To identify critical host factors necessary for human immunodeficiency virus 1 
(HIV-1) replication, large libraries of short-peptide-aptamers were expressed 
retrovirally. The target of one inhibitor peptide, Pep80, identified in this 
screen was determined to be Snapin, a protein associated with the soluble 
N-ethyl maleimide sensitive factor adaptor protein receptor (SNARE) complex that 
is critical for calcium-dependent exocytosis during neurotransmission. Pep80 
inhibited Ca²⁺ release from intracellular stores and blocked downstream 
signaling by direct interruption of the association between Snapin and an 
intracellular calcium release channel, the ryanodine receptor (RyR). NFAT 
signaling was preferentially abolished by Pep80. Expression of Snapin overcame 
Pep80-mediated inhibition of Ca²⁺/NFAT signaling and HIV-1 replication. 
Furthermore, Snapin induced HIV-1 replication in primary CD4⁺ T cells. Thus, 
through its interaction with RyR, Snapin is a critical regulator of Ca²⁺ 
signaling and T cell activation. Use of the genetically selected intracellular 
aptamer inhibitors allowed us to define unique mechanisms important to HIV-1 
replication and T cell biology.