CKR-5: New Study Confirms Some Do Not Get HIV

A major genetic study of six epidemiological cohorts of persons at risk for HIV infection has confirmed the recent findings that a few people appear to be naturally unable to be infected with HIV (see AIDS TREATMENT NEWS #254, September 6, 1996). Everyone found so far who has two copies of a defective CKR-5 gene (also called CCR-5) has been HIV negative, although these people have been in groups at high risk of HIV exposure. (The gene is considered "defective" because a section of it is missing, and it cannot produce a functional receptor which is found on certain cells. In this case, having a defective gene is an advantage, since some kinds of HIV need that receptor (in addition to the CD4 receptor) in order to enter a cell. No known harm results from this defective gene, even for those who have both of their copies defective and therefore cannot produce the normal receptor at all.)

The new results differ in some ways from what had been reported earlier:

* Having only one copy of the defective gene did not seem to offer any protection against acquiring HIV, as had been suggested previously. But it was associated with a somewhat slower disease progression -- except in hemophiliacs. [This might be because of the different way HIV is transmitted. The virus which uses the CKR-5 receptor infects macrophage-like cells which are found in the skin and mucus membranes. It appears than when HIV is transmitted sexually, the infection first establishes itself as macrophage-trophic virus (strains of HIV which preferentially infect macrophages), and T-cell-tropic virus strains evolves later. Possibly the first step can be bypassed if a large amount of virus is transmitted by transfusion of blood or blood products.]

* African Americans were tested, and a few were found to have the CKR-5 gene -- but many times fewer than Caucasians. An earlier study of Central and West Africans had found no copies at all.

Comment: Stem Cell Transplantation Research

What interests us most about this discovery is a possible treatment approach mentioned briefly in the new paper -- transplantation of stem cells from a person who had the protective genes. Stem cells are self renewing, and also produce all of the different kinds of cells found in the blood. If stem cells with two copies of the altered CKR-5 gene could be transplanted successfully, they would produce blood cells naturally immune to infection by many (but not all) kinds of HIV. While HIV can infect some non-blood cells, the great bulk of infection is in lymphocytes and macrophages, and if they were protected, the disease might not be able to sustain itself.

Possibly this approach could also repair immune damage caused by loss of part of the repertoire of immune cells in advanced HIV infection. It might also be a treatment for genetic blood diseases such as hemophilia.

Unfortunately the altered CKR-5 gene mainly protects macrophages, not lymphocytes. Other studies suggest that there may be additional forms of resistance to HIV, which may not have this limitation. But the immediate problem is that stem-cell transplantation from one person to another is in its infancy. It is a topic of intense research interest today.

In the past, efforts have been made to genetically engineer human cells to make them immune or resistant to HIV infection -- or alternatively to use cells from a baboon, since baboons are not infectable with HIV. While both of these approaches are worth trying, each has practical problems that now might be bypassed, since persons with stem cells which already are naturally HIV-resistant can now be readily identified. (Since they are always HIV-negative, there would be no risk of transmitting different strains of the virus to a recipient.) Transplantation of HIV-resistant stem cells -- which conceivably could lead to a cure even without total viral eradication -- may be less distant now that a clear case of genetic resistance to HIV infection has been confirmed.

The community needs to pay attention to stem-cell transplantation research (which is highly promising for many serious illnesses, not only HIV infection) and make sure that funding and other support are available.