During the early stages of human immunodeficiency virus (
HIV) infection, although symptoms are absent and viral replication in peripheral blood mononuclear cells is low, substantial levels of HIV replication can be documented in lymphoid tissue [G. Pantaleo, C. Graziosi, J.F. Demarest, L. Butini, M. Montroni, C.H. Fox, J.M. Orenstein, D.P. Kotler, and A.S. Fauci, Nature (London) 362:355-358, 1993, and J. Embretsen, M. Zupancic, J.L. Ribas, A. Burke, P. Racz, K. Tenner-Tacz, and A.T. Haase, Nature (London) 362:359-362, 1993]. This observation suggests that earlier treatment of
HIV infection may be indicated and that strategies for enhancing drug targeting to the lymphoid tissue reservoris of
HIV infection may be beneficial. To address this issue, we synthesized
dioleoylphosphatidyl-ddC (
DOP-ddC) and dipalmitoylphosphatidyl-3'-azido-3'-deoxythymidine (DPP-AZT),
phospholipid prodrugs which form
lipid bilayers and which are readily incorporated into
liposomes. The anti-HIV activity of
DOP-ddC was similar to that of ddC in HIV type 1-infected HT4-6C cells, but DPP-AZT was considerably less active than AZT in HT4-6C cells.
Liposomes containing DOP-[3H]ddC or DPP-[3H]AZT administered intraperitoneally to mice produced greater levels of total radioactivity over time in plasma, spleen, and lymphoid tissue relative to the results with [3H]ddC and [3H]AZT, respectively. DPP-AZT administered intraperitoneally in
liposomes as a single daily dose to mice infected with Rauscher leukemia virus prevented increased spleen weight and
reverse transcriptase levels in serum with a dose-response roughly comparable to that of AZT given continuously in the
drinking water.
DOP-ddC, DPP-AZT, and
lipid conjugates of other antiretroviral
nucleosides may provide higher levels of
drug over time in plasma and in lymph nodes and spleen, important reservoirs of
HIV infection, and may represent an interesting alternative approach to
antiviral nucleoside treatment of
AIDS.