The Immune System
1998 saw important breakthroughs in understanding how the immune system may be able to control HIV. A doctor from Harvard University, Bruce Walker, has led much of this new research. This article will provide background on how the immune system normally works against viruses, followed by information on Dr. Walker's research into how the immune system responds to HIV

The immune system is what usually protects us from illness. In the case of HIV, the immune system isn't usually able to control the virus on a long-term basis. On average, ten years after being infected with HIV, a person's immune system starts to become seriously damaged by the virus. Damage to the immune system can lead to serious illnesses called opportunistic infections. This typically slow but ongoing process of immune system damage is called disease progression

Researchers have been studying a few HIV-positive people who don't experience disease progression. They don't show damage to their immune system. They don't develop opportunistic infections. They have little or no measurable HIV in their blood. Dr. Walker may have found an explanation for this very effective immune system response to HIV.

How does the immune system normally control viruses?
The immune system is made up of different types of cells, some of which are called lymphocytes. One group of lymphocytes are called T4 (or CD4) helper cells. Your T-cell count is the number of T4 helper cells in your blood sample. T4 cells help coordinate the immune response to infections. When it comes to dealing with viruses like HIV, the T4 helper cells work alongside another type of lymphocyte called T8 (or CD8) cells. T8 cells include cytotoxic T-lymphocytes (CTLs). The job of CTLs is to kill cells that have become infected with viruses or other disease-causing organisms. When the CTLs kill enough infected cells, viruses like HIV can be kept in check and you don't get sick.

When you're exposed to a virus, only some of your T4 cells will respond. T4 cells have what are called receptors on their outer surface. It is these receptors that trigger T4 cells to respond to invading organisms like HIV. The receptor system works like locks and keys. The receptor on the T4 cell is the lock and any piece of foreign material (like a piece of virus) acts like a key. A piece of foreign material that can trigger an immune response is called an antigen.

Until a T4 cell meets an antigen that fits its receptor, the T4 cell is called a naïve T4 cell. If a naive T4 cell happens to meet an antigen that fits its receptor, the T4 cell goes into action by making lots of copies of itself (the technical term for this is proliferation). When this happens, the T4 cell is no longer call naive, it's now an activated T4 cell.

Out of all the billions of naive T4 cells in your body, only a few will have the receptor for each possible antigen. A T4 cell whose receptor matches HIV antigens (pieces of HIV that can trigger an immune response) won't do anything at all if it comes into contact with herpes virus antigens or influenza virus antigens, and a T4 cell whose receptor matches herpes antigens won't respond to HIV antigens. This is why T4 cells make lots of copies of themselves when they meet their matching antigen - from a small pool of cells, the immune system gets a whole bunch of duplicate T4 cells whose receptor also matches the antigen. These cells are called specific for that antigen, and they help coordinate the rest of the immune system so that the invading virus can be controlled.

These newly created, activated T4 cells don't live all that long. After a few days they die off, because the immune system hopes that the big burst of activated T4 cells will have controlled the virus. This burst of immune system activity when you're first exposed to a virus is part of the reason you feel sick. Some of the activated T4 cells, however, don't die off but become what's known as memory cells. These memory cells live in the body for a long time, and if the same virus becomes active they make copies of themselves very quickly, much faster than naive cells do. One way to think about memory T4 cells is as a rapid-response team, programmed to respond to antigens from one particular virus or disease-causing organism. Memory T4 cells are usually made automatically after any infection that triggers a T4 cell response.

A good example of immune system memory is Epstein-Barr virus (EBV). Most people become infected with this virus during their lives. When you're first exposed to EBV, it's common to experience symptoms called mononucleosis or mono. Mono often involves a few days of fever, fatigue, sore throat and swollen lymph nodes. During this time, naïve T-cells are becoming activated by EBV. These activated cells help bring the EBV under control. About 95% of the activated cells die off within a few days. The rest don't die, but develop into memory cells. You now have a rapid-response team against EBV. The virus is still in your body, but the EBV-specific memory cells keep it under control.

Cytomegalovirus (CMV) is another virus that about half the population of the US has been exposed to. The immune system controls CMV in the same way it does EBV. People with AIDS can lose their memory T4 cells against CMV. That's why CMV can cause disease in people with AIDS. In fact, all opportunistic infections are caused by the loss of the memory T-cells that were controlling theinfection.

Why can't the immune system control HIV?
With most viruses, the immune response described above would eventually control the problem as it does with Epstein-Barr virus. The trouble with HIV is that there is one type of cell it infects most easily - T4 helper cells. HIV takes over T4 helper cells and uses them as factories for making more HIV. In fact, the cells that are most easily infected by HIV are T4 helper cells that have been activated. In other words, the HIV-specific T4 helper cells that first respond to the virus are the first T4 cells to be infected. Most importantly, it seems that HIV infection of activated T4 cells prevents HIV-specific memory T4 cells from working properly.

Dr. Bruce Walker has found evidence of this in his studies. In most people, activated HIV-specific T4 helper cells seem to die off without leaving behind any working HIV-specific memory T4 cells. This leaves the rest of the immune system without the HIV-specific memory cells - the rapid response team - needed to coordinate the immune response and control the virus. Eventually HIV gets the upper hand. The total number of T4 cells starts to drop, and people become at risk for developing opportunistic infections.

However, it turns out that a few people develop HIV-specific memory T4 cells that work very well. There is a test called the lymphoproliferative response test (LPR for short) that can detect HIV-specific memory T4 cells in a blood sample. Dr. Walker used this test to look for HIV-specific memory T4 cells in long-term non-progressors. These individuals haven't experienced immune system damage from HIV or progressed to AIDS, even 18 years or more after being infected. In these long term non-progressors, the T4 cell count remains normal and the HIV viral load is very low or undetectable without any treatment.

Dr. Walker found that these long-term non-progressors have strong HIV-specific memory T4 cell responses. In people with progressing HIV or AIDS, no evidence of strong HIV-specific memory T4 cell responses could be found. This may be a very important finding - researchers have been trying for a long time to work out why some people progress to AIDS while others remain healthy.

Can early treatment save HIV-specific memory T4 cells?
Dr. Walker is studying a small group of people that have been treated with combination HIV drugs within days of becoming infected. This period is called primary infection. The very early results suggest that the drugs have protected their HIV-specific T4 cells from infection by HIV, and allowed HIV-specific memory T4 cells to develop. The hope is that the development of HIV-specific memory T4 cells will mean the immune system can control the virus on a long term basis, as it does in long term non-progressors.

Other studies of HIV drugs taken right after becoming infected have also been going on. David Ho, a New York doctor and researcher, was one of the first people to organize this type of study back in 1995. The original idea was to try and get rid of all the HIV in the body, by keeping people on the anti-HIV drugs until all the HIV-infected cells in the body died off. This idea was called "eradication." David Ho thought that this might be possible in 2-3 years.

Recent studies of Dr. Ho's patients have shown that some cells can live for a long time in the body even though they're infected with HIV. If the anti-HIV drugs are stopped, this HIV can reproduce and start infecting other cells again. Knowing this has made Dr. Ho cautious about stopping the anti-HIV drugs in this study, as originally planned. Instead, he's been trying to come up with ways of getting rid of these infected cells before stopping the anti-HIV treatment, but this may not be possible. Like Dr. Walker, Dr. Ho is now looking at the immune system to see if it can control the HIV that HAART can't get rid of.

Latest Update: Early Treatment Study Results
One person in Dr. Walker's study was recently taken off HAART drugs. Their viral load increased, but very slowly. It took 7 weeks for the viral load to reach 17,000 and at this point HAART was restarted. HIV-specific memory T4 cells were found in the person using the LPR test, but the response was not strong enough to completely control HIV. Dr. Walker is now studying whether a "booster" is needed to create more HIV-specific memory T4 cells.

This booster idea comes from the case of a man in Berlin, Germany who was treated with combination anti-HIV drugs a few days after becoming infected with the virus. His viral load became undetectable, but fifteen days after starting treatment he developed an infection and stopped the anti-HIV drugs for a week. HIV viral load became detectable during this week off, but disappeared again when he restarted the drugs.

After six months of treatment he stopped taking the drugs altogether. Even though he's now been off drugs for a year and a half, there's no measurable HIV viral load in his blood, and only tiny amounts of HIV-infected cells in his lymph tissue. The lymph tissue is part of the immune system where most of the HIV in the body is usually found.

Dr. Walker has studied this patient, looking for reasons why his immune system is controlling the remaining HIV without drugs. In a discovery that may be very important, he found a very strong HIV-specific memory T4 cell response. Dr. Walker and other researchers suspect that starting HIV drugs allowed HIV-specific memory T4 cells to develop, and then the week long interruption of drugs allowed HIV to replicate again, creating even more HIV-specific memory cells. This strengthened the HIV-specific memory T4 cell response and gave the immune system the upper hand against HIV.

Further support for this idea has now come from two people in David Ho's study. These two individuals appear to have gotten the same results as the man in Berlin - they've stopped their anti-HIV drugs and still have no HIV activity measurable in their blood with the standard viral load test. It's now been reported that these individuals took occasional breaks from their anti-HIV drugs, suggesting they may have boosted their memory cell response just like the Berlin patient.

These results may mean that eradication of HIV from the body is not necessary. Instead, doctors are describing what's happened to these few people as "remission." This may be a way to temporarily or permanently stop disease progression in people with HIV without the need for lifelong drug treatment.

Can new HIV-specific memory T4 cells be created?
Studies have looked for evidence of HIV-specific memory T4 cells in long-term infected people responding well to anti-HIV drugs. Unfortunately, they cannot usually be found, even in people who have had too little HIV in their blood to measure for over two years.

The promising recent news is that there may be ways of creating new HIV-specific memory T4 cells. A doctor from New York University, Fred Valentine, presented some very early results on a study of a vaccine called Remune taken with combination anti-HIV drugs. Remune is given via a shot under the skin every three months. This vaccine was invented by Jonas Salk, who also invented the original polio vaccine.

In his study, Dr. Valentine found that the vaccine seemed to be able to create HIV-specific memory T4 cells. The theory is that the vaccine is able to trigger naïve T4 cells, and they develop into HIV-specific memory T4 cells while the anti-HIV drugs are keeping the virus under control. Several studies have found that the number of naïve cells in the body can increase after about six months of treatment with HAART.

Several studies of Remune combined with HAART are now ongoing. These studies should show if Remune can help the immune system control any HIV that the drugs can't get rid of. In addition to Remune, there are several other new vaccines that may able to trigger the development of HIV-specific memory T4 cells.

Although this early information is exciting, more study is needed before any conclusions can be made. The number of people involved in these studies so far is very small. It's not unusual to find out that something that works well in one person doesn't work in everyone. News like what's reported here is often greeted with what's called cautious optimism - the information looks good, but we have to be cautious about applying it to more people until we have more information.

Internet Links with more technical information:

• Vigorous HIV-1-Specific CD4+ T Cell Responses Associated with Control of Viremia
  http://www.ama-assn.org/special/hiv/library/readroom/science/p1147.htm

  Immune Events in Early HIV Infection. Bruce Walker, MD (mistakenly listed as Robert Walker on the site) AIDS Research Center MGH-EAST

  http://webcast.aids98.org/presentations/693.htm

  Control of HIV replication requires virus-specific helper and CTL function and levels of CTL activity are in equilibrium with viral burden. Spyros Kalams, MD AIDS Research Center MGH-EAST

  http://webcast.aids98.org/presentations/196.htm

  Pharmacologic-immunologic control of HIV promising

  http://www.ama-assn.org/special/hiv/newsline/conferen/aids12/070298a.htm

  Altered T cells from healthy twins survive in HIV-infected siblings

  http://www.ama-assn.org/special/hiv/newsline/conferen/aids12/070198d.htm