Plumbing HIV pathogenesis in the gut

1 December 2010. Related: Basic science and immunology.

Richard Jefferys, TAG

A trio of recent papers delve into the gut as an important site of HIV pathogenesis. Two are from the research group of Joseph Wong at UCSF, and they involve the same small cohort individuals analysed before (in the JID paper) and after (in the journal AIDS) they started a clinical trial involving intensification of their antiretroviral therapy. [1, 2]

The third paper, led by Shari Gordon from Guido Silvestri’s laboratory, studies a larger group of 28 people with HIV (15 untreated and 13 on antiretroviral therapy) and 11 healthy controls. [3]

One unifying theme of the results is that not all gut sites are equal; both the levels of HIV infection and the proportions of CD4 vs. CD8 T cells vary when samples from the duodenum, terminal ileum, right colon and rectum are compared in Steven Yukl’s JID paper. HIV DNA levels show a trend toward a stepwise increase as the sample sites descend, with lowest levels in the terminal ileum and highest in the rectum. Conversely, unspliced HIV RNA – a potential indicator of active viral replication – shows the opposite trend, with levels highest in the terminal ileum. Shari Gordon’s study samples a
slightly different array of gut sites – terminal ileum, right colon, left colon, and sigmoid colon – but also finds variation in representation of CD4 T cell subsets; naive CD4 T cell levels are highest in the terminal ileum but decrease progressively as the sample sites get lower down the GI tract.

The Yukl paper also reports some major differences between blood and gut samples. HIV DNA levels are consistently higher in all gut sites compared to peripheral blood mononuclear cells (PBMC) and the differences are highly statistically significant with the exception of the duodenum. And while there is a positive correlation between HIV DNA levels and markers of immune activation in PBMC, there is an inverse correlation in the gut, a novel finding that the researchers suggest may be due to infected cells in the gut being tolerant or anergic (the gut is known to be a site where T cell tolerance against
commensal bacteria and food antigens is induced and maintained).

Shari Gordon’s study identifies several parallels between blood and gut. The levels of CD4 T cell depletion in blood correlated directly with the level of depletion measured in all gut sites. Levels of memory CD4 T cell proliferation (measured the Ki67 marker) were also directly correlate in both compartments. Gordon also finds that the magnitude of CD4 and CD8 T cell proliferation in the blood correlates with the severity of CD4 T cell depletion in the gut. This latter finding indicates that the loss of gut CD4 T cells impacts the normal balance (or “homeostasis”) of the immune system in a way that
contributes to systemic immune activation. Encouragingly, the study reveals substantial repopulation of gut CCR5-expressing CD4 T cells in the cohort of individuals on ART and notes that: “in our hands the extent of depletion of intestinal CD4+CCR5+ T cells appeared to be less severe than what has been reported by others during HIV infection.”

The Steven Yukl paper in AIDS describes the impact of intensifying ART with either raltegravir alone or raltegravir plus efavirenz or darunavir for 12 weeks in seven of the eight individuals whose baseline values are reported in JID (one dropped out shortly after starting the trial for personal reasons). CD4 T cell counts and HIV DNA levels remained unchanged, but a significant drop in levels of unspliced HIV RNA was seen in the terminal ileum of 5/7 participants. There was also a slight decline in levels of activated CD4 and CD8 T cells in blood and gut, with the greatest change seen in the terminal
ileum. The researchers conclude that the findings may be suggestive of some ongoing viral replication occurring in the terminal ileum that was impacted by ART intensification, but they stress that this interpretation needs to be confirmed by larger studies.

These papers add to the evidence that the gut plays an important role in the pathogenesis of HIV infection, but also highlight the need to better understand gut immunology in health as well as disease (an area of research that remains relatively obscure and under-supported). The suggestion that HIV may be establishing latency in tolerant CD4 T cells also has implications for cure research, because targeting this population may require different strategies than those being considered for other HIV reservoirs.

Source: TAG basic science blog. (17 November 2010). http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2010/11/plumbing-hiv-pathogenesis-in-the-gut.html

References:

1. Yukl SA et al. Differences in HIV Burden and Immune Activation within the Gut of HIV-Positive Patients Receiving Suppressive Antiretroviral Therapy. Journal of Infectious Diseases. Published online 12 October. 2010;202:000–000. DOI:0.1086/656722. http://www.journals.uchicago.edu/doi/abs/10.1086/656722
2. Yukl SA et al. Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy. AIDS. 2010 Oct 23;24(16):2451-60. http://journals.lww.com/aidsonline/Abstract/2010/10230/Effect_of_raltegravir_containing_intensification.4.aspx
3. Gordon SN et al. Disruption of Intestinal CD4+ T Cell Homeostasis Is a Key Marker of Systemic CD4+ T Cell Activation in HIV-Infected Individuals. Journal of Immunology, 2010. Published online 1 October 2010.doi:10.4049/jimmunol.1001801. http://www.jimmunol.org/cgi/content/abstract/jimmunol.1001801v1