Re: Is it possible for a 'retro' virus to spread modified DNA in the body?

Dear Amadeus:

Yes, indeed, it is possible for viruses, retroviruses included, to spread beneficial (or nonbeneficial) DNA in a person. In fact, some of these viruses are in clinical trials!

In the laboratory, viruses are routinely engineered to express genes. In fact, I make many retroviruses myself for this very purpose. We use a virus called MSCV, which infects just about any dividing cell, mouse or human, and leads to quite good gene expression. These viruses also are engineered with a selection element, allowing us to use antibiotics to select for cells that were infected by the virus in culture.

But you asked about people, not cells in culture. There are four difficulties in using viruses, be they retroviral or not, to deliver genes into people. First, you have to get the virus to the right place in the body to infect the cells in question (eg to the liver to express a liver gene, to the lungs to express a lung gene, such as the one encoding CFTR, which is altered in people with cystic fibrosis). Second, you need to convince the virus to infect the desired cells. Third, you have to make sure the immune system doesn't decide to recognize the new gene product as foreign, and attack the transduced cells. Finally, you need to make sure that the virus doesn't do anything else deleterious, such as integrate near another gene and cause cancer.

Delivery of the virus to the cell that needs to express a gene can be simple or difficult. Adenoviruses have been used to deliver genes to the lungs and the endothelial cells lining the blood vessels with some success. Beyond that, though, not much progress has been made with this type of vector. If the gene product is secretable, though, this may be enough, as the lungs or endothelial cells could secrete the factor and allow the bloodstream to transport it about the body.

OK, on to infecting the cells. Many viruses, including many retroviruses, need a cell to be dividing in order to infect it. This is not true of lentiviruses, such as HIV, which is why HIV is being considered as a gene therapy virus vector, scary as that sounds. The engineered virus, though, will not cause AIDS, as the pathogenic genes will have been removed - instead, it will simply act as a backbone to integrate into a nondividing cell. Also, many viruses exhibit tropism - the tendency to infect a particular cell type, usually do to that cell type possessing specific receptors for viral entry.

The third problem: the immune system. Whenever you express a new protein, be it a "natural" human gene product or a viral protein, there is the potential for the immune system to recognize it, treat it as foreign, and mount an immune response against it. The resulting immune response could be quite deleterious, leading to the destruction of the cells expressing the new gene and/or systemic problems resulting from the immune response (eg kidney damage due to immune complex formation, which can be deposited in the kidneys when the blood is filtered there).

The final problem: deleterious integration. A recent clinical trial, in which children who had severe combined immune deficiency (SCID) were given gene therapy to repair their nonfunctional gene, was stopped when one of the boys developed a leukemia-like syndrome due to where the retrovirus integrated itself in his bone marrow (a series of news articles about this appeared in the Dec 13, 2002 issue of Science).

Gene therapy holds great promise as an avenue for treating disorders of genetic origin, and a few that are not. I hope this helps answer your question.

Ingrid, MadScientist

The following are a few reviews. For a more in-depth list, visit pubmed.
Su JY, Chatterjee S, Wong KK Jr. Immunogenic issues concerning recombinant adeno-associated virus vectors for gene therapy. Curr Gene Ther. 2002 Dec;2(4):485-500.
Tamirisa KP, Mukherjee D. Gene therapy in cardiovascular diseases. Curr Gene Ther. 2002 Dec;2(4):427-35.
Kren BT, Chowdhury NR, Chowdhury JR, Steer CJ. Gene therapy as an alternative to liver transplantation. Liver Transpl. 2002 Dec;8(12):1089-108.
Audouy SA, de Leij LF, Hoekstra D, Molema G. In vivo characteristics of cationic liposomes as delivery vectors for gene therapy. Pharm Res. 2002 Nov;19(11):1599-605.