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Being Alive
Chris Griffin
March 5, 1998
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 immune system.

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.