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.