Lymph Node Inflammation and Fibrosis as a Mechanism of CD4 Loss in HIV

In our first funding period we explored the importance of fibrosis in secondary lymphoid tissues (LT) to HIV pathogenesis. We demonstrated the amount of collagen in the paracortical T cell zone (TZ) of lymph nodes (LN) and peyer[unreadable]s patches (PP) correlates to the size of the total and na[unreadable]ve CD4+ T cell count and predicts the potential for immune reconstitution with HAART. We also showed that fibrosis begins early after HIV acquisition and is likely caused by induction of an inappropriate Treg response associated with TGFb-1 expression. This work has led us to hypothesize that TGFb-1 is the proximate cause of collagen deposition into the TZ and that inhibiting its action will 1) result in less collagen formation in the TZ of LN[unreadable]s after HIV infection and 2) protect immune function by preserving or restoring the total, na[unreadable]ve, and CM CD4+ T cell populations and function in LN and peripheral blood (PB). We propose a direct test of this hypothesis in a non-human primate model of SIV infection. We will determine if administration of a drug that selectively inhibits TGFb-1 will 1) prevent collagen deposition into the TZ if administered prior to SIV infection and 2) reverse collagen damage to the TZ and improve CD4 reconstitution if administered in the chronic phase of SIV disease. We also propose tests of immune function to determine the capacity of the collagen damaged LN to respond to antigen. We have shown the reticulin conduit network of the TZ, a structure integral in cell movement through the TZ, is severely damaged and that populations of na[unreadable]ve CD4+ T cells that serve as a reservoir for CM and EM cells are profoundly depleted in the TZ. We believe this [unreadable]damaged niche[unreadable] is the cause of significant dysregulation of several important immune functions, including antigen presentation and expansion of memory CD4+ T cells. We will challenge HIV+ patients with a neo-antigen (keyhole limpet hemocyanin) and recall antigen (tetanus) and measure both humoral and cellular responses under the hypothesis that collagen deposition in the TZ inhibits antigen presentation and development and expansion of antigen specific CD4+ T cells.