The link between Th17 and HIV pathogenesis

The Th17 population is a CD4 T lymphocyte effector subset that in the simplest way can be defined as IL-17A releasing cells; although several other cytokines and transcription factors seem to be typical as well for cells that express IL-17A. These cells are protective in several bacterial and fungal diseases, particularly at mucosal parts of our body. They also are regarded as pathogenic during autoimmune conditions and the infection with Schistosoma mansoni parasite. Another interesting feature of Th17 population is the link to HIV pathogenesis. HIV virus replicates within Th17 subset and IL-17A expressing cells are preferentially depleted from the gut mucosa during HIV infection. The reduction in Th17 level has been linked to increased permeability of mucosal barrier in the digestive tract. This can lead to continuous leaking of microbial products into the bloodstream and maintains chronic immune activation – the HIV infection distinctive feature. Two recent publications reinforce the connection between Th17 and HIV.

The first link:

This publication presents data collected in the region that is affected by AIDS pandemic. Subjects of the study are Kenyan women divided into two pools – virus-negative healthy controls and HIV-positive sex workers. HIV tends to infect activated CD4 T cells that express certain co-receptors facilitating the virus entry. Additionally, α4β7 integrin known to be involved in the mucosal homing binds HIV gp120 envelope protein. Accordingly, authors perform the comparative analysis of cervical and blood CD4 T lymphocytes from healthy donors. This analysis includes enumeration of mucosal homing markers (CCR9, α4β7 and CD103), the early activation marker CD69 and HIV co-receptors (CCR5 and CXCR4).

The research aims to estimate features of potential invasion targets in the female genital tract. As the first conclusion authors have found that cervical CD4 T lymphocytes are enriched for several indicators of HIV susceptibility with α4β7 integrin, CD69 and CCR5 often being co-expressed on individual cells. It has been also established that cervical CD4 T lymphocytes include cells positive for IL-17A. The majority of these IL-17A-positive cells express α4β7 integrin and CCR5 which makes them probable targets during the initial infection stage. Next, authors examine IL-17A expression levels in blood and cervical samples from infected women. The study concludes with the evidence that IL-17A-positive CD4 T cells are strikingly depleted from the cervix mucosa of diseased participants but still present in their blood.

The second link:

Data reported in this article have been obtained from European healthy donors and patients infected with HIV that are treated with anti-retroviral therapy. People infected with HIV are continuously loosing their CD4 T cells and as a result develop the permanent immune deficiency. The anti-retroviral therapy helps rebuilding overall level of CD4 T cells but often proves ineffective in the restoration of intestinal CD4 T cell count. Investigating this matter authors focus on CD4 T lymphocytes from the small intestine and the blood to compare their gut-homing markers expression (α4β7 integrin and CCR9). Healthy controls harbor the vast majority of double positive β7+CCR9+ cells in the gut. However, infected subjects demonstrate the conspicuous reversal in proportions with most of β7+CCR9+ population being present in the blood. Additionally, HIV-positive individuals display the reduction of CCL25 (CCR9 ligand) expression level on intestinal epithelial cells.

This result implies that HIV infection may disturb the redistribution of CD4 T lymphocytes to the gut by unbalancing the CCR9-CCL25 interaction. Authors also associate the low level of intestinal β7+CCR9+ CD4 T cells with increased indicators of damage to the intestinal epithelium. Finally, it is demonstrated that β7+CCR9+ subset is richer in IL-17A secreting cells than β7+CCR9 population. However, in most of their experiments authors did not discriminate between Th17 and other CD4 T cell subsets.

I am following the Th17-HIV story because it emphasizes certain point, which I think is important from the immunologist perspective. Data seem to indicate that HIV infection drives the reduction of Th17 cells at mucosal surfaces. This reduction seems to be irreversible and it disturbs the intestinal homeostasis. Changes in mucosal environment may lead to the enhanced rate of microbial translocation which fuels the unique HIV trait – systemic immune activation. The link between Th17 and HIV pathogenesis makes me wonder whether the consequences of Th17 depletion from mucosal sites arise because of insufficient protection versus enteric pathogens or inadequate accommodation of intestinal commensals.

Our immune system is often metaphorically viewed as well trained and properly equipped coercive body that provides protection against foreign invaders. That’s right – the immune system does provide protection and it is very good at it. But such metaphor might be too narrow to adequately reflect what our immune system actually is, especially at mucosal surfaces. After all we are inhabited by diverse commensal organisms to be reckoned with but not to be disposed of.

Obviously our digestive tract needs protection as it is constantly exposed to harmful bacteria and sometimes the distinction between pathogen and commensal is not entirely clear. Additionally, pathogens are equipped with virulence tools like secretion systems that may provide them with possibilities to stand out from the crowd. But if you consider the sheer biomass argument, commensal organisms prevail over pathogens by such enormous margin that their proper accommodation definitely looks like more urgent matter than the efficient protection against few marauders. So returning to the insufficient protection versus inadequate accommodation dilemma – my gut feeling is that the second option might be more correct.

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