Understanding Innate Immunity and HIV

What role do innate immune responses play in defending against HIV infection?

Humans are repeatedly exposed to various pathogens, including viruses and bacteria. The body defends itself against these pathogens using a complex network of cells, tissues, and organs, which together form the human immune system (see VAX July 2008 Special IssueUnderstanding the Immune System and AIDS Vaccine Strategies). There are two branches of the immune system, innate and adaptive, that play a critical role in eliminating invading pathogens.

The innate immune system is the first line of defense against viruses and bacteria. The cells of the innate immune system both detect the invading virus and try to control or eliminate it. Dendritic cells and macrophages are among the most important in recognizing invading viruses like HIV and are found in mucosal tissues, as well as at other sites. These cells are like the body’s 24-hour security force and are constantly patrolling for foreign invaders. Once they come in contact with viruses, they grab hold of the warring particles with the help of finger-like projections. The dendritic cells then cut the virus into small fragments called epitopes that are displayed on the cell’s surface. When these dendritic cells travel to the lymph nodes, which are the communication hubs of the immune system, the HIV fragments on their surfaces act as warning flags, alerting other immune cells of the invading virus.

Innate immune responses are activated soon after an infection occurs but they are not specific, so whether the enemy is a cold virus or HIV, the innate immune system responds in the same way. If the innate immune response is not capable of eliminating the virus or bacteria, or if these responses are evaded by the pathogen, the adaptive branch of the immune system kicks in. The adaptive immune responses, which include cellular immune responses (CD4+ and CD8+ T cells) and antibodies (Y-shaped proteins that work primarily by latching onto viruses and preventing them from infecting their target cells), are pathogen-specific and therefore take longer to become activated—typically several days.

Studying immune responses

The adaptive immune responses produced following HIV infection have been well studied and are still being fully characterized. AIDS vaccine researchers are also able to detect and measure the cellular and antibody responses induced in individuals that have received various vaccine candidates in clinical trials.

However, even though innate immunity is widely considered to be critical in shaping the body’s immune response to HIV, this type of response is much more difficult to study. Innate immune responses are only active for about six to seven days following HIV transmission, and so newly HIV-infected individuals would have to be identified very soon after they become infected for researchers to study innate responses. Also, HIV is most often a sexually transmitted infection and so the innate immune responses, which may play a key role at or very soon after transmission, may be hidden at mucosal sites that are difficult to study. Despite these complications, efforts are underway to identify infected individuals as soon as possible after HIV transmission and to better classify the very early interactions between the virus and the innate immune system.

It is also likely that the innate immune system plays an important role in the response to AIDS vaccine candidates, but this is not very well understood. Investigators involved with the Phase IIb test-of-concept trial known as STEP are currently analyzing the types of innate immune responses induced in volunteers who received Merck’s vaccine candidate. These analyses may offer new clues about the role of innate immunity following vaccination.

A wily virus

HIV has several tricks it uses to evade the immune responses mounted against it. One of the virus’s advantages is that it primarily targets and infects CD4+ T cells, a vital component of the adaptive immune response against HIV. HIV’s ability to constantly mutate also allows it to evade antibody responses.

But scientists still do not completely understand how HIV manipulates the innate immune system. It is possible that macrophages and dendritic cells may unwittingly be helping HIV by delivering virus particles directly to target CD4+ T cells, which the virus then infects. HIV is also thought to disrupt other functions of the innate immune system, including the functional capacity of a subset of cells called natural killer (NK) cells, which would otherwise recognize and destroy HIV-infected cells.

Ongoing study

To help clarify the murky role that innate immunity plays in HIV infection, researchers are studying different groups of individuals. One group of interest is highly exposed seronegatives—individuals who remain uninfected for years despite known and often repeat exposure to the virus. Past studies have found that some women inexplicably resist HIV infection despite participating in commercial sex work and having been repeatedly exposed to the virus. Some scientists have theorized that innate immunity may explain their apparent ability to avoid HIV infection.