Understanding the Early Stages of HIV Infection
How can studying what happens immediately following HIV infection help researchers design an AIDS vaccine?
There are many reasons why HIV is such a difficult virus to combat. One is that HIV directly attacks the human immune system, the body's defense against pathogens like viruses and bacteria. The primary target of HIV is the CD4+ T cells, an important immune cell that directs the body's response to an infection. During HIV infection huge numbers of these cells are infected and killed each day, but new ones take their place.
Doctors or nurses can monitor the progression of HIV disease by CD4+ T-cell counts, which are a measure of the number of CD4+ T cells circulating in the blood. For many years after initial infection the quantity of these important immune cells can stay the same or drop only slightly, but in most people the virus will eventually take over and the total number of CD4+ T cells will start to dwindle.
A typical definition of AIDS is when the total number of CD4+ T cells in an HIV-infected person dips below 200 in a milliliter of blood (in people with healthy immune systems there are between 600-1200 CD4+ T cells in this same amount of blood) or when a person develops one of several AIDS-associated illnesses. Once the CD4+ T-cell count is dangerously low, the immune system is incapable of defending the body from attack by other pathogens and a person also becomes susceptible to many opportunistic infections, which can be deadly.
Measuring the number of CD4+ T cells in the blood is a convenient way for researchers to estimate the damage HIV is doing to the immune system, since blood samples are easily obtained. But the majority of the body's CD4+ T cells aren't in the blood. Rather they are found in the mucosal tissues, such as those lining the respiratory, gastrointestinal, and genital tracts. Looking only at the blood may paint an inaccurate picture of what is really happening during HIV infection, so researchers have recently focused on studying the immune responses occurring specifically at these mucosal sites.
Looking at the gut
When researchers looked at mucosal tissues they found something very interesting. In both animal models and humans, researchers observed a massive killing of CD4+ T cells at mucosal surfaces in the intestine, or gut, very early in the course of HIV infection. For many years scientists were more concerned with the dynamics of the human immune system much later in HIV infection when it begins to fail. But research now suggests that a critical destruction of immune cells occurs long before a person exhibits symptoms or develops AIDS, and often even before an individual knows they are infected with HIV (see VAX November 2005 Primer on Understanding HIV Testing).
The bulk of CD4+ T-cell death in these tissues actually occurs within a few weeks after a person contracts the virus, during a period referred to as acute infection. Although the number of CD4+ T cells in the blood also decreases during this initial stage of HIV infection, researchers found that the greatest depletion is seen in the mucosal tissues of the gut.
Researchers have also found that the immune system has trouble repairing damage in these mucosal tissues. CD4+ T-cell counts often rebound quickly in the blood once an individual starts taking antiretrovirals (ARVs), but the CD4+ T cells in the gut are restored much more slowly than in blood, even in HIV-infected individuals who have been receiving treatment with ARVs for several years.
This may mean that the loss of CD4+ T cells at the mucosal surfaces is a better predictor of disease progression than monitoring their quantity in the blood.
But it would be difficult to monitor HIV-infected individuals by repeatedly measuring CD4+ T-cell counts at mucosal sites. Testing these tissues requires a procedure known as a biopsy, which is a more invasive process than collecting a blood sample. Researchers are now looking for ways to analyze subtle differences between CD4+ T cells in the blood in order to more easily determine and predict what is happening in the gut.
Implications for vaccines
This research has many implications for AIDS vaccine design and research. If the critical battle between HIV and the immune system takes place in the earliest stages of HIV infection, as this research suggests, it is important to closely study the virus that is transmitted and to characterize the nature of the immune responses in the first weeks and months of infection.
Many organizations involved in developing AIDS vaccine candidates are therefore interested in studying recently HIV-infected individuals. IAVI is one group conducting this type of epidemiological study with recently HIV-infected volunteers at several centers in Africa (see Global News, this issue).
Other research organizations are working with collaborators to identify and follow newly-infected individuals at sites in many countries around the world. Information collected from these studies may offer clues to help better define the target for a preventive vaccine.
Another important implication from this research is the need for AIDS vaccine candidates that induce strong immune responses at mucosal tissues, especially those lining the intestine. Several researchers think this will be necessary for a preventive vaccine to be effective and many methods are now being explored to enhance the mucosal immunity induced by existing AIDS vaccine candidates (see VAX December 2005 Primer on Understanding Mucosal Immunity).