Understanding the Conundrum of Immune Activation in HIV/AIDS

Why is it that chronic activation of the immune system during HIV infection actually leads to disease progression?

In most circumstances, the body’s deployment of the immune system (both the innate and adaptive arms) allows it to conquer an invading pathogen (see VAX July 2008 Special IssueUnderstanding the Immune System and AIDS Vaccine Strategies). But HIV is unique in that it directly attacks the cells of the immune system, slowly breaking down the body’s defenses. Once the adaptive immune system is alerted to an HIV infection, it responds by producing HIV-specific CD4+ T cells, which orchestrate the function of CD8+ T cells, also known as killer T cells because of their ability to kill virus-infected cells. While these T cells are beneficial in suppressing HIV, they are also preferentially targeted and destroyed by the virus. As more CD4+ T cells are generated in response to HIV, there are also more cells for the virus to infect and kill, setting off a destructive cycle.

Once the virus destroys a critical number of these immune cells, the body’s ability to control HIV is severely compromised. A person is diagnosed with AIDS once their number of CD4+ T cells declines below a certain level (fewer than 200 cells in a milliliter of blood). When the immune system is compromised to this degree, a person also becomes susceptible to many other bacterial and viral infections. In a person with AIDS, these are referred to as opportunistic infections.

Many T cells are lost during the course of HIV infection because they are directly infected and killed by the virus. However researchers suspect that HIV also uses other mechanisms to induce immune dysfunction. These mechanisms are not fully understood but some scientists believe that the presence of HIV overstimulates the immune system. HIV is a chronic infection and there is little or no evidence that any HIV-infected individual has ever been able to clear the virus from their body. As long as HIV is present, the immune system is in a constant state of activation or high alert—struggling to produce immune responses that could control the rapid spread of the virus. There is a broad consensus among researchers that this chronic state of immune activation contributes to the virus’s ability to cause disease, an idea referred to as pathogenesis. However, while there are some hypotheses about how HIV causes chronic immune activation, the precise mechanisms are still under investigation.

Clues from nonhuman primates

Studies in nonhuman primates infected with simian immunodeficiency virus (SIV), the monkey equivalent of HIV, suggest that chronic immune activation may play a crucial role in pathogenesis. Rhesus macaques, which are most often used in AIDS vaccine research, develop an AIDS-like disease following SIV infection. However there are some species of nonhuman primates, including sooty mangabeys and African green monkeys, which do not develop AIDS-like symptoms or any deleterious consequences following SIV infection (see VAX Sept. 2008 Primer onUnderstanding Control of Virus Replication). Although SIV-infected sooty mangabeys have high levels of virus circulating in their blood, they are able to maintain normal levels of CD4+ T cells. Interestingly, researchers have also observed that the immune systems of SIV-infected sooty mangabeys are not chronically activated, as they are in SIV-infected rhesus macaques or HIV-infected individuals. This may be partly why they are able to avoid developing AIDS. Researchers plan to do additional studies to see if artificially increasing the level of immune activation in these animals will trigger disease progression.

Causes of immune activation

Studies in HIV-infected humans have shown that during the very early stages of infection, the virus rapidly infects and kills T cells in mucosal tissues, with the greatest depletion of CD4+ T cells occurring in the intestine, or gut (see VAXApril 2006 Primer on Understanding the Early Stages of HIV Infection). In most people, the numerous immune cells in the gut that are lost early in infection are never restored, even following initiation of highly active antiretroviral therapy. Some researchers propose that this massive depletion of T cells in the gut allows disease-causing bacteria that normally live in the intestine to leak out and circulate more widely in the body, further burdening the immune system. This is one factor that researchers think may contribute to the high level of immune activation in HIV-infected individuals.

HIV may also interfere with a subset of T cells that are responsible for dampening immune responses and keeping the immune system in check. These so-called regulatory T cells play an important role in suppressing immune responses once an infection is eliminated, and also prevent the immune system from becoming overzealous and attacking the body’s own cells. Little is known about the function of regulatory T cells in HIV infection, but this is an active area of investigation and may provide additional insights about the role of immune activation in HIV pathogenesis.

Although the ideal goal is to develop an AIDS vaccine that could prevent HIV infection entirely, a partially effective vaccine that could control the virus in the early days of infection might help prevent severe damage to the immune system and allow the body to better control HIV. This could alleviate some of the causes of chronic immune activation and might help delay disease progression in individuals who may become HIV infected through natural exposure to the virus, despite vaccination.