Previous studies of HIV pathogenesis have largely ignored events in the intestines of HIV-infected patients and have mostly concentrated on events in the blood, perhaps owing to the difficulty in obtaining intestinal lymphoid-tissue samples. However, two groups now report that the gastrointestinal tract has the most marked depletion of CD4+ T cells, and this occurs rapidly and at all stages of HIV infection, regardless of administration of highly active antiretroviral therapy (HAART).

Given that the gastrointestinal tract and other lymphoid tissues harbour most of the body's CD4+ T cells, and that in the gut, a large number of these cells are activated and express the HIV co-receptor CC-chemokine receptor 5 (CCR5), the intestinal CD4+ T cells are potentially highly susceptible to infection with HIV and are therefore of crucial importance in HIV pathogenesis. So, the authors of both studies set out to examine CD4+ T-cell depletion in the intestine of patients with HIV.

Danny Douek's group compared T-cell depletion in intestinal tissue, lymph nodes and blood from untreated HIV-infected patients (at all stages of disease) and from HIV-uninfected individuals. As expected, the frequency of CD4+ T cells was significantly lower in each compartment in HIV-infected patients compared with HIV-uninfected individuals; however, the greatest loss of CD4+ T cells was seen in the gastrointestinal tract, even in acute infection. This preferential depletion of intestinal CD4+ T cells was confirmed by histological studies, showing that lymphoid aggregates, which are abundant in normal intestinal-tissue samples, were largely absent in samples from patients with HIV. Further analysis revealed that the CD4+ T-cell depletion in the gut was specific for those cells expressing CCR5 and the activation marker Ki67, which is consistent with the observation that HIV preferentially replicates in and causes the death of activated CD4+ T cells.

It is well known that chronic infection with HIV results in a state of general immune activation. Accordingly, Douek's group observed that effector memory T cells accumulated abnormally in the lymph nodes of HIV-infected patients, possibly owing to the activation and recruitment of these cells to the site of viral replication. Moreover, this increased T-cell activation was associated with collagen deposition in the lymph nodes, a marker of inflammation associated with chronic immune activation. This led the authors to suggest that disrupted lymphoid architecture might disturb normal lymphoid-tissue homeostasis, which might then impair CD4+ T-cell reconstitution of the gut following depletion by infection with HIV.

Martin Markowitz's group studied T-cell depletion in patients with acute or early HIV infection, and compared untreated patients with those who had received HAART. Consistent with observations by Douek's group, in primary HIV infection, they found that CD4+ T-cell depletion was most marked in the gastrointestinal tract and that it occurred before changes observed in the blood. Specifically, deletion mainly occurred in the effector sites (the lamina propria) as opposed to the inductive sites (Peyer's patches and lymphoid follicles) of the gastrointestinal mucosa.

To examine whether HAART would allow the reconstitution of CD4+ T cells in the gut, they studied patients who had initiated HAART during primary infection. However, although CD4+ T-cell numbers in the blood of these patients were mostly restored following HAART, reconstitution in the gastrointestinal tract remained incomplete despite up to 5 years of fully suppressive therapy.

Both of these studies, which are in agreement with earlier studies of macaques infected with simian immunodeficiency virus, highlight the need for further investigation of the mucosal compartment, given its crucial role in HIV infection, replication and persistence.