CD4 cell loss in gut is not restored by HIV treatment, may have long-term consequences

CD4 cells in the wall of the human gut continue to be seriously depeleted even after successful antiretroviral treatment has reduced HIV in the blood to undetectable levels, according to a study of 54 people who began treatment during early or acute HIV infection published this month in PLoS Medicine. The long-term clinical consequences of this depletion of memory CD4+ cells cannot be predicted, say the researchers, but they warn clinicians will need to be vigilant for the emergence of gastrointestinal problems caused by poor immunity in patients who appear to be doing well on antiretroviral therapy over decades of treatment.

Massive loss of CD4+ memory cells in the lymphoid tissue of the gut is known to occur during the first two to four weeks of HIV infection. These cells are essential to the long-term health of the immune response, because in their entirety they contain a `memory` of all the infections and foreign agents that the body has encountered during its lifetime.

Although this loss occurs immediately after infection, the CD4 cell count in the blood – the standard tool for monitoring the progression of HIV disease – may not reflect the loss. Nor is its impact on the course of HIV disease progression properly understood, since CD4 cell numbers in the gut lymphoid tissue can only be measured by taking samples of tissue from the gut.

Still less is known about the effect of antiretroviral therapy on the CD4+ memory cell population in the gut.

Researchers at the Aaron Diamond AIDS Research Center and New York University School of Medicine set out to investigate immune reconstitution in the gut in 54 HIV-positive individuals who began antiretroviral treatment during acute or early HIV infection, and compared their immune cell populations with those of 18 uninfected, unmatched control patients who had undergone a colonoscopy.

Eighteen HIV-positive patients were studied with a longitudinal series of biposies over the first three years of treatment, while 22 were studied at random intervals up to seven years after they had started treatment. Thirty-two of the HIV-positive patients also underwent biopsies before they began treatment.

The study assessed the proportion of lymphocytes in the tissue sample that were CD4+ cells, and found that CD4 cell percentage was significantly lower in HIV-infected people and did not increase substantially with time on treatment. However, 30% of the patients on treatment did show a normalisation in the absolute number of CD4 cells in the gut samples when compared with the HIV-negative control group.

They also found that CD4+ and CD8+ memory cells in the gut remained activated after antiretroviral treatment began, while activation diminished in the peripheral lymph nodes and blood. The less activation that was detected, the better the immune reconstitution in the gut, the researchers found.

The explanation for the ongoing loss of memory cells and immune activation in the gut lymphoid tissue did not appear to be a high level of HIV-expressing cells, since the group found it difficult to detect such cells in people receiving antiretroviral treatment.

“We hypothesise that, owing to viral factors, host factors, or both, the host’s ability to down-regulate nonspecific inflammatory responses may be one of the important determinants of the lack of mucosal CD4+ T cell reconstitution,” write the authors.

Lack of recruitment of effector memory cells into the gut lymphoid tisssue during immune reconstitution is also blamed for the deficit.

“It is evident that, with treatment, patients do not demonstrate any short-term effects of having a 50% loss of CD4+ T cells in the GI lamina propria. However it is important to recognise that, given the projected long-term survival of HIV-1 infected patients, significant loss of mucosal CD4+ T cells could accelerate immune senescence with attendant consequences. In recent clinical studies, an increased risk of polyps and colorectal malignancies has been observed in HIV-1 infected individuals independent of antiretroviral therapy.”