Mechanisms of immune activation of human immunodeficiency virus in monocytes/macrophages.
Monocytes/macrophages (M/M) are the major host of human immunodeficiency virus (HIV) in solid tissues. However, blood monocytes are nonpermissive for HIV infection, indicating that M/M activation or differentiation is necessary for HIV replication. Since M/M are activated during immune responses, we investigated the effect of T-cell activation on HIV expression in M/M derived from peripheral blood of HIV-infected individuals. Previously, we reported that coculture of monocytes from HIV-infected donors with T cells and mitogens resulted in M/M differentiation and HIV expression. Production of HIV by M/M from infected donors required direct contact between monocytes and T cells (for the first 24 h), and the response to alloantigens, but not mitogens, was restricted to HLA-DR. In this study, we found that HIV was more readily recovered from M/M of asymptomatic HIV seropositive donors (69%) than from M/M of symptomatic donors (57%). Viral antigens (e.g., inactivated herpes simplex virus) could initiate the immune response and HIV expression. The ability of noninfected T cells to activate HIV expression in M/M and observations that treatments of M/M with antibodies to deplete T cells did not reduce HIV expression suggested that the monocytes were endogenously infected. To define the aspects of immune activation specifically involved in initiating HIV expression in M/M, interactions of M/M and T cells and participation of cytokines were investigated. The T cell which activated M/M was CD4+ CD8-. Fixed allogeneic cells are known to induce T-cell activation but were not able to serve as antigen for M/M differentiation, suggesting that M/M may need to function as antigen-presenting cells to receive the signal to differentiate and express HIV. Blocking of M/M-T-cell interaction with antibodies directed against LFA-1 or interleukin-1 prevented HIV expression. However, inhibition of later stages of T-cell activation, such as blocking of interleukin-2 receptors, did not diminish HIV expression in M/M. Consistent with the requirement for cell-cell contact between M/M and T cells, a variety of cytokines were unable to initiate HIV replication in M/M. The ability of T cells to induce cellular differentiation and HIV replication in M/M in vitro suggests that initiation of an immune response to an antigen, such as an opportunistic pathogen, could be a mechanism by which HIV disseminates to tissues in vivo.
Schrier
R D
RD
Department of Pathology, University of California, San Diego, La Jolla 92093.
McCutchan
J A
JA
Wiley
C A
CA
D015703:Antigens, CD / Q000502:physiology; D017252:CD3 Complex / Q000276:immunology; D015704:CD4 Antigens / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D006678:HIV / Q000276:immunology*; D016655:HIV Core Protein p24 / Q000032:analysis; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology*; D009000:Monocytes / Q000276:immunology*; D012016:Reference Values; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; D017252:CD3 Complex; D015704:CD4 Antigens; D016655:HIV Core Protein p24