Research Project
10109970
PROJECT SUMMARY / ABSTRACT HTLV-1 is a retrovirus that infects 10-20 million people worldwide with a seroprevalence of 2-3% in Peru. HTLV-1 infects CD4+ T lymphocytes, causing cells to be immortalized. Clinical manifestations include autoimmune diseases (especially HTLV-1 associated myelopathy with tropical spastic paraparesis), increased numbers of regulatory T-cells and susceptibility leading to specific infections (including Strongyloides hyperinfection and skin infections), and malignant transformation (T-cell lymphoproliferative disorders including Adult T-cell Leukemia/Lymphoma (ATL). Once diagnosed, ATL is often rapidly fatal, but it only develops after a prolonged latent period, typically >30 years of infection. HTLV-1 predisposes to infection with Strongyloides stercoralis (SS). SS is a soil-transmitted nematode that infects an estimated over 100 million people worldwide. Most SS infections cause few symptoms. SS is associated with early onset of Adult T-cell Leukemia/Lymphoma in HTLV-1 infected patients. The exact mechanism by which SS accelerates ATL development in HTLV-1 subjects is not understood. Co-infection has been associated with an increase in proviral load. We have demonstrated an increase in regulatory T-cells in co-infected patients. Recent studies have demonstrated evidence of bacterial translocation in chronic strongyloidiasis. We hypothesize that SS infection leads to increased HTLV-1 proviral load, cellular proliferation, and immunomodulation, which in turn predisposes patients to malignant transformation. This might be due to bacterial translocation, non-specific or antigen-specific lympho-proliferation, or increased regulatory T-cells. To this purpose, we will take advantage of 3 unique features: a) a large cohort of HTLV-1 patients being followed at our institute in Lima Peru, b) the recent observation that CADM1 is uniquely expressed on the surface of HTLV-1 infected cells, and c) the association of decreased expression of CD7 as an early marker of cellular transformation for T-cells. The specific aims of this project will test two hypotheses: 1) Strongyloides stercoralis infection leads to increased HTLV-1 proviral load, increased numbers of infected cells, and early transformation of infected CD4+ T-cells. We will compare proviral load and number of infected CD4+ T-cells in the peripheral blood using CADM1 staining and loss of CD7 (an early marker for transformation). In HTLV-1/SS co-infected patients before and up to six months after treatment of strongyloidiasis; cases of co-infection with >5 years? follow-up or controls; HTLV-1/SS coinfected patient following prospectively. 2) Early cell transformation (CADM1 positive, CD7 low) is driven by the following mechanisms: a) Viral driven lymphoproliferation (proviral load, spontaneous and antigen-driven lymphoproliferation); bacterial translocation and associated inflammation, and/or expansion of regulatory T-cells These studies will test the importance of SS infection as a co-factor in lymphoproliferative disorders and explore a rationale for more aggressive approaches to SS in HTLV-1 patients as well as in general populations.
