Syndecans serve as attachment receptors for human immunodeficiency virus type 1 on macrophages.

Macrophages are thought to represent one of the first cell types in the body to be infected during the early stage of human immunodeficiency virus type 1 (HIV-1) transmission and represent a potential viral reservoir in vivo. Thus, an understanding of HIV-1 attachment to these cells is fundamental to the development of novel anti-HIV-1 therapies. Although one of the major targets of HIV-1 in vivo--CD4(+) T lymphocytes--express high CD4 levels, other major targets such as macrophages do not. We asked in this study whether this low CD4 level on macrophages is sufficient to support HIV-1 attachment to these cells or whether cell surface proteins other than CD4 are required for this process. We show that CD4 alone is not sufficient to support the initial adsorption of HIV-1 to macrophages. Importantly, we find that heparan sulfate proteoglycans (HSPGs) serve as the main class of attachment receptors for HIV-1 on macrophages. Most importantly, we demonstrate that a single family of HSPGs, the syndecans, efficiently mediates HIV-1 attachment and represents an abundant class of attachment receptors on macrophages.

Human immunodeficiency virus type 1 hijacks host cyclophilin A for its attachment to target cells.

Our laboratory has identified a new facet of human immunodeficiency virus type 1 (HIV-1) entry. We demonstrated that the incorporation of host cyclophilin A (CypA) into nascent viruses is absolutely required for HIV-1 attachment to target cells. Although CypA is initially incorporated into the interior of the virus, we found that during maturation CypA relocates to the viral surface. Our work indicates that exposed CypA mediates HIV-1 attachment to target cells via heparans. We believe that this interaction between CypA and heparan represents the initial step in HIV-1 entry.

Host cyclophilin A mediates HIV-1 attachment to target cells via heparans.

The present study proposes a novel mode of action for cyclophilin A (CypA) in the HIV-1 life cycle. We demonstrate that CypA-deficient viruses do not replicate because they fail to attach to target cells. We show that CypA is exposed at the viral membrane and mediates HIV-1 attachment. We identify heparan as the exclusive cellular binding partner for CypA. Furthermore, CypA binds directly to heparan via a domain rich in basic residues similar to known heparin-binding motifs. This interaction between exposed CypA and cell surface heparans represents the initial step of HIV-1 attachment and is a necessary precursor to gp120-binding to CD4. In conclusion, HIV-1 attachment to target cells is a multi-step process that requires an initial CypA-heparan interaction followed by the gp120-CD4 interaction.

Selective modulation of elements of the immune system by low molecular weight nucleosides.

To optimally modulate a system as complex as the immune system, one must ultimately control its elements individually. Up to this time, use of polyclonal immune stimulants has necessarily involved modulation of a block of immune functions, frequently including undesired activities as well as the activity of interest. We now report selective modulation of individual elements of the immune system by low molecular weight nucleosides, within the context of a fully functional immune system. Loxoribine (7-allyl-8-oxoguanosine) is a well characterized pleiotropic agonist of the immune system in a variety of species, including mouse and humans. In B-cells it binds to soluble cytoplasmic binding proteins, which upregulate transcription upon translocation to the nucleus. By altering specific portions of the loxoribine molecule, multiple distinct, bioactivity profiles have now been obtained. These include: 1) selective augmentation of antibody responses without effects on B-cell proliferation or NK-cell activity; 2) selective enhancement of NK-cell activity and B-cell proliferation in the absence of antibody responses; and 3) selective enhancement of NK-cell activity and antibody responses without B-cell proliferation. Predominant NK-cell responses with minimal B-cell activity of either type also can be generated. The pattern of cytokine mRNA transcription induced is consistent with the spectrum of cellular activities observed. Thus, it is possible to modulate selective activities of the immune system by relatively minor structural modifications of a broad-spectrum immunomodulator in an unseparated cell system.

Tolerance-related V beta clonal deletions in normal CD4-8-, TCR-alpha/beta + and abnormal lpr and gld cell populations.

We have analyzed tolerance-related clonal deletion of Mls-and I-E-reactive thymocytes at the RNA level using a multi-V beta probe RNAse protection assay, and used this phenomenon to identify the maturation stage of the abnormally expanded CD4-8-, TCR-alpha/beta + subset in lpr and gld homozygous mice, and of the phenotypically similar minor thymocyte subset found in normal mice. Essentially complete V beta clonal deletions were detected in lpr and gld cells of all appropriate background strains. Substantial, but not complete, V beta clonal deletions were also detected in the CD4-8- TCR-alpha/beta + subset of normal mice. Since expression of CD4/CD8 is required for V beta clonal deletions to occur, we conclude that lpr and gld cells, and at least a portion of CD4-8- TCR-alpha/beta + thymocytes in normal mice, are derived by secondary loss of CD4/CD8 accessory molecules from more mature CD4+8+ precursors. One possible interpretation of these findings is that such CD4/CD8 loss may affect a class of self-reactive thymocytes that have escaped direct clonal deletion. Exportation and expansion of such cells in the periphery may be an important contributory factor in the induction of systemic autoimmunity.