Clinical evidence suggests that cellular immunity is involved in controlling human immunodeficiency virus-1 (HIV-1) replication. An animal model of acquired immune deficiency syndrome (AIDS), the simian immunodeficiency virus (SIV)-infected rhesus monkey, was used to show that virus replication is not controlled in monkeys depleted of CD8+ lymphocytes during primary SIV infection. Eliminating CD8+ lymphocytes from monkeys during chronic SIV infection resulted in a rapid and marked increase in viremia that was again suppressed coincident with the reappearance of SIV-specific CD8+ T cells. These results confirm the importance of cell-mediated immunity in controlling HIV-1 infection and support the exploration of vaccination approaches for preventing infection that will elicit these immune responses.

Infection of macrophage lineage cells is a feature of primate lentivirus replication, and several properties of primate lentiviruses seem to have evolved to promote the infection of macrophages. Here we demonstrate that the accessory gene product Nef induces the production of two CC-chemokines, macrophage inflammatory proteins 1alpha and 1beta, by HIV-1-infected macrophages. Adenovirus-mediated expression of Nef in primary macrophages was sufficient for chemokine induction. Supernatants from Nef-expressing macrophages induced both the chemotaxis and activation of resting T lymphocytes, permitting productive HIV-1 infection. These results indicate a role for Nef in lymphocyte recruitment and activation at sites of virus replication.

Residues 17 and 18 in nef of SIVmac239 were changed from RQ to YE to create a translated sequence of SRPSGDLYERLLRARGETYGRLLGEVEDGYSQSP from residues 10-43. The YXXL motifs in this context match very well with consensus sequences for SH2 binding domains and are similar to ones present in nef of the acutely lethal pathogen SIVpbj14. The YE variant of SIVmac239, unlike SIVmac239 but like SIVpbj14, replicated well in resting peripheral blood mononuclear cell cultures, caused extensive T lymphocyte activation, and produced an acute disease in rhesus and pigtailed monkeys characterized by severe diarrhea, rash, and extensive lymphoid proliferation in the gastrointestinal tract. The YEnef gene transformed NIH 3T3 cells in culture. Both 239nef and YEnef were found to associate with src in cotransfected COS cells, and both 60 kDa src and 34 kDa nef were phosphorylated at tyrosine in these cells. The extent of tyrosine phosphorylation of 239nef was considerably less than that of YEnef in these assays. These findings identify an important determinant of the SIVpbj14 phenotype, and they provide evidence of a role for nef in signal transduction and cellular activation.

Nonhuman primates provide valuable animal models for human diseases. However , studies assessing the role of cell-mediated immune responses have been difficult to perform in nonhuman primates. We have shown that CD8؉ lymphocyte-mediated immunity in rhesus monkeys can be selectively eliminated using the mouse-human chimeric anti-CD8 monoclonal antibody cM-T807. In vitro, this antibody completely blocked antigen-specific expansion of cytotoxic T cells and decreased major histocompatibility complex class I-restricted , antigen-specific lysis of target cells but did not mediate complement-dependent cell lysis. In vivo administration of cM-T807 in rhesus monkeys resulted in near total depletion of CD8؉ T cells from the blood and lymph nodes for up to 6 weeks. This depletion was not solely complementdependent and persisted longer in adults than in ju- Defining the role of the cellular and humoral components of the immune response to pathogens has furthered our understanding of the pathophysiology of various infectious diseases. Knowledge of these immune responses has also been valuable in designing immunization and other prophylactic strategies to prevent infection by these organisms. Animal models that permit passive administration of immunoglobulins or adoptive transfer of lymphocytes to naive hosts have been crucial for demonstrating the contribution of specific components of the immune response in controlling certain infections.Numerous experimental approaches have been used to study the role of CD8ϩ cell-mediated immunity in the control of infections. Studies demonstrating the importance of cellular immunity in various viral infections have been performed by adoptive transfer of lymphocytes in syngeneic mice. 1,2 Genetic knockout mice in which the CD8 or ␤ 2 microglobulin genes have been disrupted have been useful for defining the immunopathogenic role of cytotoxic T lymphocytes (CTL) in specific infectious agents. 3,4 Finally, rodents depleted of CD8ϩ lymphocytes by administration of CD8-specific monoclonal antibodies have been useful in determining the role of CTL in controlling pathogens.