Fibrosis linked to rapid loss of gut CD4 cells after HIV infection

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Rapid and extensive deposition of fibrous tissue called collagen in the lymphatic tissue of the gut during HIV infection has been linked to the dramatic and enduring depletion of CD4 cells from the gut. The findings, published in the August 15th issue of Journal of Infectious Diseases, may provide insight into one of the long-standing mysteries of HIV treatment, namely why antiretroviral therapy, which is successful in reconstituting blood CD4 levels, is considerably less potent in the gut.

The lymphatic tissue associated with the gut, called GALT, is home to a large proportion of the body’s CD4 cells. In fact, only about 2% of the body’s CD4 cells are found in the blood; the remainder is in the GALT and other lymphatic tissues such as lymph nodes. Within the GALT, CD4 cells are found embedded in the lamina propria, a layer within the mucous membrane lining the gut, and in Peyer’s patches, specialised nodules of lymphoid tissue.

During acute HIV infection, levels of CD4 cells decrease, with loss in the GALT being greater than that in peripheral blood. GALT CD4 cells, which are often activated due to the constant challenge by microbes, may be particularly susceptible to HIV, which preferentially infects activated cells.

Glossary

gut-associated lymphoid tissue (GALT)

Immune cells lining the gut that are a critical component of the immune response to pathogens (microbes). The GALT is usually severely depleted very early in the course of HIV infection, a depletion that is believed to be mostly irreversible.

 

CD4 cells

The primary white blood cells of the immune system, which signal to other immune system cells how and when to fight infections. HIV preferentially infects and destroys CD4 cells, which are also known as CD4+ T cells or T helper cells.

lymph nodes

Bean-sized structures throughout the body's lymphatic system, where immune cells congregate to fight infections. Clusters of lymph nodes are found in the underarms, the groin, and the neck.

acute infection

The very first few weeks of infection, until the body has created antibodies against the infection. During acute HIV infection, HIV is highly infectious because the virus is multiplying at a very rapid rate. The symptoms of acute HIV infection can include fever, rash, chills, headache, fatigue, nausea, diarrhoea, sore throat, night sweats, appetite loss, mouth ulcers, swollen lymph nodes, muscle and joint aches – all of them symptoms of an acute inflammation (immune reaction).

fibrosis

Thickening and scarring of connective tissue. Often refers to fibrosis of the liver, which can be caused by an inflammatory reaction to long-term hepatitis infection. See also ‘cirrhosis’, which is more severe scarring.

Treatment with antiretroviral therapy generally leads to increases in blood CD4 counts that, over time, may reach pre-infection levels. A similar reconstitution of CD4 cells in the GALT is not seen, even with extended therapy, and researchers are not sure why.

Schacker and colleagues at the University of Minnesota, Minneapolis have been studying fibrosis as one potential mechanism, and have shown promising results in both primate and human studies. “The major new finding in this study,” they write in the current report, “is the early and extensive collagen deposition in GALT…which we show to be correlated with greater depletion and limited reconstitution of CD4 cells in the gut.”

Getting at the GALT

For their study, the investigators recruited 35 HIV-positive and 11 HIV-negative participants. HIV-positive participants were grouped as being recently infected (within six months of seroconversion), asymptomatic (CD4 cell count > 200 cells/mm3) or having AIDS (CD4 cell counts < 200 cells/mm3). None had received HIV therapy.

HIV-positive participants began antiretroviral, and at baseline and again at month six, all participants provided blood samples to quantify blood CD4 levels. Participants also underwent biopsy of the small intestine and of a lymph node from the groin. CD4 cells were quantified by measuring their total surface area in cross sections of biopsied tissue.

Investigators also evaluated the presence of different subpopulations of CD4 cells, including naïve cells, central memory (CM) cells and effector memory (EM) cells. The latter two subpopulations develop following infection, reside long-term in the lymph tissues and become a source of lasting immunity to reinfection.

The GALT does not recover

When looking at baseline samples, investigators noted that samples from HIV-positive participants had significantly fewer CD4 cells than HIV-negative samples. Blood samples showed a 0.50-fold reduction (p < 0.001); lymph node, a 0.59-fold reduction (p = 0.001); Peyer’s patches, a 0.72-fold reduction (p = 0.02); and the lamina propria, a 0.66-fold reduction (p = 0.008). “This decrease occurs in EM cells, the major CD4 cell subset population in the lamina propria”, conclude the investigators based on further analyses.

Investigators then evaluated samples from participants who completed six months of antiretroviral therapy. They observed the expected rise in blood CD4 cell counts, with a median increase of 97 cells/mm3 or 41%, but saw no significant increases in any of the tissue samples. In lymph node, CD4 cell population size increased by 15% (median increase in area, 5.56%; p = 0.094). In Peyer’s patches, the population decreased by 22% (median change in area, -3.57%; p = 0.68), and in lamina propria, there was a decrease of 10% (median change in area, -0.54%; p = 0.26). More detailed analysis of different CD4 cell subpopulations revealed an increase in CM cells in the Peyer’s patches of the two patients who started treatment while they were in the acute-early stage of infection.

HIV therapy, the investigators write, “initiated at later stages of HIV-1 infection does not result in gut reconstitution, but we provide new evidence in support of the conclusion that reconstitution of subpopulations of gut CD4 cells is possible with early treatment.”

Is collagen the culprit?

The reasons behind the dramatic and sustained decrease in GALT CD4 cells remain unknown. Based on previous studies in primates and humans, Schacker’s group propose a mechanism they call the damaged niche, in which fibrosis disrupts the structure of lymph tissue and inhibits the survival of immune cells.

In this study, the team assessed the degree of fibrosis, measured as deposition of collagen, in the GALT. The mean percentage of GALT tissue that stained for collagen was 15.5% for HIV-positive participants, versus 4.4% for HIV-negative participants (p = 0.002). Specifically in Peyer’s patches, the extent of collagen deposition was inversely correlated to the sizes of the total and naïve CD4 cell populations. HAART had little effect on fibrosis in the GALT. There were no significant differences in collagen deposition between samples taken at baseline and at six months.

Looking specifically at participants in the acute stage of infection, investigators noted greater amounts of collagen in Peyer’s patches of the GALT compared with lymph node (p = 0.03), suggesting that collagen is deposited earlier in the GALT than lymph nodes, the source of blood CD4 cells. “We think that the rapid and more extensive collagen deposition in the gut may be an important mechanism that contributes to the disproportionate levels of early and sustained depletion of CD4 cells in GALT,” they write.

A model of GALT damage

The investigators build a model in which fibrosis in Peyer’s patches and lamina propria plays a role in the early loss of both naïve and memory CD4 cells in the gut. Without memory cells, reconstitution of CD4 populations is hampered especially in the lamina propria, which derives much of its population from Peyer’s patches. This loss, they hypothesise, “may be important in determining rates of progression to disease.”

If borne out, the findings from this study could have profound implications for treating HIV infection, especially acute infection. “Our observations”, the investigators conclude, “suggest that earlier therapy might better preserve and restore the critical CM CD4 cell population in GALT. We also speculate that antifibrotic drugs might have a role as adjunctive therapy in HIV-1 infection, both in limiting depletion and improving reconstitution during [antiretroviral therapy].”

In an accompanying editorial, Read and Sereti of the National Institutes of Health, provide a tempered view: “These findings are intriguing and the call for earlier therapy in HIV infection is supported by other evidence; however, further studies with longitudinal sampling of subjects who start therapy at various pretherapy CD4 T cell counts will be required to confirm these observations and to better understand their clinical implications.”

References

Estes J et al. Collagen deposition limits immune reconstitution in the gut. J Infect Dis 198:456 – 464, 2008.

Read SW and Sereti I HIV infection and the gut: scarred for life? J Infect Dis 198:453 – 455, 2008.