Recombinant DNA Advisory Committee - 2/10-11/92 
lymphoma that are not HTV seropositive. 
Hematopoietic cells are the major reservoir for HIV; in BMT, infected cells are replaced 
by noninfected donor cells. Therefore, the idea developed that it might be possible to 
perform BMT followed by administration of AZT in order to prevent infection of the 
newly infused cells. This procedure is taking place in several BMT centers. 
Dr. Greenberg outlined a few problems associated with this procedure. The first problem 
is that AZT is not likely to be fully effective in eliminating the virus since BMT patients 
can only tolerate low doses of AZT. Also, there are HTV strains that are AZT resistant. 
The question is whether there is a way to add an additional antiviral agent in this setting 
that would provide better protection to the patient and not cause some of the toxicities 
that are usually associated with the drugs used to treat viral diseases. 
Dr. Greenberg said that patients with HIV typically have a cytotoxic T lymphocyte (CTL) 
response to their virus. There are data suggesting that this response is important for the 
patients' ability to delay progression of the disease. In other diseases, a CD8 response 
(CTL response) prevents viral diseases and serious infections. 
Previous studies have shown that patients with cytomegalovirus (CMV) who have 
undergone BMT develop severe infections because of the lack of the CTL response to the 
virus. Presumably, if the response could be reconstituted for CMV, the development of 
this disease could be prevented. This type of reconstitution could be extended to HIV 
infection. The endogenous response that exists in a patient will be ablated by the same 
conditioning regimen that ablates the rest of the hematopoietic system; the patient will no 
longer have the CTL response to the virus. Additional antiviral activity may be provided if 
the CTL response can be reconstituted. 
Dr. Greenberg discussed several issues relevant to HIV. The addition of a suicide gene 
for these T-cell clones may provide some improved safety and make the study easier to 
evaluate. It is very difficult to isolate T-cells specific for viral proteins in patients who 
have not been exposed to the viruses. Clearly, an HIV-seropositive donor will not be used. 
The virus-specific T-cells being isolated are rare, unprimed cells that presumably have 
frequencies of less than 1 in 10 7 . Since the patient will have T-cells specific to the virus, 
such T-cell clones can be isolated, expanded in large number, and then administered. 
However, these clones may have a relatively short in vivo survival if the cells are 
recognized as being foreign by the transplanted bone marrow cells. 
The technology used to expand the clones, examine their DNA, and compare it to the 
infused cells requires from several weeks to two months. This timeframe is not adequate 
for analyzing patients when a rapid way of assessing whether these clones survive is 
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