Remember back in 1981 when the mysterious disease we today call AIDS first showed up? It was labeled GRID, for gay-related immune deficiency, because the only thing obvious about this new killer was that it struck gay and bisexual men, seemed to be transmitted sexually, and wreaked havoc on the very system responsible for protecting the body against infection. In the beginning, immunology–the science of the immune system–occupied center stage. That changed two years later when researchers identified HIV, and virology–"It's the virus, stupid"–took over. Virologists focused more on the enemy–HIV–and for the most part immunology and ideas about how the immune system might fight back took a backseat.

That was then, this is now. Over the past decade, we've learned an enormous amount about the human immune system and how it responds to an invader like HIV, a retrovirus that hijacks the immune system's cellular soldiers to do its dirty work. Although we're still in the dark about many aspects of immunology, a relatively young field compared with virology, we've learned enough to glimpse the future and the hope it offers about our ability to harness the remarkable power of the immune system to keep HIV in check.

In the following pages, we've tried to provide a road map of what we know and what we hope to find out about this new frontier.

Military metaphors are often used to describe the immune system, a complex network that can be compared to an army with many commanders and specialized divisions. Its main task is to protect the body against infection and reinfection, and it does this through a web of cells, molecules, organs and tissues. Each of us is born with an immune system that has evolved over time. We also acquire immunity through exposure to invading organisms–including viruses, fungi, and parasites. Inflammation and allergies, for example, signal that your immune system is responding to foreign invaders.

The immune system is broken down into two main divisions: innate immunity refers to the first line of defense against infectious agents and is made up of soluble factors, protein molecules, and white blood cells called phagocytes, which include monocytes and macrophage cells, as well as neutrophil polymorphs. Adaptive immunity kicks in when the body has been effectively invaded. A phenomenon called immunologic "memory" allows the immune system to recognize and remember an invader it has previously encountered. Here, the main players are T-lymphocytes, also known as T-cells, and molecules called antibodies, produced by B-lymphocytes, or B-cells.

All of the cells involved in the immune response arise from bone marrow cells, known as stem cells–"the mother of all cells." As these cells mature, they develop different features to do different jobs. T-cells are part of the initial arm of the adaptive immune response, called cellular immunity, while B-cells are part of the secondary, or humoral response.

The battlefield is located largely in lymphoid tissue and organs. The lymphoid system is made up of two primary organs: the thymus, where T-cells are produced, and the bone marrow, which generates B-cells. Secondary lymphoid organs include the lymph nodes, spleen, and the mucosal-associated tissue that makes up the tonsils and Peyer's patches of the gut, for example.

The lymphoid system can also be thought of as a giant highway, with pit stops and lots of potential traffic jams. The various cells of the immune system constantly patrol a highway made of a clear fluid called lymph, which runs parallel to the bloodstream. Like cops, the cells are equipped to spot invading organisms, and when they do, they'll send some cops to stop the invader, call others over for backup, and haul the perp to a nearby lymph node–a mini-house of detention. While that's going on, immune traffic is halted going in or out of the lymph nodes. That's why the first signs of HIV infection, for example, are often swollen lymph nodes and fever–they indicate the immune system has captured the enemy and is trying to keep it in lockdown. During that time, the perp sometimes gets away, stealing a cop car–a T-cell–to hide out in. Since HIV is a virus, it needs a host cell, in this case, a T-cell, to survive. HIV spreads through the body via infected T-cells, which may affect the T-cell's ability to function or cause the cell and neighboring cells to die. These infected T-cells are also targeted by other immune cells because they harbor the enemy. The result is a steady depletion of the body's natural defenses, which leaves it vulnerable to infections it can normally control. That is why HIV infection leads to acquired immune deficiency syndrome.

This is the simple picture. When it comes to HIV, the best metaphor of all is a very complicated dance, like a tango, in which the virus and the immune system lock themselves together in dramatic struggle. As you'll see below, there are many other players and complicated steps. But new approaches to therapy are, in effect, changing the tempo of the dance, and may allow the immune system to switch its role and take the lead.

Help Me, Rhonda!
The CD4 helper T-cell is a familiar character in the immune system drama, at least in name. The number of CD4 T-cells in a blood sample has long been used as a rough guide to the progression of HIV infection. In 1993 a CD4 T-cell count of less than 200 was added to the list of markers that indicate an AIDS diagnosis. Although studies have shown a clear link between dropping CD4 T-cell counts and the onset of immune dysfunction, details of what these immune cells actually do and how they do it have proved more difficult to uncover.

In the past few years, immunologists have begun to piece together important parts of the CD4 T-cell puzzle. The T-cells belong to the lymphocyte cell class, as do B-cells, and their role is to fight infection. Lymphocytes are found in blood, lymph, and lymphoid tissues. The B-cells become memory or plasma cells, but T-cells can turn into several different types: helper (CD4 T-cells); cytotoxic (CD8 killer T-cells); and memory (both CD4 and CD8 T-cells).

As its full name suggests, the CD4 helper cell primarily provides help to fellow immune system players, such as B-cells and CD8 T-cells. The rather demure, dispensable notion of help may have contributed to an underappreciation of the critical role CD4 T-cells play in fighting infectious agents like HIV. Scientists have likened the role of CD4 T-cells to a quarterback calling the plays for the rest of the team.

To get to know this critical character a little better, it helps to take a peek at what might be called the unfinished biography. Immunologists have done a lot to shed light on the life and times of CD4 T-cells, but many dimly understood aspects remain.

The Journey Begins
Focusing on what is known with reasonable certainty, a CD4 T-cell begins its life, like all other blood cells, in the bone marrow, the mushy cell-making factory hidden within your bones. At this point, the cell is not a CD anything but simply an immature, or progenitor, white blood cell. If a white blood cell's destiny is to become a CD4 T-cell, it will head from the bone marrow to the thymus, a small organ located just behind your breastbone.

The thymus plays a pivotal role in T-cell development. It is here that the two major markers (CD4 or CD8) that help define a T-cell's function are acquired. The CD marker is actually a structure that appears on the T-cell's surface. CD stands for "cluster of differentiation," a technical way of saying that a particular CD marker on a T-cell tells something about what the cell does. Although they work alongside each other, CD4 and CD8 T-cells have different jobs to do.

Naive, But Promising
Another important milestone in the life of a baby CD4 T-cell also occurs in the thymus. The CD4 T-cell develops another surface structure called a T-cell receptor, or TCR for short. Again, metaphors can help: TCRs act like eyes, helping blind, newborn T-cells see their target. The receptor acts as a docking bay for the pieces of an infectious agent that will, if encountered by the CD4 T-cell, trigger an immune response. Each developing CD4 T-cell generates its receptor in an essentially random shuffling of its genetic code, or DNA. Millions of possible receptors can be generated in this way, assuring that all kinds of possible infections can be seen or responded to by at least some CD4 T-cells.

The downside is that some CD4 T-cells will develop receptors that can recognize or dock with pieces of your own body tissues, called self, instead of a foreign infectious particle, called nonself. If these CD4 T-cells were to leave the thymus and enter the bloodstream, they would cause a highly undesirable immune response against your own body, called autoimmunity. To prevent autoimmunity from happening, the thymus' final job is to eliminate any CD4 T-cells (or other T-cells) with receptors or eyes for other self-identified cells. In fact, a stunning 95 percent of freshly minted T-cells are eliminated in the thymus for this very reason.

The remaining survivors, a lucky 5 percent that will only lock onto foreign particles, enter the body's circulation through blood or lymph glands to patrol for infections. If the acquisition of the CD marker and TCR are thought of as prenatal development, this entry into the circulation represents the final stage of CD4 T-cell birth. Appropriately, these youngsters are called naive in the scientific parlance. That means that although they might encounter a piece of infectious agent (nonself) and respond, they haven't yet. They are still rookies.

Mother's Little Helpers
Having followed the development of a CD4 T-cell from the perspective of a single cell, it's time to briefly step back and look at the big picture. As you might guess, the body doesn't produce just one CD4 T-cell at a time. Instead, the highest rate of T-cell production occurs during childhood, with billions of naive CD4 T-cells exiting the thymus daily. That's how children gradually develop immunity to infections. An average adult will have around 900 billion naive CD4 T-cells that have left the thymus and are at work, patrolling around the body.

Until recently, it was believed that individuals had to rely on this same pool of naive CD4 T-cells for the rest of their lives. The thymus was thought to shrink and stop functioning. One of the most important findings of recent research is that although the thymus dramatically slows down its activity in adults, it continues to produce new naive T-cells throughout our lives. Fresh naive CD4 T-cells have been found in people over 90 years old. This continued production of new naive cells seems vital to proper immune system function and health.

To get a sense of why this is important, think back to the big pool of 900 billion naive CD4 T-cells in every adult, each equipped with unique receptor eyes. What would happen if a novel infectious agent showed up that didn't match these receptors? The CD4 T-cells couldn't respond. Ideally, you'd want to keep replenishing this naive pool by adding new cells with freshly generated TCRs. That's exactly what the thymus does. Although the production of naive T-cells slows down in adulthood, it's estimated that around 700 million new naive CD4 T-cells exit the thymus every day. As they get added to the larger naive CD4 T-cell pool, an equivalent number of older naive cells die off. Think of the naive pool as a lake, with a small river flowing in and out. The constant input and output of even a small amount of water keeps the lake fresh and prevents stagnation.

Adulthood–and Memories
This isn't the end of a CD4 T-cell's journey. There's an additional step that only some cells take. When a patrolling naive CD4 T-cell encounters an enemy (nonself), it becomes activated and goes into a Xerox copying mode called proliferation, producing many duplicates of itself. An army can be cloned in a matter of hours to fight the infection. Most of these duplicate CD4 T-cells will automatically die when the infection is brought under control. But a few cells survive to become memory CD4 T-cells, equipped to remember the old enemy in case it ever shows up again. During their battle, these memory cells undergo a final stage of maturation and acquire important infection-fighting skills that naive CD4 T-cells lack. This memory state can be thought of as full adulthood, which is why immunologists refer to them as mature T-cells. An average adult has around 1.1 trillion memory CD4 T-cells. That's 1,100,000,000,000, in other words, quite a lot.

The Swat Team
The enhanced talents of memory CD4 T-cells prove vital to proper immune system function. These cells can be thought of as an elite, rapid-response team designed to stay on top of whatever infectious agent triggered their development. Chicken pox provides a classic example of why memory T-cells are important, and it sheds light on HIV.

Chicken pox is caused by the herpes zoster virus. Most people become exposed to this easily transmitted virus during childhood. When it first enters the body, certain specialized cells, called antigen-presenting cells, take pieces of the virus and present them to T-cells, including CD4 T-cells. Some of the big pool of 900 billion or so naive CD4 T-cells will have receptors that dock snugly with pieces of herpes zoster, or herpes zoster antigens, as they're called. These CD4 T-cells swing into action, quickly cloning copies of themselves into a mini-army to fight the herpes zoster antigens. This battle between the immune system and herpes zoster produces the familiar symptoms of chicken pox, including fever and blistering.

In five to seven days, some of the activated naive CD4 T-cells will reach full maturity and later survive as memory cells. These memory cells will only respond to herpes zoster, and if they encounter the virus again, they'll respond even faster than naive CD4 T-cells, releasing infection-fighting chemicals called cytokines and chemokines. By comparison, naive CD4 T-cells have to copy themselves several times before they can begin releasing these same chemicals, which is part of the reason the body's initial response to infections like chicken pox is often slow enough to allow symptoms to occur.

Like many other infections, herpes zoster remains in your body your whole life. This type of infection is called latent. There are many other infections that commonly remain latent, such as Pneumocystis carinii pneumonia (PCP), toxoplasmosis, human herpesvirus, cytomegalovirus (CMV), and mycobacterium avium complex (MAC). The first time you become exposed to one of these viruses, you may develop symptoms of acute infection as the immune system swings into gear and the army gets cloned. Once that initial infection has cleared, a squad of memory T-cells controls what becomes a dormant viral infection, in a state of remission. HIV also appears to cause a latent infection, and one of the current goals is to see if we can achieve long-term immune control of the virus.

In the case of herpes zoster, this immune control is accomplished with the help of another type of T-cell–the CD8 T-cell mentioned earlier. Although he had no way of knowing at the time, Edward Jenner's famous 18th-century experiments using dried cowpox virus to protect against smallpox worked because of the critical differences between naive and memory CD4 T-cells. Since cowpox and smallpox viruses share a similar structure, Jenner's dead cowpox preparation was able to trigger the development of memory T-cells with receptors that fit, or recognize, smallpox antigens. So someone given the cowpox treatment became protected against smallpox disease.

Key Players: CD8 T-cells
The evidence so far suggests that cellular immunity is more important than humoral immunity for controlling latent infections like herpes zoster and, some believe, HIV. As the team quarterback, the CD4 T-cell orchestrates the cellular immune response, delivering key signals to teammate CD8 T-cells. These CD8 immune cells develop in almost exactly the same way as CD4 T-cells, but instead of a CD4 receptor, they acquire a CD8 receptor while in the thymus. They too begin life as naive T-cells that mature and can be cloned to fight infections, leaving a subset of memory CD8 T-cells primed to recognize previously encountered antigens. These memory cells are also an elite, rapid response team with enhanced infection-fighting functions, compared with naive CD8 cells. In total numbers, an average person has about half as many CD8 cells as CD4 T-cells.

The most important type of CD8 cell is thought to be the killer cell, also called a CD8 cytotoxic T-lymphocyte, or CTL for short. Killer cells have the job of targeting infected cells in the body and lysing, or eliminating, them. They do so by the rapid release of not only cytokines but an important cell-killing substance called perforin. For this reason, CTLs have been a primary focus of immune system research for at least a decade.

A crucial new insight from recent scientific studies in HIV is that CD8 CTLs need a signal from CD4 T-cells that allows them to go after their target. So to control a latent herpes zoster infection, for example, you need a squad of both memory CD4 and CD8 T-cells.

Experimental studies have looked at what happens to killer cells if you deprive them of their CD4 compadres. It turns out that their ability to carry out important cell-killing functions is impaired. In particular, the ability of killer cells to release perforin appears to be compromised without a signal from the CD4 quarterback.

So we now have more clues about how memory T-cells control latent infections. A crack squad of both memory CD4 and CD8 T-cells develops when you're first exposed to an infectious agent, and they must keep working together to keep the latent infection in check, even though it's never entirely eliminated from the body.

Turning to latent HIV infection, what happens when the virus begins to knock out these critical defensive squads? In a nutshell, the immune system's memory of HIV becomes impaired. Even if antiviral drugs can be used to control active HIV infection, it's unclear how well a damaged immune system can control latent HIV infection. Today a number of strategies, including new vaccines, are being tested to try to boost these lost immune defenses.

Now that immunologists have begun to reveal some of the mysteries of T-cell function, the next step is to work out how HIV fits into this new picture. Two decades into the epidemic, there is still little consensus among scientists as to how HIV damages the immune system.

HIV's Arrival
HIV usually enters the body via what scientists call the mucosa (see "Wet and Wild"). New research reveals that a type of immature dendritic cell located in the mucosal surface called a Langerhans cell, carries infectious HIV to mature dendritic cells and then into the lymph nodes, and transfers the virus to T-cells (see glossary). There is no evil intent on the part of the dendritic cell–taking foreign particles (or antigens) to the lymph nodes is part of its job, which is why these cells are known as antigen-presenting cells or APCs. Once in the lymph nodes, dendritic cells and T-cells snuggle up together. If the antigen on the dendritic cell–in this case HIV–fits the T-cell's receptor, they engage, like a key in a lock. For this reason, lymph nodes can be thought of as immune system command centers–it's here that the immune responses to infectious agents are initiated.

HIV cunningly subverts this feature of the immune system for its own ends. The virus swings into the lymph nodes attached to the very cell–an antigen-presenting dendritic cell–whose job is turning on T-cells. In this way, HIV is brought into direct contact with CD4 helper T-cells. The virus primarily infects these helper T-cells by latching onto a molecule found on the T-cell surface called CD4, then penetrates the cell membrane through a series of complicated steps. In order for HIV to complete its life cycle and release a whole bunch of new HIVs, the CD4 T-cell has to become activated and enter Xerox-copying proliferation mode. This happens when the dendritic cell carrying HIV cuddles up to a T-cell and presents it with HIV.

When HIV first arrives in the body, there are no immune memory T-cells that know how to deal with it. The body's never experienced HIV. As with any other first exposure to an infection (like herpes zoster, for example), it is the job of rookie naive T-cells to respond. Returning to the scene in the lymph nodes, naive CD4 T-cells with receptors that match HIV antigens get recruited to fight the invader and in turn, they too become infected. As these T-cells begin to proliferate, HIV is able to complete its life cycle and send out an average of 200 or so new viruses (or virions as sciency types like to call them) from each infected cell. Viral load counts in the blood will usually skyrocket as a result.

Faulty Memories
This whole process begins within a few days of HIV first getting into the body, a period called primary, or acute, infection. Scientists know that with other common viral infections, a fraction of the proliferating naive T-cell pool later reverts to a resting state, harboring a "memory" of how to fight the invader. This crack squad of memory T-cells is called on whenever the invader reappears. But in HIV disease, the naive CD4 T-cells are instead used by the virus as HIV factories. (Perhaps surprisingly, some memory CD4 T-cells specific for HIV antigens do seem to mature from the naive CD4 T-cell pool in the normal way.) A number of studies show that, from the earliest stages of infection, HIV-specific memory CD4 T-cells can be defective. Instead of a crack squad of anti-HIV CD4 T-cells, what results is a lame duck squad of cells unable to perform their vital HIV-fighting function.

Having glanced at early steps and stumbles in the CD4 T-cell response to HIV, what happens to CD8 T-cells? To date, there's plenty of evidence to show that when HIV shows up, naive CD8 T-cells with receptors to match the virus do respond. These cells also generate a pool of resting memory CD8 T-cells that normally work alongside their CD4 teammates to control infections. But since the memory CD4 T-cells that deal with HIV haven't properly matured, they don't seem to provide the right help, or provide the right chemical message, that allows memory CD8 killer cells to respond. Instead, these cells become lethargic. In science-speak, that's called anergy–meaning the memory killer cell squad is unresponsive. Perhaps most importantly, helpless memory CD8 T-cells seem unable to efficiently kill HIV-infected cells.

Having wreaked havoc on the memory T-cell squads, HIV can keep on reproducing itself. Out of the 700 million or so new naive CD4 T-cells that the thymus produces every day, some will respond to HIV antigens. It's likely that as they become activated and proliferate, they will also provide more targets for the virus to infect. Again and again, what's left behind is a legacy of impaired immune memory to HIV.

It is during the acute phase that HIV also seeds latent HIV reservoirs in lymphoid tissue. During this period, a small fraction of the T-cells that are activated to fight HIV revert back to a resting, or memory, state. As the cells become dormant, so do the viruses or viral fragments (called provirus) they may harbor. In effect, HIV causes two infections: an active infection that spreads via infected T-cells to other parts of the body, including the brain; and a dormant, or latent infection, that persists in lymphoid tissue reservoirs.

The Immune System in Trouble
If this process is allowed to continue unchecked, the immune system eventually runs into trouble. The reasons appear twofold. First, the large pool of naive T-cells becomes slowly drained. To understand why, think of the lake metaphor: the constant activation of naive T-cells by HIV is like siphoning off water from the stream feeding the lake. The water still flows out of the lake at the same rate, so if the siphoning isn't stopped, the lake eventually empties. Studies have shown that the naive T-cell pool does indeed dwindle in HIV infection. In fact, a very recent study from Dr. David Ho's group at the Aaron Diamond AIDS Research Center shows that the loss of newly produced naive T-cells is strongly linked to disease progression.

Secondly, HIV affects the memory T-cell pool. Other studies have shown that people with HIV lose their ability to respond to latent infections. When a person progresses to AIDS, he or she often gets sick from old infections that were previously controlled by memory T-cells. Exactly how HIV affects the memory pool has not been proved but, again, recent immunology research has provided some clues. A critical fact is that the body only has a certain amount of room for memory T-cells.

Immunologists have proposed that when a new memory T-cell matures in response to a new infection, an existing memory cell has to die off to make room for the newcomer. Although this sounds like a recipe for disaster, an average person is likely to have enough room in their memory T-cell pool to accommodate all the memory T-cell squads they need to stay healthy (for example, the herpes zoster squad, the Pneumocystis carinii pneumonia squad, the cytomegalovirus squad). If a particular memory T-cell squad gets low on members, when new memory T-cells show up, rookie or naive T-cells can always be recruited if the infection reappears.

HIV infection, however, appears to lead to the continual addition of defective HIV-specific memory T-cells to the pool. In 1997, a team of Italian researchers led by Adolfo Turano documented that this accumulation causes a reduction in the number of functional memory squads needed to control other latent infections. They noted that this "may explain the occurrence of different infections, including opportunistic microorganisms, during the more advanced stages of HIV infection." It also explains why some people on HIV therapy remain vulnerable to OIs. They may have lost their "memory" to these infections.

Fixing the Problem
These new clues as to how HIV causes immune system dysfunction, although useful, still make the situation sound pretty grim. But buried within all the complexity may be a silver lining. It turns out that the 3 percent or so of people with HIV who don't experience disease progression have something in common–a functional squad of memory T-cells that respond to HIV. No one knows exactly why this is, but some researchers speculate that if naive CD4 T-cells manage to respond to HIV and proliferate, yet escape viral infection, they can properly mature into functional HIV-specific memory T-cells. That means the immune system may have the potential to regain its lost ability to take on the virus, and, some propose, to contain it over time. Ongoing experiments are aimed at doing just that, using a variety of experimental approaches debated in the accompanying roundtable discussion.

Richard Jefferys is a treatment advocate with the AIDS Treatment Data Network (ATDN). He wrote about new HIV treatment strategies in our September 1999 issue. Additional research by Anne-christine d'Adesky