Apolipoprotein (apo) A-1 is the major protein component of high density lipoproteins (HDL). Studies from this laboratory have indicated that the alpha helical segments of apo A-1 (as well as several other apolipoproteins) are amphipathic in nature. The amphipathic helix class associated with the apolipoproteins, as opposed to that associated with polypeptide hormones, is unique. Positively-charged residues cluster at the polar-nonpolar interface, and are believed to provide additional free energy favoring lipid-association via the contribution of the significantly hydrophobic portions of Lys and Arg to overall hydrophobicity. Several apolipoproteins are thought to be the ligands to cell surface receptors in a number of different tissues. Relevant to this fact, a number of biological properties have been implicated for apo A-1 and its synthetic amphipathic peptide analogs. These properties include: inhibition of neutrophil activation, competition with the putative HDL receptor in adrenal cells, and stimulation of the release of human placental lactogen from trophoblast cells. Interestingly, there are two potentially amphipathic helical domains within the carboxy-terminus of the gp160 envelope protein of HIV. There is evidence that these two domains may associate with the membrane, suggesting that they may somehow be involved in membrane processes, such as fusion. It is therefore intriguing that the distribution of charged amino acids on the polar surfaces of these amphipathic helical domains has striking similarities to that found in the apolipoprotein class of amphipathic helixes: in particular there is clustering of positively charged amino acids at the polar-nonpolar interface. Interruption of virus-induced fusion has been shown to reduce viral replication and syncytium formation in a number of virus systems. We have recently shown that apo A-l and its amphipathic peptide mimics are efficient inhibitors of HIV-induced cell fusion. Additionally, we have found that apo A-l and its analog peptides show antiviral activity in the herpes simplex viral system. In order to follow up on these initial studies, we propose the following specific aims: 1. Determination of the ability of analogs of the amphipathic helix to inhibition HIV infectivity. 2. Design and synthesis of optimally-inhibitory amphipathic helixes. 3. Determination of the mechanisms of action of the peptide analogs. 4. Identification and characterization of amphipathic helical domains in HIV gp160. 5. Testing of peptide analogs in animal models. 6. Study of the epidemiology of HDL levels versus HIV infection in humans.
