pretransplant conditioning to ablate the host immunohematopoietic system, which represents 
the major reservoir of HIV, followed by BMT with concurrent administration of AZT or 
other antiviral drugs, will reduce the HIV burden and provide the host with an effective 
donor-derived immune system. Ablative pretransplant therapy appears necessary, since 
treatment with AZT combined with infusion of syngeneic PBL and marrow provided only 
transient improvement of immune function and did not eliminate viremia or prevent 
progression of HIV-related disease [15]. Preliminary studies of BMT with pretransplant 
ablative conditioning and AZT have provided some encouraging results. An HIV seropositive 
patient transplanted for malignant lymphoma tolerated the conditioning regimen, and, although 
recurrent lymphoma caused a fatal outcome on day 47, HIV could neither be detected in the 
blood posttransplant nor in autopsy tissue by PCR for the HIV genome [14]. BMT in six 
subsequent patients (three syngeneic and three allogeneic) similarly demonstrated successful 
engraftment and acceptable posttransplant toxicity, but five of these six patients exhibited only 
a transient reduction in viral burden and soon became positive for HIV by virus culture or 
PCR (H.K. Holland, personal communication). These results demonstrated the feasibility of 
administering AZT posttransplant and validated the concept that a large reservoir of HIV 
infected cells can be ablated by BMT, but suggested the need to eradicate residual HIV 
infected cells and/or prevent infection of donor hematopoietic cells posttransplant. 
! . 
B. Class I MHC-restricted CD8+ T. Immunity and HIV Progression 
The importance of Class I MHC-restricted CD8 + T c in controlling infection has not been as 
well documented for HIV as for CMV or influenza virus for which there are small animal 
models [16-19], but is supported by correlative data from HIV-infected patients. Prior to 
developing AIDS, HIV seropositive patients commonly have Class I MHC-restricted CD8 + T c 
detectable in high frequency in peripheral blood, specific for numerous HIV proteins 
including the products of the env, gag , pol, vif and nef genes [20-26]. CD8 + HIV-specific T c 
have been shown to inhibit replication of HIV in human lymphocytes in culture and there is 
circumstantial evidence that maintenance of HIV-specific T c may retard the development of 
AIDS in vivo. In contrast to other latent viruses such as CMV and EBV [27,28] where host 
virus-specific CD8 + T c responses persist throughout life, HIV infected patients gradually lose 
detectable HIV reactive CD8 + T c , and this decline in T c responses correlates with increases in 
plasma viremia, reductions in CD4 + T cell counts, and the development of clinical AIDS [29- 
31]. These data suggest that, in bone marrow transplant protocols, the ablation of residual 
host HIV-specific CD8 + T c coupled with the lack of an effective donor HIV-specific CD8 + T c 
response during the early post BMT period may contribute to the difficulty controlling HIV. 
Thus, adoptive immunotherapy with in vitro expanded HIV-specific CD8 + T c effector cells 
might have a beneficial post BMT antiviral effect. Such CD8 + T c clones could be isolated for 
expansion from the HIV seropositive BMT recipient pretransplant and adoptively transferred 
in the posttransplant period to potentially reconstitute immunity to HIV. 
C. Adoptive T Cell Transfer for Human Disease 
The principles, safety and therapeutic efficacy of adoptive T cell transfer for viral and 
malignant diseases have previously been established in animal models [32] but only recently 
have investigators explored T cell transfer for the treatment of human disease. These clinical 
studies have established the feasibility and safety of this approach and demonstrated in vivo 
biological effects of transferred effector cells. 
1 . LAK and TIL Cell Therapy in Cancer Patients 
I 
[612] 
Recombinant DNA Research, Volume 15 
