θ-Defensin pseudogenes in HIV-1-exposed, persistently seronegative female sex-workers from Thailand

The leukocytes of rhesus monkeys contain cyclic octadecapeptides (θ-defensins) that can protect cells from infection by HIV-1 in vitro. Although humans express mRNA from one or more θ-defensin pseudogenes, these transcripts contain a premature stop codon that prevents formation of θ-defensin peptides. We hypothesized that some highly exposed persistently seronegative (HEPS) individuals might have intact θ-defensin (DEFT) genes and produce functional θ-defensins that might account for their resistance to HIV-1 infection. We sequenced DEFT genes from 30 women in Chiang Rai, northern Thailand: 11 HEPS female sex-workers and 19 control women (10 HIV-1 infected and 9 HIV-1 uninfected). We found that θ-defensin genes from all 11 HEPS women contained the crucial signal sequence stop codon, as did the 19 control women. Synthetic θ-defensins based on the cDNA sequences to generate a human θ-defensin (termed retrocyclin-1 and -2) were capable of inhibiting replication of Thai HIV-1 subtype B and CRF01_AE isolates regardless of the coreceptor utilization of the isolates. Although our study indicates that synthetic θ-defensin peptides are effective in vitro against Thai subtype B and CRF01_AE isolates of HIV-1, the presence of premature stop codons in the DEFT genes of these HEPS women makes it unlikely that endogenous θ-defensin production accounts for their resistance to HIV-1.