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.

Public Health Relevance

Human T lymphotrophic virus 1 (HTLV-1) is a virus that causes chronic infections and can lead to leukemias. The intestinal worm Strongyloides stercoralis co-infects people with HTLV-1 and has been associated with higher risk of developing leukemia. We will test for the mechanisms by which this worm leads to the early stages of developing leukemias.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Park, Eun-Chung
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Universidad Peruana Cayetano Heredia
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