Background: HIV-1 integration into host DNA is essential in establishing viral replication and expression. Lentiviral integration occurs primarily in a random fashion and is not oncogenic in humans. However, HIV-infected individuals are at relative risk for developing cancers. Recent data have suggested that non-random integration may occur in selective settings including HIV-associated malignancies. The goal of this study was to identify preferential sites of HIV-integration, which may be important in oncogenesis.

Methods: Initially, an in vitro system was designed using isolated macrophages from uninfected donors and the HIV-1 strain, p89.6, followed by a linker-primer PCR technique. In the second phase, inverse-PCR was used to analyze DNA from specimens obtained from necropsy cases with a diagnosis of HIV-associated malignancies. In appropriate cases, a tumor-specific primer, from the identified integration site, was used to screen uninvolved tissue from the same patient.

Results: HIV-integration near a toll-like receptor on chromosome 4 was found in the isolated macrophages. Tumor specimens from 11 autopsy cases of HIV-associated malignancies or controls were obtained. One case of a large cell lymphoma successfully identified sequence data demonstrating HIV integration in chromosome 22q13.2 in EST cluster Hs.99330. One of the cellular genes located within 300kb 5' of HIV provirus includes HSCBCIP1, a CAP-binding protein complex interacting homologue. Primers derived from the tumor specimen were then used to screen a non-malignant sample from the same patient, which did not amplify the site specific region.

Conclusions: The preliminary results demonstrate that in both an in vitro system and in human malignant tissue, it is possible to identify specific viral integration. Toll receptors are associated with the down stream signaling of cytokines through the initial cascade phosphorylation of serine kinases. Binding of the Toll/IL-1 receptor domain may lead to a cytoplasmic cascade in which transcription factors are activated to induce the production of pro-inflammatory cytokines. In the actual tumor tissue, integration near a CAP-binding complex, a transcriptional activator involved in DNA binding, could be important in a cascade of events leading to malignancies. This information could be important in understanding some types of HIV-associated cancers as well as identifying targets for intervention, both prevention and treatment.

Keywords: lymphoma; kaposi's sarcoma; integration