Treatment with suboptimal doses of raltegravir leads to aberrant HIV-1 integrations

Abstract

Integration of the DNA copy of the HIV-1 genome into a host chromosome is required for viral replication and is thus an important target for antiviral therapy. The HIV-encoded enzyme integrase (IN) catalyzes two essential steps: 3′ processing of the viral DNA ends, followed by the strand transfer reaction, which inserts the viral DNA into host DNA. Raltegravir binds to IN and blocks the integration of the viral DNA. Using the Rous sarcoma virus-derived vector RCAS, we previously showed that mutations that cause one viral DNA end to be defective for IN-mediated integration led to abnormal integrations in which the provirus had one normal and one aberrant end, accompanied by rearrangements in the host genome. On the basis of these results, we expected that suboptimal concentrations of IN inhibitors, which could block one of the ends of viral integration, would lead to similar aberrant integrations. In contrast to the proviruses from untreated cells, which were all normal, ∼10-15% of the proviruses isolated after treatment with a suboptimal dose of raltegravir were aberrant. The aberrant integrations were similar to those seen in the RCAS experiments. Most of the aberrant proviruses had one normal end and one aberrant end and were accompanied by significant rearrangements in the host genome, including duplications, inversions, deletions and, occasionally, acquisition of sequences from other chromosomes. The rearrangements of the host DNA raise concerns that these aberrant integrations might have unintended consequences in HIV-1-infected patients who are not consistent in following a raltegravir-containing treatment regimen.strand transfer inhibitor | chromosomal rearrangements | integrase inhibitors H IV-1 integration is a two-step process: first, in the cytoplasm, an integrase (IN) dimer binds to each end of the newly synthesized linear viral DNA and removes two nucleotides from each of the 3′ ends, exposing the conserved CA dinucleotide. The preintegration complex (PIC) is translocated from the cytoplasm into the nucleus, where the viral DNA is integrated into the host genome. In the strand transfer (ST) reaction, the two exposed 3′ hydroxyl groups on the newly processed viral DNA ends attack phosphodiester bonds on the opposite strands of the target DNA at positions that lie across the major groove, 4-6 bp apart. This reaction is carried out by a tetramer of IN; each of the viral DNA ends is associated with an IN dimer. This transesterification reaction generates an intermediate in which the 3′ ends of the viral DNA are covalently joined to the host DNA and there are 4-to 6-bp gaps in the host DNA associated with both of the 5′ ends of the viral DNA. Cellular machinery repairs these gaps, creating a 4-to 6-bp duplication (the size of the duplication varies for different retroviruses) of the host DNA flanking the integrated viral DNA (1-4). HIV-1 integration generates a 5-bp duplication of the host DNA at the integration site (5, 6).Raltegravir (RAL) and all of the potent IN inhibitors thus far discovered bind to...

Factors contributing to risk for cancer among HIV-infected individuals, and evidence that earlier combination antiretroviral therapy will alter this risk

“…Protease inhibitors have been linked to a higher risk of anal cancer in observational studies after adjustment for important confounders [••55–57] and efavirenz, a non-nucleoside reverse transcriptase inhibitor, was associated with increased risk of Hodgkin lymphoma in one study [58]. In a recent report, raltegravir, an integrase inhibitor, was found to induce host DNA rearrangements, which, from a theoretical point of view, may have unforeseen consequences including an increased risk of cancer [59]. It is also biologically plausible that, by reducing immunological surveillance of malignant cells, CCR5 inhibitors, a drug class increasingly used in treatment-experienced individuals who failed previous cART regimens, may also lead to an increased incidence of NADM [60].…”

Incidence of cancer and overall risk of mortality in individuals treated with raltegravir‐based and non‐raltegravir‐based combination antiretroviral therapy regimens

“…Therefore, global improvement of immune surveillance against cancer cells was also postulated as a likely mediator of the benefit of cART in reducing cancer risk . However, experimental data suggest that specific drugs, such as RAL, may have potential carcinogenic effects .…”

HIV‐1, HAART and cancer: A complex relationship

“…HIV‐integrase strand transfer inhibitors (INSTIs) may cause aberrant HIV‐integration and rearrangements in the host DNA when used in low doses . Low‐dose INSTI may create the situation when strand transfer reaction is blocked at only one of two ends of viral DNA, which subsequently leads to mutation‐prone integration of a blocked end via the host enzymes . Thus, these drugs are potentially mutagenic and carcinogenic; however, there is no evidence for increased cancer risk in patients exposed to INSTIs.…”

“…165,170 HIV-integrase strand transfer inhibitors (INSTIs) may cause aberrant HIV-integration and rearrangements in the host DNA when used in low doses. 171,172 Low-dose INSTI may create the In cancer, PI3K/Akt activation inhibits apoptotic enzymes; promotes transcription regulation that increases growth, survival, proliferation, increases MMPs (migration, invasion and metastasis) and VEGF (angiogenesis) expression via mTOR and NF-κB axes; causes chemo/radiotherapy resistance by deregulation of DNA damage response. PIs inhibit the PI3K/Akt pathway, possibly through binding to Hsp90 and inhibiting its chaperone function.…”