HIGH HUMAN T-CELL LYMPHOTROPIC VIRUS TYPE-1 (HTLV-1) SPECIFIC PRECURSOR CYTOTOXIC T-LYMPHOCYTE FREQUENCIES IN PATIENTS WITH HTLV-1 ASSOCIATED NEUROLOGICAL DISEASE

The frequencies of human T cell lymphotropic virus type 1 (HTLV-1)-spe cific CD8+ precursor cytotoxic T lymphocytes (pCTL) were quantitated f rom lymphocytes obtained from the peripheral blood and cerebrospinal f luid (CSF) of infected individuals with and without HTLV-1-associated neurological disease. An estimate of the pCTL was obtained by separati ng CD8+ cells, plating these cells in limiting dilution, and testing w ells for HTLV-1 specific lysis. Targets consisted of autologous lympho blastoid cell lines (LCL) infected with vaccinia constructs expressing HTLV-1 gene products or LCL pulsed with HTLV-1 synthetic peptides. In patients with HTLV-1-associated myelopathy/tropical spastic parapares is (HAM/TSP), the frequency of HTLV-1 p40X-specific pCTL was at least 40-280-fold higher than in asymptomatic HTLV-1-infected individuals. A ll HAM/TSP patients (five of five) predominantly recognized HTLV-1 pro ducts encoded within the pX region. Lower pCTL to env were demonstrate d in three patients, and only one of five HAM/TSP patients had pCTL to gag. A synthetic peptide corresponding to the tax region of HTLV-1 (p eptide 11-19, amino add sequence LLFGYPVYV) was recognized in associat ion with human histocompatibility leukocyte antigen (HLA)-A2 in two HL A-A2 HAM/TSP patients with a high CD8+ pCTL frequency of 1/325 and 1/2 65, respectively. A second immunodominant region of HTLV-1 tax (peptid e 90-55, amino add sequence VPYKRIEEL) was identified to be restricted by HLA-B14 in two HLA-B14 HAM/TSP patients with a CD8+ pCTL frequency of 1/640 and 1/1,125, respectively. Lymphocytes from the CSF of a pat ient with HAM/TSP also showed a pCTL frequency against p40X of similar magnitude to that demonstrated from peripheral blood lymphocytes (PBL ). The HLA-A2-mediated CSF pCTL activity to the immunodominant tax-spe cific peptide 11-19 was also comparable to pCTL from PBL. These result s indicate that an extremely high pCTL frequency to HTLV-1 tax-encoded peptides may be related to pathogenesis of myeloneuropathy associated with HTLV-1.