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The gut reaction to HIV —

The gut contains 40-60% of the body's immune cells. As a result, gut tissue is uniquely vulnerable to HIV, and careful investigation of gut tissue is likely to provide important clues to the pathology underlying HIV infection.

It might seem counter-intuitive that by examining the gut one can learn a great deal about a blood-borne virus that attacks the immune system. However, the surface of the gut is a mucosal membrane, and like all mucosal membranes is associated with specialized immune, or lymphoid, tissue. The gut-associated lymphoid tissue (GALT), the largest lymphoid organ in the body, serves as a substantial reservoir of HIV in infected people, and plays important roles in the pathology of HIV infection.

Mucosal membranes in the rectum and the urogenital tracts serve as entry points for sexually transmitted HIV; therefore, viral dynamics in these tissues are particularly relevant to the etiology of HIV disease. This holds true even for lymphoid tissue in mucosal membranes when the initial infection occurs elsewhere. SIV, a virus related to HIV that infects monkeys, will become established in GALT within days of infection even when the virus was inoculated intravenously. This highlights the special vulnerability of GALT to infection with HIV.

Three factors contribute to this vulnerability. First, GALT contains a large population of cells known as activated helper T lymphocytes. These are the very cells that HIV prefers most to infect. Second, gut mucosal membrane is specialized in transporting material into the body for evaluation by immune cells, and this activity provides a potential mechanism for HIV to enter even healthy mucosal tissue. Third, recent data now indicate that chemokine receptors, the cell surface molecules that HIV uses as attachment points for entering into cells, are expressed at high levels on cells found in the gut, making infection that much easier for the virus.

The gut contains large numbers of susceptible cells

The majority of the material that enters the body is breathed in or swallowed, and the first contact this material has with the body is at mucosal surfaces along the respiratory or digestive tracts. In the case of material that is swallowed, much of it will be essential nutrients that must be absorbed, while other material will be potentially harmful. GALT must correctly differentiate between what the body requires, what is inert, and what must be excluded.

The lining of the human gut has 200 times more surface area than the skin. Naturally, this much area requires great numbers of immune cells for vigilance. The gut is estimated to contain 40-60% of the body's total lymphocyte population.

These immune cells are normally in a mild state of activation. This is generally useful, since activated lymphocytes are more vigilant against harmful material. On the other hand, proteins from food are not always fully digested by the time they reach the intestines, and would serve as antigens that induce a strong inflammatory response†an allergic reaction†if some mechanism were not available for tolerance as well. As a result, a balance is normally struck between activation mechanisms for protection and immune tolerance mechanisms to prevent aberrant (and potentially harmful) responses to inert materials or essential nutrients.

This chronic mild activation of GALT immune cells exacerbates the damage caused by HIV in the gut. HIV will productively infect several classes of cells, but displays a preference for infecting the helper T cell type, the subset of lymphocytes that bears the marker CD4. When helper T cells are activated, as many that reside in the gut are, they become even more susceptible to HIV infection.

One would expect from this that cell loss in HIV infection would be highest in GALT regions in which helper T cells are concentrated, and this is what has been observed. The lamina propria is a region of GALT that is rich in activated helper T cells. The lamina propria sits right near the mucosal surface, and is separated from all the material in the gut by a single layer of epithelial cells. A number of papers have described cell loss in GALT in patients with HIV, and in monkeys infected with SIV. In both cases, there is a selective loss of CD4+ helper T cells within the lamina propria, and there are indications that helper T cells are depleted in the lamina propria before there is loss detected in the blood.

The chronic mild activation level of gut T cells renders them vulnerable to HIV infection. At the same time, the tolerance mechanisms that provide a brake against aberrant activity might possibly serve to retard effective anti-HIV responses.

HIV enters in a Trojan Horse?

HIV and SIV are much more efficient at infecting compromised mucosal membranes than intact ones, but infection of intact membranes has been documented. Recent work has raised the intriguing possibility that HIV can usurp normal mechanisms for transporting material across these surfaces to gain entry into the body.

The mucosal surface of the gut is surrounded by a layer one cell thick, the epithelium. This thin layer is all that stands between the interior of the body and all the nutrients and potentially infectious agents within the intestines. The cells of the gut epithelium are specialized to transport antigens across this layer to the GALT for analysis (to either launch an immune response if the antigen is considered harmful or to tolerate it if is considered benign). Intact viruses can also be transported across the epithelium by these cells.

"M" cells are the cell type within the epithelium thought to be responsible for the transport and presentation of antigens to lymphoid cells within. Lymphocytes migrate towards the M cells to become educated about the material the gut is being exposed to. Many of these lymphocytes are the activated helper T cells that are particularly vulnerable to infection with HIV. HIV can adhere to the surface of M cells, and it is possible that T cells inside the gut mucosa become infected when they migrate out to meet M cells.

It is not yet clear that HIV can infect the intact gut in this manner, but a related cell type † the dendritic cell † is known to promote HIV infection of activated helper T cells within lymph nodes by just this mechanism. The long-lasting retention of intact virus by dendritic cells is a significant impediment to eradicating HIV from lymph nodes with antiviral treatments. Since extensive networks of dendritic cells exist in the gut as well, it also might impact the clinical course of treatment.

High chemokine receptor levels add to the gut's vulnerability

HIV infects cells that express particular cell surface molecules that act as attachment points for the virus. These molecules are called chemokine receptors, because they normally bind chemokines, signaling molecules that activate lymphocytes and macrophages (another kind of white blood cell).

Using the endoscopic rectal biopsy technique, Dr. Peter Anton and associates at UCLA reported at the XII World AIDS Conference in Geneva, Switzerland that the chemokine receptor profile of T lymphocytes in the gastrointestinal tract render them particularly vulnerable to infection by HIV.

Upon isolating T cells from the rectal biopsies, Dr. Anton's group measured the level of one particular type of chemokine receptor, known as CCR5. HIV prefers to attach to this type of chemokine receptor during transmission. Once an infection is established, the virus develops an affinity for other kinds of chemokine receptors. The expression profile of CCR5 in GALT immune cells is therefore a particularly relevant parameter in models of HIV infection.

The percentage of helper T cells that bear CCR5 is significantly greater in the gut T cell population than in the blood T cell population. This is true in healthy, uninfected individuals as well as in HIV-infected individuals. The number of CCR5 molecules present on each cell is also significantly higher in gut CD4+ T cells than in blood CD4+ T cells.

One can conclude from this that the potential for infection of CD4+ T cells in the gut is high, but there is another variable that can affect the degree to which this is true. Activated lymphocytes secrete the very chemokines that normally occupy these receptors, thereby preventing HIV from binding. These chemokines also cause CD4+ T cells to remove the receptors from their membranes, closing the door to HIV infection. Unfortunately, although there is a degree of immune activation under normal conditions in the gut that would tend to favor chemokine secretion, this activation also recruits additional T cells to the gut lining from the blood, providing potentially more viral targets.

GALT is a significant HIV reservoir.

Rectal biopsies of HIV-infected people have established that GALT is a significant repository of virus, and declines in select T cell populations within the gut are correlated with the stage of disease. As discussed in the article, "Whole Body Viral Burden" (page 21), viral replication occurs at a faster rate within GALT than in blood or lymph nodes. It is likely that HIV infection of GALT is a significant contributor to progression to AIDS.

A longitudinal study within individual patients has not been attempted before, to establish the relationship between the viral dynamics in GALT and the rest of the body. Accordingly, AIDS RESEARCH Alliance's collaborative effort with Dr. Peter Anton of UCLA (see page 11 for the study description) aims to establish a repeatable measure of viral burden within GALT tissue that can be used for analyzing such relationships. These studies will be key to elucidating mechanisms of pathology caused by HIV infection.