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Understanding Long-term Nonprogressors

What can AIDS vaccine researchers learn from studying people who are HIV infected but progress more slowly to AIDS?

It takes, on average, about a decade for an HIV-infected individual to develop AIDS. This progression occurs gradually as the virus attacks and destroys CD4+ T cells, a subset of immune cells that are an essential component of the body's immune response to pathogens such as viruses and bacteria. Other mechanisms are also implicated in the gradual depletion of these cells. Many CD4+ T cells are initially replenished by the immune system and as a result most HIV-infected individuals remain healthy with few, if any, symptoms for several years. But eventually the immune system begins to fail and the number of CD4+ T cells slowly declines. This is often accompanied by an increase in the HIV viral load, which physicians measure by quantifying the number of copies of virus in a sample of blood.

A person with a healthy immune system has between 600-1200 CD4+ T cells in a milliliter of blood. When the number of CD4+ T cells falls below 200, a person is clinically defined as having AIDS. At this point it is recommended that individuals begin taking antiretrovirals (ARVs) that can suppress the virus. Typically a person's CD4+ T cell count begins to rebound soon after starting ARV therapy and their viral load drops dramatically, often falling below the limit detectable by routine tests.

But some HIV-infected individuals are able to control the virus for much longer than a decade without ever taking ARVs. Researchers have even identified people who have been HIV infected for as long as 28 years and have never progressed to AIDS. These individuals are known as long-term nonprogressors, and they maintain very low viral loads and either don't progress to AIDS or do so much more slowly. Researchers estimate that 1% of all people who are HIV infected are long-term nonprogressors.

Just what makes these individuals able to control HIV for longer than others is still something of a mystery, and it is further complicated because it could be due to different factors in different people. Several characteristics of the virus or the individual's genetic makeup could be partly responsible for this difference and researchers are actively studying long-term nonprogressors to determine exactly what enables them to control their HIV infection. AIDS vaccine researchers are particularly interested in determining the type of immune responses that are responsible for slowing disease progression because mimicking these responses might be the key to producing an effective vaccine.

This could be especially true for a partially-effective vaccine (see Spotlight article), one that would most likely not prevent HIV infection entirely but could lower viral load in people who do become infected. This lowered viral load would reduce the risk of them transmitting the virus to others, so a partially-effective vaccine could significantly reduce the number of new HIV infections. Long-term nonprogressors may hold important clues about what type of immune responses an AIDS vaccine would have to induce to keep HIV viral load under control.

Possible explanations

Researchers began studying long-term nonprogressors more than 15 years ago and they have identified several possible explanations for why some people have the ability to control HIV more effectively than others. One is that the virus that these individuals are infected with is weaker and therefore less able to infect and kill CD4+ T cells. Some people are infected with a strain of HIV that is missing a key viral protein, known as Vpr, which limits its ability to infect cells.

Another possible explanation is that people have CD4+ T cells that are resistant to HIV infection. Individuals have been identified who lack a receptor on the surface of these immune cells that is normally used by HIV to gain entry into and subsequently infect the cell. Researchers think there are probably also other genetic properties that allow a person's immune cells to target and kill HIV more effectively.

But there are also many individuals who are long-term nonprogressors who are not infected with a weakened version of HIV or who do not have any of the known genetic properties that bolster their resistance to the virus. Researchers have studied these individuals to see if their immune systems are somehow able to mount more effective immune responses against HIV. So far none of the immune responses they've studied in long-term nonprogressors are any different than in people who progress to AIDS more quickly.

Elite controllers

To try to solve this puzzle and identify the particular immune response that might be important in controlling HIV infection, a team of scientists are now collaborating on a project to study specific subsets of long-term nonprogressors known as elite or viremic controllers. Elite controllers are HIV-infected individuals not taking ARVs who maintain viral loads that are considered undetectable (<50 copies of virus per ml of blood). About 1 in every 300 HIV-infected people is considered an elite controller. Viremic controllers are infected people not taking ARVs whose viral load remains below 2000 copies/ml of blood.

Bruce Walker and colleagues at the Harvard Medical School are now working with other AIDS vaccine researchers to identify a group of 1000 elite and viremic controllers around the world—they estimate there are about 2000 in the US alone, most of whom don't know it. They plan to analyze the immunologic and genetic characteristics of these individuals utilizing the information collected by the Human Genome Project that successfully mapped the thousands of human genes. By comparing this information across a larger cohort of controllers, researchers are hopeful that they will be able to identify the specific genes or immune responses that allow some people to control their HIV infection. Hopefully this will yield important clues for the future design of AIDS vaccines.