Targeted lysis of HIV-infected cells by natural killer cells armed and triggered by a recombinant immunoglobulin fusion protein: implications for immunotherapy.

Natural killer (NK) cells play an important role in both innate and adaptive antiviral immune responses. The adaptive response typically requires that virus-specific antibodies decorate infected cells which then direct NK cell lysis through a CD16 mediated process termed antibody-dependent cellular cytotoxicity (ADCC). In this report, we employ a highly polymerized chimeric IgG1/IgA immunoglobulin (Ig) fusion protein that, by virtue of its capacity to extensively crosslink CD16, activates NK cells while directing the lysis of infected target cells.

HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites.

The ability of human immunodeficiency virus (HIV-1) to persist and cause AIDS is dependent on its avoidance of antibody-mediated neutralization. The virus elicits abundant, envelope-directed antibodies that have little neutralization capacity. This lack of neutralization is paradoxical, given the functional conservation and exposure of receptor-binding sites on the gp120 envelope glycoprotein, which are larger than the typical antibody footprint and should therefore be accessible for antibody binding.

HIV envelope induces a cascade of cell signals in non-proliferating target cells that favor virus replication.

Certain HIV-encoded proteins modify host-cell gene expression in a manner that facilitates viral replication. These activities may contribute to low-level viral replication in nonproliferating cells. Through the use of oligonucleotide microarrays and high-throughput Western blotting we demonstrate that one of these proteins, gp120, induces the expression of cytokines, chemokines, kinases, and transcription factors associated with antigen-specific T cell activation in the absence of cellular proliferation.

The role of the CD4 receptor versus HIV coreceptors in envelope-mediated apoptosis in peripheral blood mononuclear cells.

We examined the role of CD4, CXCR4, and CCR5 in HIV envelope-mediated apoptosis by measuring the response of activated PBMCs to recombinant envelope proteins derived from CXCR4- and CCR5-utilizing viruses. Apoptosis of T cells was assessed by annexin-V staining and TdT-mediated dUTP-biotin nick-end labeling. Treatment of CCR5Delta32 homozygote PBMCs with a CCR5-specific envelope induced apoptosis in T cells, demonstrating that envelope--CD4 interactions are sufficient to induce apoptosis.

Biochemical and biological characterization of a dodecameric CD4-Ig fusion protein: implications for therapeutic and vaccine strategies.

Drug toxicities associated with HAART lend urgency to the development of new anti-HIV therapies. Inhibition of viral replication at the entry stage of the viral life cycle is an attractive strategy because it prevents de novo infection. Soluble CD4 (sCD4), the first drug in this class, failed to suppress viral replication in vivo.