1990;172:1055C1063. a marked human CD4+ T-cell depletion along with a drop in levels of human immunoglobulin M in serum and release of soluble factors at both infection times, while the X4 virus induced severe immune dysfunctions only at 2 h. Of interest, injection of hu-PBLs into SCID mice resulted in a marked up-regulation of CCR5 on human CD4+ Rabbit Polyclonal to GTPBP2 T cells. The percentage of CXCR4+ cells did not change after transplantation, even though a significant decrease in antigen expression was observed. Comparative experiments with two molecular clones of HIV-1 (X4 SF2 and R5 Laropiprant (MK0524) SF162) and two envelope recombinant viruses generated from these viruses showed that R5 viruses (SF162 and the chimeric env-SF162-SF2) caused an extensive depletion of human CD4+ T cells in SCID mice at both 2 h and 2 weeks after reconstitution, while the X4 viruses (SF2 and the chimeric env-SF2-SF162) induced CD4 T-cell depletion only when infection was performed at the 2-h reconstitution time. These results emphasize the importance of the state of activation/differentiation of human CD4+ T cells and gp120-coreceptor interactions at the time of primary infection in determining HIV-1 pathogenicity in the hu-PBL-SCID mouse model. Human immunodeficiency virus type 1 (HIV-1) replication is a dynamic process influenced by a combination of viral and host factors, whose Laropiprant (MK0524) interactions may shape the natural history of HIV-1 infection in AIDS patients (11). Viral characteristics sustaining viral replication within a patient include replicative fitness and cell tropism. Cell tropism is strongly linked to the ability of different HIV-1 envelopes to utilize CC or CXC chemokine receptors as coreceptors for initiating viral fusion and entry into target cells (1, 7, 9, 24, 32, 51). CXCR4 has been shown to mediate the entry of T-cell-line-adapted SI HIV-1 strains (namely, X4 strains), while CCR5 has been identified as the coreceptor for macrophage-tropic NSI strains (denominated as R5 strains) (3). R5 strains are most frequently transmitted during primary HIV-1 infection and persist throughout Laropiprant (MK0524) the course of infection, while expanded coreceptor usage and evolution to T-tropic viruses are closely linked with disease progression (51). Further studies have shown that CXCR4 is primarily expressed on naive CD4+ T cells, whereas CCR5 is mainly expressed on memory CD4+ T cells (4). Notably, memory CD4+ T cells have been shown to be highly permissive to HIV-1 infection (38, 40, 43, 50). An in vivo acute or Laropiprant (MK0524) chronic state of activation of the immune system may be an important factor in rendering the host more receptive to HIV-1 infection and more susceptible to virus-induced pathological effects. In fact, several in vitro data indicate that a particular cellular activation state is required for the establishment of a productive HIV infection (31, 41, 44). Moreover, studies of African populations suggest that in vivo immune activation, due to endemic parasitic infections, may be an important cofactor in susceptibility to progressive HIV infection and disease (2, 36). Thus, the state of activation/differentiation of the immune system at the moment of primary infection may be a crucial factor in determining the extent of early viral replication (21) and the establishment of a pool of latently infected cells (6, 12) that have been shown to represent a long-lasting reservoir for HIV-1. Small animal models represented by SCID mice engrafted with human peripheral blood lymphocytes (25, 48), lymphoid cells (20), or tissues (22, 28) have been largely employed to investigate the mechanisms underlying HIV-1 infection and AIDS pathogenesis (16, 19, 20, 23, 26, 27, 29, 35, 37). In particular, previous studies with the hu-PBL-SCID mouse model had shown that X4 HIV-1 strains, which are highly cytopathic for T cells in vitro (5), caused little CD4+ T-cell depletion in SCID mice reconstituted with human peripheral blood lymphocytes.