Recombinant DNA Advisory Committee - 06/7-8/93 
facilitate the transport of HIV RNA from the nucleus to the cytoplasm for completion of 
the virus replication cycle. The transdominant mutant form of the rev protein inhibits 
this transport and keeps HIV in the latent phase. Therefore, the ultimate goal is to 
protect the CD4(+) cells that are not yet infected with HIV. 
In addressing the safety issues raised by Dr. Smith, Dr. Nabel stated that in vitro 
transduction by the retrovirus vector will be performed in the presence of anti-HIV drugs 
and Pseudomonas exotoxin, which kills cells that have HIV gpl20 env protein. Such 
measures will minimize the generation of HIV from these cells. Dr. Nabel stated that 
the probability of generating a novel strain of HTV by the amphotropic vector is 
extremely small as discussed in Drs. Galpin and Casciato's protocol. Regarding the trial 
design. Dr. Nabel said that a total of 12 patients will be enrolled, 4 groups of 3 patients 
each. There will be 2 transduction methods; in each transduction group, there will be 2 
subgroups with different lymphocyte stimulation procedures, CD3/IL-2 and CD3/CD28. 
Dr. Nabel agreed to simplify the language in the Informed Consent document in order to 
make it more understandable to patients. Patients will not be required to pay for any 
costs associated with the gene transfer aspects of the protocol. Ms. Meyers mentioned 
that long-term follow-up of patients is important if any unforeseeable event occurred in 
the gene transfer trial. 
Responding to Dr. Miller's question, Dr. Nabel said that in cell culture experiments, the 
Rev M10 mutant protects lymphocytes from producing HIV by 3 to 4 orders of 
magnitude. However, this protection is not absolute; it can be overwhelmed by higher 
titer of virus production. The proposed human study is designed to test in vivo 
protection. No animal model is currently available in which to test this hypothesis. Dr. 
Miller asked whether the present proposal is different from the protocol submitted by 
Dr. Clay Smith, Memorial Sloan Kettering Cancer Center, New York, New York, which 
was previously deferred by the RAC. Dr. Post mentioned that in Dr. Smith's protocol, 
all experiments were performed in cell lines. The present protocol has additional data 
that was obtained using fresh peripheral blood lymphocytes from HIV patients. 
Responding to Dr. Zallen's question about the long-term planning of the present study, 
Dr. Nabel said future directions depend on the outcome of this initial trial. If no 
protective effect is observed, useful knowledge will still be obtained in terms of 
transducing CD4( + ) cells. But if there is positive protective effect, these transduced 
CD4( + ) cells can be isolated and expanded in tissue culture and reinfused back to 
patients for a more aggressive therapeutic trial. Dr. Parkman remarked that in this 
initial stage of the study, the word "benefit" in the Informed Consent document is not 
appropriate. Dr. Smith stated that he was still concerned about the safety issues 
surrounding the use of an amphotropic retrovirus vector in HIV patients but felt that he 
could defer to those members with greater expertise in this area. He stated that he 
Recombinant DNA Research, Volume 17 
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