and antigen presentation in vitro in cells in which HIV-1 virions are replicating. 5 If 
MHC down regulation occurs in vivo, this may be responsible for lower levels of CTL 
induction, because MHC molecules present foreign antigens to the immune system, and 
(3) HIV- 1 infects and disables CD4 T-cells, which results in the progressive functional 
loss of this critical immune cell population as the infection spreads. 6 The virus can 
heavily infect CD4 cells in lymph nodes even in the early stages of infection. 7 The loss 
of CD4 cells correlates with profound immunosuppression, leaving the subject 
unprotected against opportunistic infections and cancers, which lead to the morbidity and 
mortality of HIV- 1 infection. 
2.1.5 Given these tactics by the virus, it is not altogether surprising that the therapeutic 
contributions made by humoral and cellular immunity in controlling the pathologic effects 
of HIV- 1 infection are poorly understood. HIV-1 specific antibodies, some of which 
possess neutralizing activity in vitro 8 , are generated during the natural course of HIV-1 
infection. NA may eliminate extracellular virus in vivo, but HIV-1 can also spread by 
cell-to-cell fusion. Thus HIV-1 infection and spread may continue in the presence of 
antibodies. 
2.1.6 T-cell-mediated immunity, involving the induction of CD8 + CTL that directly destroy 
virus-infected cells, has been shown to be important in limiting the severity and duration 
of several viral diseases 9 . CD8 + CTL, capable of lysing target cells expressing HIV-1 
envelope, gag, polymerase and nef proteins in vitro have been detected in HIV-1 
seropositive subjects, and may be important in controlling HIV-1 infection in vivo 10 . 
Although the precise impact of the immune response on HTV-1 infection remains to be 
elucidated, it is likely that the HIV-1 viral infection and replication process does not 
permit the full therapeutic benefit of the immune response to be invoked. 
2.2 Rationale for an HIV-1 Gene Transfer Immunotherapeutic 
2.2. 1 The rationale for use of HIV-IT (V) is to stimulate the production and activity of HIV-1 
specific CD8 + CTL above levels induced by natural infection. Some of the CTL may be 
stimulated against novel epitopes and provide cross-strain protection from progressive 
HIV-1 infection. Previous immunotherapeutic studies have relied on soluble antigen (i.e. 
gpl60) or inactivated virus as immunogens. Theoretically, these antigens would boost 
humoral immune responses. 
2.2.2 Generally, a long, symptomless period follows the initial acute infection with HIV- 1. 11 
Infected individuals could, therefore, benefit from an immunotherapy that stimulates 
augmented HTV-1 specific CD8+ CTL. CD8 + CTL are efficient "killers" of virally 
infected cells. 12 Class I MHC restricted CD8 + CTL represent the arm of the immune 
system that has been specifically developed to combat viral infections. 10 HIV-IT (V) is a 
promising agent for clinical trials as a treatment in HIV-1 infection because injecting HIV- 
IT (V) has been shown to specifically induce the CTL immune responses of mice and of 
non-human primates. HIV-IT (V) also elicits an antibody response in both murine and 
primate systems directed against the HIV-1 DIB envelope protein. 
-’Scheppler, J.A., et al., J. Clin. Invest., 72:398 (1983). 
6 R osenberg, Z.F., et al., AIDS Res. and Human Retroviruses, 5:104 (1989). 
7p antaleo, G., et al., Nature 362:355-358 (1993). 
8R obert-Guroff, M., et al., Nature, 316:72-74 (1985) 
9R ouse, R.T., Rev. Infect. Dis., 10:16-33 (1988). 
^Koenig, S., et al., J. Immunol. 145:127-135 (1990). 
^Robert-Guroff, M., et al., Nature, 316:72/7 4 (1985). 
12 Klavinskis, L.S., et al., 7. ViroL, 63:43 1 1-43 16 (1988). 
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