Understanding HIV Transmission
What events lead to the sexual transmission of HIV and how can mucosal immune responses protect against infection?
Most infectious agents, including viruses and bacteria, enter the body through mucosal surfaces. These surfaces, or membranes, are the moist tissues that line the body’s internal cavities, such as the lungs, nose, intestine, and genitals. HIV is most commonly transmitted from person to person through sexual contact—researchers estimate that 85% of infections are sexually transmitted. HIV transmission can also occur from direct blood-to-blood contact, which occurs primarily when injection-drug users share needles, or through mother-to-child transmission, either during delivery or from tainted breast milk.
Since the majority of infections are due to sexual transmission, immune responses induced at these mucosal surfaces are the first line of defense against HIV and are critical to stopping the virus in its tracks. Researchers have attempted to develop HIV prevention methods, including microbicides, which could block the virus at the mucosal surfaces of the genitals or rectum, where exposure to the virus first occurs.
In recent years researchers have also focused on developing AIDS vaccine candidates capable of inducing potent immune responses at mucosal surfaces (see Spotlight article, this issue). Scientists are studying different types of immunization strategies, as well as ways to measure mucosal immune responses in clinical trials (see VAXDecember 2005 Primer on Understanding Mucosal Immunity). They have also been closely studying the events leading up to sexual transmission using animal models to better understand the type of mucosal immune responses that would be necessary to thwart HIV infection in humans.
Crossing the barrier
HIV preferentially infects CD4+ T cells, which are a subset of immune cells that are vital to the functioning of the human immune system. These cells are located throughout the body but certain compartments, such as the mucosal tissues lining the intestine or gut, contain the greatest number of CD4+ T cells. For this reason, the intestine is one of the main breeding grounds for HIV during the early stages of infection (see VAX April 2006 Primer on Understanding the Early Stages of HIV Infection).
But before HIV reaches cells in the intestine or other areas of the body, it must first get beyond the genital or rectal mucosal tissues. These tissues are often referred to as the mucosal barrier because viruses have difficulty penetrating the outer layer of cells, known as the epithelium. This is one method the immune system uses to fend off infectious agents.
The mucosal barrier is actually quite effective at blocking HIV—researchers estimate that only one successful HIV infection occurs for every 1,000 times a person is exposed to the virus during vaginal intercourse. There are relatively few target cells in the vaginal mucosal tissues that are susceptible to HIV, which makes it more difficult for HIV to reproduce. If a vaccine or microbicide induces potent immune responses against HIV at these surfaces, it may make it even more of a struggle for HIV to establish an infection, especially in the vaginal tissues. Researchers have observed that in studies with non-human primates, transmission of a related monkey virus known as simian immunodeficiency virus (SIV) occurs more easily rectally than vaginally, and therefore HIV infection may also be more difficult to block at rectal tissues.
It is much easier for HIV to establish an infection at mucosal sites if these tissues are damaged in some way. For example, other sexually-transmitted infections can cause inflammation and irritation, or even ulceration, of the mucosal tissues. This attracts more immune cells to the site, increasing the total number of target cells for HIV and making it easier for the virus to establish an infection. For this reason, infection with other STIs is thought to increase an individual’s risk of contracting HIV. During sexual intercourse, small tears or scrapes are often created in the mucosal surface and researchers think this too can compromise the mucosal barrier effect.
The speed with which HIV spreads makes it impractical to study transmission and the earliest stages of infection in human volunteers. Instead, researchers conduct studies with nonhuman primates, mostly rhesus macaques, using SIV. After SIV crosses the mucosal barrier, research suggests that the virus first establishes a small, localized infection in the genital mucosal tissues. After that, it begins to spread rapidly and is quickly dispersed to other areas of the body through the blood. Results from some animal studies suggest that within one week, and sometimes even within a day, SIV can spread to and be detected at different sites throughout the animal’s body.
If HIV is disseminated as quickly, mucosal immune responses (antibodies and/or cellular immune responses) induced by an AIDS vaccine candidate would have to be induced very rapidly to completely prevent an HIV infection. Typically, immune responses elicited by vaccines take between three and five days to become active. Once HIV begins spreading to other regions of the body that are rich with target cells, such as the mucosal lining of the intestine, research has shown that the virus reproduces explosively and destroys large populations of CD4+ T cells. This is referred to as the acute stage of HIV infection. The quick and often irreversible loss of these immune cells further weakens the immune system’s ability to fight the virus.
Even at this stage, mucosal immune responses can play an important role in helping to limit or control HIV infection. An AIDS vaccine candidate capable of inducing immune responses at mucosal sites, including the intestine, could help prevent some damage to CD4+ T cells and therefore preserve the immune system’s defenses. Systemic or more generalized immune responses would also help control the progression of HIV infection at this stage. -Kristen Jill Kresge