The goal of this project is to better understand the effects of host cells and other co factors of human retroviral and pathogenesis. Viral-cell interactions both at the surface and intracellularly can alter the delicate balance of regulatory controls of normal cellular processes such as cytokine production and/or action leading to pathogenic consequences. Like cells, the enveloped viruses contain a complex set of protein, carbohydrates and lipids on their cell surface. Recent evidence suggests that multiple interactions between molecular determinants of viruses and cells are needed for efficient viral fusion and entry. Some of these attachment factors for HIV entry can be glycosylaminoglycans and glycosphingolipids. We have shown at least two different glycosphingolipids on primary T cells can be used for HIV infectivity. Since viral entry inhibitors have become important anti-HIV compounds, we recently reported that peptide T (derived from an octapeptide gp120 sequence near the V2-stem), is a potent anti-viral entry inhibitor for early passage patient R5 or R5/X4 isolates, as well as laboratory R5 strains like BaL. Peptide T blocks infection by inhibiting entry, primarily through R5 receptors by interfering with gp120 binding to R5. We are determining if peptide T disrupts formation of the CD4/gp120 complex, the binding of gp120 to R5, or other attachment factors or by multiple interactions. Intracellular interactions between HIV and host proteins can either lead to suppressing viral production or activating latent HIV reservoirs of immune cells. We have previously identified two mechanisms that activate expression of latent HIV provirus, immune activation and hypomethylation. On the other hand, acute HIV infection leads to an increased cellular capacity to methylate cellular and viral genes through increase activity of DNA methyltransferase-1 (DNMT1). Interferon-gamma (IFN-gamma) is one cellular gene that is methylated during HIV infection. This hypermethylation leads to a decreased IFN expression, decreased type1 immune response and increased viral spread. HIV proviral integration is not necessary for stimulating these on methyaltion. Some 49/96 patients on long term HAART therapy have greatly diminished ability to produce IFN-gamma that can be restored though hypomethylation of the IFN-gamma promoter. Bisulfite genomic sequencing has shown that the IFN gamma promoter can remain hypermethylated during HAART therapy. Unlike HIV, little is known about the requirements for HTLV-I entry. We are determining the interactions between the HTLV envelope proteins and host cell proteins that are critical for efficient binding and entry. Using a soluble form of the envelope of the human retrovirus HTLV-I, we found that expression of a cell surface protein critical for viral entry is increased during immune activation. In addition, we identified nave CD4+ T cells as the first human cell type not possessing detectable HTLV-I binding protein(s). This HTLV-I SU binding protein may play a role in normal immune function as the HTLV-I SU is a potent inhibitor of a mixed leukocyte reaction. In addition to genetic and biochemical approaches to identify residues on the envelope protein that are involved in viral binding, we are also identifying cell-surface molecules that play a critical role in HTLV entry, either as primary receptors or as attachment factors. We have recently determined that cholesterol depletion on the membrane dramatically reduces entry, and that unlike most retroviruses, polycations inhibit HTLV Env binding and entry suggesting that HTLV-1 has either novel entry factors or new structural complexes.

National Institute of Health (NIH)
Division of Basic Sciences - NCI (NCI)
Intramural Research (Z01)
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Basic Sciences
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Takenouchi, Norihiro; Jones, Kathryn S; Lisinski, Ivonne et al. (2007) GLUT1 is not the primary binding receptor but is associated with cell-to-cell transmission of human T-cell leukemia virus type 1. J Virol 81:1506-10
Jones, Kathryn S; Fugo, Kazunori; Petrow-Sadowski, Cari et al. (2006) Human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 use different receptor complexes to enter T cells. J Virol 80:8291-302
Jones, Kathryn S; Akel, Salem; Petrow-Sadowski, Cari et al. (2005) Induction of human T cell leukemia virus type I receptors on quiescent naive T lymphocytes by TGF-beta. J Immunol 174:4262-70
Ruscetti, Francis W; Akel, Salem; Bartelmez, Stephen H (2005) Autocrine transforming growth factor-beta regulation of hematopoiesis: many outcomes that depend on the context. Oncogene 24:5751-63
Jones, Kathryn S; Petrow-Sadowski, Cari; Bertolette, Daniel C et al. (2005) Heparan sulfate proteoglycans mediate attachment and entry of human T-cell leukemia virus type 1 virions into CD4+ T cells. J Virol 79:12692-702
Polianova, Maria T; Ruscetti, Francis W; Pert, Candace B et al. (2005) Chemokine receptor-5 (CCR5) is a receptor for the HIV entry inhibitor peptide T (DAPTA). Antiviral Res 67:83-92
Wielgosz, Matthew M; Rauch, Daniel A; Jones, Kathryn S et al. (2005) Cholesterol dependence of HTLV-I infection. AIDS Res Hum Retroviruses 21:43-50
Taub, Dennis D; Mikovits, Judy A; Nilsson, Gunnar et al. (2004) Alterations in mast cell function and survival following in vitro infection with human immunodeficiency viruses-1 through CXCR4. Cell Immunol 230:65-80
Finnegan, Catherine M; Rawat, Satinder S; Puri, Anu et al. (2004) Ceramide, a target for antiretroviral therapy. Proc Natl Acad Sci U S A 101:15452-7
Puri, Anu; Rawat, Satinder S; Lin, Han-Ming Joseph et al. (2004) An inhibitor of glycosphingolipid metabolism blocks HIV-1 infection of primary T-cells. AIDS 18:849-58

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