Innate Lymphoid Cell Loss in HIV-1 and SIV Infection - Joseph C. Mudd
Innate lymphoid cell loss in HIV-1 infection
Project Summary
As of 2016, roughly half of the 36 million people living with HIV/AIDS worldwide are accessing antiretroviral
therapy (ART). While these numbers represent significant advances in the number of patients receiving
treatment, HIV-1+ subjects on ART continue to exhibit shorter lifespans, averaging a risk of death roughly six
times higher than that of the general population. A significant proportion of these deaths relate to non-AIDS
defining co-morbidities such as cardiovascular, cancer, and liver diseases. Several large cohort studies have
attributed these co-morbidities in part to residual damage to the gastrointestinal (GI) tract that is sustained early
in HIV-1 disease course. Under normal circumstances, gut mucosal function is maintained in part by the
cytokines IL-17 and IL-22. CD4+ T cells are important sources of these, yet there are also innate sources of IL-
17 and IL-22 in the gut that are less explored. Innate lymphoid cells (ILCs) are capable of producing IL-17 and
IL-22 and along with Th17/Th22 cells, are rapidly lost in the gut during HIV-1 and SIV infection. Thus, in
order to develop more effective therapies aimed at curtailing GI damage in treated HIV-1 infection, a more
complete understanding of the role of ILCs in gut mucosal health is needed. Here, we propose to examine the
mechanisms by which ILCs are lost in both HIV-1+ humans and nonhuman primate progressive hosts of SIV
infection.
ILCs are not permissive to HIV-1/SIV infection, and ILC depletion is not a generalized feature of all viral
infections. In preliminary studies, we have identified CD4 T cell loss and inflammatory mediators as important
determinant of ILC depletion in HIV-1/SIV infection. We hypothesize that CD4 T cells provide essential
survival factors to ILCs and that loss of both of these populations contributes to GI barrier damage. In aim I, we
will explore the precise mechanisms underlying CD4-help to ILCs. We will assess these mechanisms by in
vitro co-culture experiments of purified CD4 T cells and ILCs from healthy donors, using measurements of ILC
viability and functionality as readouts. We will extend these findings to then look at these mechanisms in
settings of immune dysfunction during ART, which are often characterized by suboptimal CD4 T cell responses
to therapy.
In the second aim, we will expand upon aim I by therapeutically targeting ILC reconstitution as a way to boost
gut mucosal health in SIV-infected primates receiving ARVs. We hypothesize that therapies aimed at
improving gut mucosal health will be associated with increases in ILC survival and functionality. To address
this, we will utilize gut mucosal samples of SIV+ pigtail macaques treated with ARVs and the pleiotropic
cytokine IL-21. Il-21 supplementation has previously been shown to enhance GI barrier repair, and we will
evaluate the effect of IL-21 therapy on ILC gene expression profiles, as well as ILC survival and functionality
when compared to these parameters in SIV+ animals receiving ARVs alone.
Taken together, these studies will provide an in-depth assessment into the contribution of ILCs to gut mucosal
function in treated HIV-1 and SIV infection, and provide important fundamental insights into mechanisms
regulating ILC survival.
