theta-Defensin pseudogenes in HIV-1-exposed, persistently seronegative female sex-workers from Thailand.
The leukocytes of rhesus monkeys contain cyclic octadecapeptides (theta;-defensins) that can protect cells from infection by HIV-1 in vitro. Although humans express mRNA from one or more theta;-defensin pseudogenes, these transcripts contain a premature stop codon that prevents formation of theta;-defensin peptides. We hypothesized that some highly exposed persistently seronegative (HEPS) individuals might have intact theta;-defensin (DEFT) genes and produce functional theta;-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 theta;-defensin genes from all 11 HEPS women contained the crucial signal sequence stop codon, as did the 19 control women. Synthetic theta;-defensins based on the cDNA sequences to generate a human theta;-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 theta;-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 theta;-defensin production accounts for their resistance to HIV-1.
Yang
Chunfu
C
Division of AIDS, STD, and TB Laboratory Research, National Center for HIV, STD, and TB Prevention, Centers for Disease Control and Prevention (CDC), Mail Stop D-12, 1600 Clifton Road, Atlanta, GA 30333, USA. cyang1@cdc.gov
Boone
Louvonia
L
Nguyen
Tung X
TX
Rudolph
Donna
D
Limpakarnjanarat
Khanchit
K
Mastro
Timothy D
TD
Tappero
Jordan
J
Cole
Alexander M
AM
Lal
Renu B
RB
D000595:Amino Acid Sequence; D002460:Cell Line; D018388:Codon, Terminator; D023082:Defensins / Q000235:genetics* / Q000494:pharmacology; D005260:Female; D018023:HIV Seronegativity / Q000235:genetics* / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D011544:Pseudogenes / Q000235:genetics*; D011477:Sex Work; D013785:Thailand; D014779:Virus Replication / Q000187:drug effects
D018388:Codon, Terminator; D023082:Defensins; C450142:theta-defensin