Effects of in vivo CD8(+) T cell depletion on virus replication in rhesus macaques immunized with a live, attenuated simian immunodeficiency virus vaccine.

The role of CD8(+) T lymphocytes in controlling replication of live, attenuated simian immunodeficiency virus (SIV) was investigated as part of a vaccine study to examine the correlates of protection in the SIV/rhesus macaque model. Rhesus macaques immunized for >2 yr with nef-deleted SIV (SIVmac239Deltanef) and protected from challenge with pathogenic SIVmac251 were treated with anti-CD8 antibody (OKT8F) to deplete CD8(+) T cells in vivo. The effects of CD8 depletion on viral load were measured using a novel quantitative assay based on real-time polymerase chain reaction using molecular beacons. This assay allows simultaneous detection of both the vaccine strain and the challenge virus in the same sample, enabling direct quantification of changes in each viral population. Our results show that CD8(+) T cells were depleted within 1 h after administration of OKT8F, and were reduced by as much as 99% in the peripheral blood. CD8(+) T cell depletion was associated with a 1-2 log increase in SIVmac239Deltanef plasma viremia. Control of SIVmac239Deltanef replication was temporally associated with the recovery of CD8(+) T cells between days 8 and 10. The challenge virus, SIVmac251, was not detectable in either the plasma or lymph nodes after depletion of CD8(+) T cells. Overall, our results indicate that CD8(+) T cells play an important role in controlling replication of live, attenuated SIV in vivo.

HTLV-1 gene expression in adult T-cell leukemia cells elicits an NK cell response in vitro and correlates with cell rejection in SCID mice.

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent of adult T-cell leukemia (ATL). We have previously shown that the ATL cell line, RV-ATL, formed tumors when inoculated into severe combined immunodeficient (SCID) mice. In contrast, the HTLV-1 in vitro-transformed cell line, SLB-1, was nontumorigenic in SCID mice. ATL cells contain HTLV-1 proviral DNA sequences but lack detectable viral gene expression, in contrast to HTLV-1 in vitro-transformed cells, which express all viral gene products. We investigated the role of HTLV-1 gene expression in tumorigenesis by superinfecting RV-ATL cells with HTLV-1. The resulting cell line, HT-1RV, expressed HTLV-1. Injection of HT-1RV cells into SCID mice resulted in a reduced tumorigenic phenotype compared to the parental RV-ATL cells. In vitro natural killer (NK) cell cytotoxicity assays revealed that cell lines expressing HTLV-1 gene products, SLB-1 and HT-1RV, were sensitive to NK cell cytolysis. In contrast, nonexpressing RV-ATL cells were resistant to NK cell cytolysis. These studies indicate that lack of viral gene expression allows HTLV-1-infected cells to elude detection by murine NK cells and increases tumorigenicity in SCID mice. Thus the loss of HTLV-1 gene expression in ATL cells may be an important mechanism by which leukemic cells escape immune surveillance in humans.