit Early and Hard
His conclusions not only shed new light on the infection/immune
response process, but also provide persuasive support for early
and potent drug therapy against HIV. Dr. Walker showed how
aggressive treatment with potent antivirals in the very first
stage of infection might prevent the need to restore a damaged
Using the results of several laboratory and clinical studies,
Dr. Walker illustrated how the suppression of HIV viral
replication during the first weeks of infection could head off
CD4 depletion and thus leave a person with an immune response
capable of fighting lower levels of HIV-a situation similar to
that experienced by a long-term non-progressor.
Two Contrasting Case Studies
Dr. Walker began by contrasting the cases of two patients. The
first was a "rapid progressor" with "very explosive disease."
When first seen in the hospital (with fever, rash and
headache), he had a viral load of 700,000. This was long before
protease inhibitors and HAART became available and the standard
of care. As expected, over time this rapid progressor's viral
load remained high, and he suffered a rapid CD4 cell decline.
Within a year he developed AIDS, and within four years of
diagnosis he had died.
The second patient, who was hospitalized in 1979 with acute HIV
infection (and identical symptoms), remains well today, 19
years later, with a normal CD4 count and an undetectable viral
load. He has never taken any antiretroviral drug. Dr. Walker
proceeded to painstakingly lay out his analysis of what was
going on in each of these individual's immune systems. Since
both of them showed weak "neutralizing antibody"
responses-neither of their systems were creating sufficient
antibodies to the virus-he next examined their cellular immune
responses, and discovered significant differences.
Cytotoxic T-cell Lymphocytes (CTLs)
In response to an infection, the body produces both CD4
(T-helper) cells and CD8 (T-suppressor) cells. The CD8s become
activated "cytotoxic T-cell lymphocytes" (CTLs): they can
recognize, attack and kill virus-infected cells, thus
eliminating them from the blood and body. In the presence of
any invading virus, CTL activity (the killing of infected
cells) will be high, as the immune system shifts into gear to
fight the infection.
Dr. Walker discovered that the rapid progressor's blood showed
clear evidence of CTL activity within the first three months of
infection, but that this activity did not persist. Twenty-one
months after infection this activity had become completely
undetectable; the CTLs were still there, but were not activated
and therefore non-functional. Something had interrupted the
maturation of the CTLs into activated killer cells.
On the other hand, the long-term non-progressor, even 18 years
after infection, showed enormous activated CTL activity,
despite a viral load that was undetectable. His CTLs, unlike
those of the rapid progressor, were still doing their job,
without the help of any virus-inhibiting drugs.
Dr. Walker suggested that the non-progressor's CTLs were not
only targeting and killing HIV-infected cells in this person,
but also somehow inhibiting the replication of virus within
cells, thereby lowering viral load by intervening in the virus'
reproduction cycle. The non-progressor's CTL response remained
highly active, continuing to attack and kill virus-infected
cells, thereby stopping the replication of new virus copies.
CTLs and Viral Load
When HIV infects a CD4 cell, it soon starts replicating itself
within that cell, producing multiple copies of itself even as
it kills the cell within which it is reproducing. Multiple
copies of the invading virus "burst" out of the cell into the
host's bloodstream, resulting in ever-escalating viral load and
the eventual death of that cell.
Dr. Walker related how in laboratory studies, CD4 cells were
infected in the test tube with HIV, which then began its
process of replicating within the cells. A "clone" of CTL was
then added to the mix, resulting in a CTL response that caused
a 10,000-fold decrease in HIV production. After 14 days this
CTL "clone" was removed, but even without the CTL presence
these previously-infected CD4 cells did not reproduce virus.
This means that HIV had been effectively eliminated from those
cells by the CTL.
A CTL response therefore has the potential of being
extraordinarily effective against HIV infection, by controlling
the viral "burst size," the number of replicated viruses that
will emerge from an infected cell. If CTL can attack and kill
an infected cell before it reproduces more new virus, then this
will result in effectively lowering the overall viral load.
The central question then is: What controls the magnitude and
the activity of those CTLs?
CD4 Cells Are Crucial
Dr. Walker asserted that the T-helper CD4 cells are absolutely
crucial for effective immune response. Their activities and
processes help to orchestrate effective immunity in all arms of
the immune system. In the presence of viral infection, if you
remove T-helper responses, CTL responses will soon wane and
then stop, and viremia will recur (which sounds exactly like
what occured in the rapid progressor).
Under normal circumstances, our bodies are fully capable of
containing and controlling viral infections, even chronic
incurable ones, such as herpes. Even if we can't eliminate a
given viral infection, we can effectively contain it, and
therefore it won't cause life-threatening problems.
"But with HIV infection," Dr. Walker said, "the most glaring
defect in the immune repertoire is the lack of T-helper cell
function." In the case of the rapid progressor mentioned above,
no evidence of any HIV-specific T-helper cell response was
found, from the very earliest stages of infection all the way
through to death. In the non-progressor, however, whose viral
load today remains under 400, not only is there T-helper cell
response present, but it's of enormous magnitude, and has been
persistently so over a period of two years. Significantly,
further clinical studies have shown that the amount of T-helper
cell response correlates directly with the level of HIV viral
load. High viral load means no T-helper cell function; low
viral loads consistently show strong T-helper cell responses.
Furthermore, high CD4 response correlates with high CTL
activity: without the presence of CD4s, the immune system
cannot maintain CTL activity.
A Unifying Hypothesis
All of these findings led Dr. Walker to his "unifying
hypothesis" of how HIV infection progresses. Put simply (and
vastly oversimplified): upon acute infection (the very earliest
stage of the infection), the immune system activates what Dr.
Walker refers to as "pre-T-helper cells" (CD4s) and "pre-CD8
cells"-both these types of cells will require a maturation
process. The "pre-T-helpers" will develop into activated CD4
T-helper cells. The "pre-CD8 cells" will become activated
"pre-CTL cells", which will in turn also need to mature, under
the influence of help from the CD4s, to become fully functional
CTLs, capable of targeting and killing infected cells. In other
words, to become fully active and functional, the CTLs need the
presence of activated CD4s.
As stated before, the crucial problem in HIV infection is that
it is an infection of the immune system: these activated CD4
T-helper cells are susceptible to the very infection they are
called upon to control. In fact, HIV preferentially infects
activated CD4 cells. The infecting and eliminating of these CD4
cells by HIV interrupts the maturation process of the CTLs,
leaving people with an ineffective immune response. Like the
rapid progressor above, an infected person will get an initial
CTL response, which then declines as viremia recurs. The CD4s
can't help the CTLs mature, therefore CTL activity decreases,
and the viral load rebounds.
Dr. Walker then theorized that if you could manipulate the
immune system during acute infection in such a way as to allow
the CTLs to mature, you could thereby gain the upper hand on
the virus, ending up with a situation analogous to that of the
long-term non-progressor: HIV+, with a high degree of CTL
activity despite an undetectable viral load.
Protease Inhibitor Intervention
Such manipulation has been made possible by the advent of
protease inhibitor treatment and HAART. Walker and others
treated newly-infected persons with potent anti-retrovirals,
aiming to protect the activated CD4s from being infected and
killed by HIV, thereby allowing them to help in the maturation
of CD8s into fully active CTLs. This they were able to do: in
every one of 11 patients treated with HAART in the earliest
acute stages of infection, T-helper cell activity first was
undetectable, but after two to three months these people were
able to generate both CD4 and CTL responses.
Most importantly, they found that if they did not treat people
in the very earliest stage of acute infection-if they waited a
year, say, to begin HAART-they did not get these CD4 and CTL
responses. This led Dr. Walker to conclude that there is a
narrow window of opportunity-perhaps only six months-for
restoring these immune responses, and that waiting to begin
HAART may mean that these responses will never be recovered.