Two neutralizing human mAbs, 2F5 and 4E10, that react with the HIV-1 envelope gp41 membrane proximal region are also polyspecific autoantibodies that bind to anionic phospholipids. To determine the autoantibody nature of these Abs, we have compared their reactivities with human anti-cardiolipin mAbs derived from a primary antiphospholipid syndrome patient. To define the role of lipid polyreactivity in binding of 2F5 and 4E10 mAbs to HIV-1 envelope membrane proximal epitopes, we determined the kinetics of binding of mAbs 2F5 and 4E10 to their nominal gp41 epitopes vs liposome-gp41 peptide conjugates. Both anti-HIV-1 mAbs 2F5 and 4E10 bound to cardiolipin with Kd values similar to those of autoimmune anti-cardiolipin Abs, IS4 and IS6. Binding kinetics studies revealed that mAb 2F5 and 4E10 binding to their respective gp41 peptide-lipid conjugates could best be defined by a two-step (encounter-docking) conformational change model. In contrast, binding of 2F5 and 4E10 mAbs to linear peptide epitopes followed a simple Langmuir model. A mouse mAb, 13H11, that cross-blocks mAb 2F5 binding to the gp41 epitope did not cross-react with lipids nor did it neutralize HIV-1 viruses. Taken together, these data demonstrate the similarity of 2F5 and 4E10 mAbs to known anti-cardiolipin Abs and support the model that mAb 2F5 and 4E10 binding to HIV-1 involves both viral lipid membrane and gp41 membrane proximal epitopes.

Xenotropic murine leukemia virus-related virus (XMRV) is a new human gammaretrovirus identified inprostate cancer tissue from patients homozygous for a reduced-activity variant of the antiviral enzyme RNase L. Neither a casual relationship between XMRV infection and prostate cancer nor a mechanism of tumorigenesis has been established. To determine the integration site preferences of XMRV and the potential risk of proviral insertional mutagenesis, we carried out a genome-wide analysis of viral integration sites in the prostate cell line DU145 after an acute XMRV infection and compared the integration site pattern of XMRV with those found for murine leukemia virus and two human retroviruses, human immunodeficiency virus type 1 and human T-cell leukemia virus type 1. Among all retroviruses analyzed, XMRV has the strongest preference for transcription start sites, CpG islands, DNase-hypersensitive sites, and gene-dense regions; all are features frequently associated with structurally open transcription regulatory regions of a chromosome. Analyses of XMRV integration sites in tissues from prostate cancer patients found a similar preference for the aforementioned chromosomal features. Additionally, XMRV integration sites in cancer tissues were associated with cancer breakpoints, common fragile sites, microRNA, and cancer-related genes, suggesting a selection process that favors certain chromosomal integration sites. In both acutely infected cells and cancer tissues, no common integration site was detected within or near proto-oncogenes or tumor suppressor genes. These results are consistent with a model in which XMRV may contribute to tumorigenicity via a paracrine mechanism.Prostate cancer is the most common noncutaneous cancer diagnosed in men in developed countries and is responsible for the deaths of approximately 30,000 men per year in the United States (43). Despite its impact on male health, the molecular mechanisms involved in the pathogenesis of prostate cancer, particularly the events contributing to initiation and progression, remain relatively unknown in comparison with those for other common cancers. Epidemiological studies of kindreds with hereditary prostate cancer, who often display early-onset disease and account for 9% of all cases (16), identified HPC1 as a susceptibility locus for prostate cancer (94). HPC1 is linked to RNASEL, which encodes a regulated endoribonuclease for single-stranded RNA and functions in the antiviral action of interferon (IFN) (15, 17). In response to stimulation by viral double-stranded RNA, IFN treatment of cells induces a family of 2Ј-5Ј oligoadenylate synthetases that produce 2Ј-5Ј-linked oligoadenylates, which then activate the latent and ubiquitous protein RNase L, resulting in degradation of viral and cellular RNA and apoptosis induction (112). Several germ line variants of HPC1 and RNASEL have been observed in hereditary prostate cancer (91), including a common (35% allelic frequency) missense variant of RNase L in which a G-to-A transition at nucleotide position 13...

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