Human T Cell Lymphotropic Virus Type I (HTLV-I)-Specific CD4+ T Cells: Immunodominance Hierarchy and Preferential Infection with HTLV-I

Abstract

CD4+ T cells predominate in early lesions in the CNS in the inflammatory disease human lymphotropic T cell virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), but the pathogenesis of the disease remains unclear and the HTLV-I-specific CD4+ T cell response has been little studied. We quantified the IFN-γ-producing HTLV-I-specific CD4+ T cells, in patients with HAM/TSP and in asymptomatic carriers with high proviral load, to test two hypotheses: that HAM/TSP patients and asymptomatic HTLV-I carriers with a similar proviral load differ in the immunodominance hierarchy or the total frequency of specific CD4+ T cells, and that HTLV-I-specific CD4+ T cells are preferentially infected with HTLV-I. The strongest CD4+ T cell response in both HAM/TSP patients and asymptomatic carriers was specific to Env. This contrasts with the immunodominance of Tax in the HTLV-I-specific CD8+ T cell response. The median frequency of HTLV-I-specific IFN-γ+ CD4+ T cells was 25-fold greater in patients with HAM/TSP (p = 0.0023, Mann-Whitney) than in asymptomatic HTLV-I carriers with a similar proviral load. Furthermore, the frequency of CD4+ T cells infected with HTLV-I (expressing Tax protein) was significantly greater (p = 0.0152, Mann-Whitney) among HTLV-I-specific cells than CMV-specific cells. These data were confirmed by quantitative PCR for HTLV-I DNA. We conclude that the high frequency of specific CD4+ T cells was associated with the disease HAM/TSP, and did not simply reflect the higher proviral load that is usually found in HAM/TSP patients. Finally, we conclude that HTLV-I-specific CD4+ T cells are preferentially infected with HTLV-I.

The Role of CTLs in Persistent Viral Infection: Cytolytic Gene Expression in CD8+ Lymphocytes Distinguishes between Individuals with a High or Low Proviral Load of Human T Cell Lymphotropic Virus Type 1

“…ϩ T cells appears to be significantly greater in patients with HAM/ TSP than in ACs with the same proviral load (24,25). This observation raises the possibility that such CD4 ϩ T cells contribute to the pathogenesis of the inflammatory disease; their role in defense against HTLV-1 infection is not known.…”

Human Dlg protein binds to the envelope glycoproteins of human T-cell leukemia virus type 1 and regulates envelope mediated cell-cell fusion in T lymphocytes

“…Owing to over-expression of several adhesion molecules (Kambara et al, 1999;Tanaka, 1999;Valentin et al, 1997), HTLV-1 chronically infected cells grow as tight clusters in culture, creating constant cell contacts. In vivo, HTLV-1 transmission through cell-cell contacts could occur during antigen recognition, as illustrated by the preferential infection of T cells directed to HTLV-1 epitopes (Goon et al, 2004;Hanon et al, 2000). Hence, hDlg may be constantly recruited to the plasma membrane due to frequent cell-cell contacts encountered in HTLV-1-infected cells both in vivo and in vitro culture conditions.…”

HTLV-1 propels untransformed CD4+ lymphocytes into the cell cycle while protecting CD8+ cells from death

“…On the contrary, both CD4 + and CD8 + lymphocytes are involved in the immunological control of the infection and in the inflammatory processes that govern the pathogeny of HAM/TSP, uveitis and infectious dermatitis (24)(25)(26). CD4 + lymphocytes infected by coculture with an HTLV1 cell line display a signifi cantly higher viral transcription rate than CD8 + cells infected with the same procedure (27), suggesting that the T cell pheno type itself, probably via transcription factor availability, influ ences viral transcription and replication.…”