Morphologic changes and CD4+ T cell depletion of the GALT

Untreated, the intestine of a HIV-seropositive person undergoes histologic changes such as crypt hyperplasia, villous blunting and atrophy which was already described early on in the era of HIV as “HIV-enteropathy” (153). Direct virotoxic effects on enterocytes with impairment of the glucose uptake were described, being held partly responsible for the HIV-related malnutrition (154). Severe functional changes of the ileum with reduced absorption of vitamin B12 and bile acids are observed in AIDS patients that potentially lead to neurologic disorders and diarrhoea. The discrepancy between severe bowel dysfunction and often only minimal morphologic changes is remarkable (155).

Citrulline is a useful biomarker to assess the loss of enterocytes in the small bowel as it is solely produced by the enterocytes as part of the glutamine metabolism.

Decreased citrulline plasma levels are measured in HIV-seropositive patients, indicating a decrease of the number of functional enterocytes which is associated with an impairment of the gut epithelium and malabsorption (156).

Moreover, increased levels of intestinal fatty-acid binding protein (I-FABP) are observed even in treated chronic HIV-seropositive patients. I-FABPs are expressed and released from enterocytes in the event of epithelial damage and indicate ongoing mucosal destruction (157).

Another factor that contributes to the damage of the intestinal epithelium is the accumulation of HIV-infected macrophages on the mucosal surface. These infected macrophages induce an inflammation of the mucosa and show a reduced phagocytic function compared to healthy macrophages, thus they predispose to an increased translocation of microorganisms (158).

CD4 was found to be the principal cellular receptor for HIV fusion and entry (159).

In the past decade it has been discovered that additional to CD4, a chemokine co-receptor, usually either chemokine receptor four (CXCR4) or five (CCR5), is essential for viral entry into target cells.

After infection the virus moves rapidly to regional lymph nodes and subsequently spreads via the bloodstream to other lymphoid tissues of the body. The GALT is a major target where the virus replicates extensively with the consequence of a massive depletion of CD4+ T cells in the gut early after infection (160). Most CD4+T cells in the GALT are activated memory cells, also called effector memory cells, and express CCR5, which functions as the co-entry-receptor for HIV, making them the preferred target cells (161). Moreover, the HIV-envelope glycoprotein GP120 binds to the integrin 47. This integrin, expressed on T cells, serves as homing receptor and is responsible for the migration of the lymphocytes to the GALT which may further explain the affinity to and massive replication of the virus in this lymphoid tissue (162).

The underlying cause for the massive depletion of the mucosal CD4+ T cells during the acute infection phase is direct cell infection and, subsequently, a virus-induced immune response followed by elimination of the cell (163). This takes place early in the course of infection; almost two thirds of memory CD4+ T cells are infected when the peak levels of viremia are reached, and within four days 80% of CD4+ T cells are destroyed (164). This observation carries even more importance due to the fact that the mucosal CD4+ T cell compartment contains the majority of the T-cell population in the body.

In untreated HIV-seropositive patients, the CD4+ T cell depletion is most pronounced in the gastrointestinal mucosa during all disease phases (160). As the decrease of the CD4+T cells is more distinct in the GALT than in the blood (165), the assessment of the disease and its progression by examining blood alone most likely does not give us the complete picture of the extent of immunosuppression.

Isolation of specific T cell subsets via flow cytometry with subsequent identification of viral DNA with polymerase chain reaction is able to quantify the number of infected cells within cell populations of interest. This technique confirmed that many more T cells in the gastrointestinal tract, the CCR5+ CD4+ T cells, are virus-infected than the CD4+ T cells in the blood; actually a ten-fold higher infection rate was reported which, in turn, mirrors the huge extent of the viral reservoir in the gut compartment (166,167). Notably, the depletion of these CCR5+ CD4+ T cells is observed all along the gastrointestinal tract, including the colon and rectum (168), hence the HIV-infection leads to a pronounced destruction of the gut’s effector cells, the LPL (164).

CD4+ T cell loss is further promoted by HIV-induced changes of the lymph node tissue with subsequent disruption of the physiological processes that usually take place herein. Peripheral lymph nodes are organized in such a way that facilitates interaction between antigens, lymphocytes and chemokines and which triggers an immunologic response that controls the balance between CD4+ and CD8+ T-cell population and their proliferation (169). The response of the innate and adaptive immune system to the HIV replication induces inflammation in the lymphoid tissue leading to deposition of collagen, thus changing the structure of the lymph node architecture (170). As CD4+ T cells depend on a working lymph node environment

these changes contribute to the loss and decreased life time of this T cell subset (171).

Interaction of T cells with follicular dendritic cells is also sustained by a functional lymph node structure; in fibrosed lymph nodes this important interplay is impaired, hence, the immune system suffers partial loss of an important site of antigen presentation.

In summary, the destruction of CCR5+CD4+T cells in the gut together with structural damage of lymphoid tissue leads to a significant reduction of the quantity of CD4+T cells in the body with a reduced memory T-cell pool (160).

Architectural changes and collagen deposition is not only limited to the peripheral lymph nodes. The immune-inductive sites of the GALT, namely the PP, are also affected by collagen deposition leading to permanent changes in this compartment.

Notably, CD4+ T cell reduction reportedly correlates with the amount of collagen deposition in the secondary lymphatic tissue (170).