Proteins can help cells protect themselves from infection with HIV

Naturally occurring proteins involved in the repair of cellular DNA appear to be able to interrupt a vital process involved in the infection of cells with HIV, according to research published in the March 21^st edition of the Proceedings of the National Academy of Sciences. The investigators found that cells with the proteins XPB and XPD were able to destroy HIV’s DNA before the virus was able to integrate it into the cell’s chromosome, therefore preventing infection with the virus.

The investigators, from the Ohio State University Comprehensive Cancer Center are hopeful that their findings may lead to the development of a new target for HIV therapy that may be particularly useful for individuals who have developed resistance to existing antiretrovirals.

The investigators undertook laboratory research into the process by which HIV integrates itself into human cells. Before HIV infects a cell its genetic material is in the form of RNA. Once inside a cell, it copies its genes into DNA. This DNA copy – called by the researchers cDNA - then travels to the nucleus of the cell where it is integrated into the cell’s DNA.

Two processes are required to complete the cell’s infection with HIV. HIV provides the enzyme integrase, but the host cell completes the process using enzymes to repair the DNA.

The Ohio investigators wanted to identify the repair enzymes involved in this process. In the course of their research, they identified that cells with high levels of the proteins XPB and XPD – proteins involved in the repair of damaged cell DNA - had lower levels of HIV in their chromosomes.

In further research, the investigators introduced mutations into the cells of these proteins which inhibited their ability to repair HIV. When these cells were infected with HIV, the amount of the virus in their chromosomes was higher.

Intrigued by this finding, the investigators looked at proviral levels in cells. In particular, they wanted to see if levels of provirus in these cells were affected by HIV’s production of cDNA or whether cDNA was being destroyed before it was integrated into the cell.

Accordingly, the investigators exposed newly-infected cells to the drugs from the non-nucleoside inhibitor class – the anti-HIV drug efavirenz (Sustiva) and the drug foscarnet, which although primarily used as a therapy for the opportunistic infections such as CMV, is also active in the test tube against HIV.

The cDNA was destroyed faster in the cells with normal levels of XPB and XPD compared to those with mutant forms of these proteins. What’s more, cells with normal levels of XPB and XPD were able to destroy HIV’s cDNA before it had integrated itself into the cells chromosomes.

“Our results indicate that these two DNA repair proteins participate in the destruction of HIV cDNA in cells…this process reduces the pool of cDNA that can integrate into host chromosomes, thereby protecting cells from infection”, write the investigators.