produced to date has been tested by the standard marker rescue procedure and contains no 
helper virus. We will test for helper virus again (see section 6 of protocol and Points to 
Consider for methods) and the helper virus-free supernatant will be aliquoted and 
frozen at -80°C. 
C. Justification for Proceeding to a Human Trial & Discussion of Animal Models . We are 
proceeding to a Phase I human trial now for numerous reasons that include: 1) the 
pressing need for therapeutic advances, 2) the fact that pharmacological therapy with 
presently available primary anti-retroviral agents such as nucleoside reverse- 
transcriptase inhibitors (AZT, ddl, ddC) has proved toxic and of very limited efficacy 
(27), 3) the unique simplicity and long term benefits that gene therapy potentially 
offers for HIV treatment, 4) the availability of a retroviral vector and packaging line 
previously tested to be safe in humans (2,24,25,37) and 5) the lack of a good animal 
model for HIV-1 pathogenesis (and hence for in vivo testing of therapies). 
In particular, the lack of an animal model for AIDS, despite an extraordinarily wide- 
ranging and intensive search for one, has led to a broad consensus that many questions 
crucial to experimental HIV vaccine and treatment development must be answered 
directly in human trials (26). No available animal model of HIV-1 infection adequately 
mimics the infection and pathogenesis process in humans. The only animals well- 
documented to be susceptible to HIV-1 infection are the chimpanzee and the gibbon ape. 
However, these animals develop neither disease nor immunological correlates of disease 
such as CD4-depletion. In addition, chimpanzees and gibbons are endangered species. 
(26-36) 
While persistent experimental HIV-2 infection of macaques has been achieved, the 
animals again do not commonly develop syndromes comparable with AIDS (26). Infection 
of Asian macaques with SIV results in an immune-deficiency syndrome (29). However, 
these animals do not develop immune responses analogous to human infected with HIV-1 
and there are important differences such as the invariant V3 region of the envelope 
protein in SIV (29,31). Moreover, because of the marked divergence of HIV-2 and SIV 
from HIV-1, a ribozyme recognizing a totally different target sequence would have to be 
evaluated and this would not be truly indicative of either efficacy or risk of 
administration of an HIV-1 ribozyme. 
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