Peptide Cracks Cell Defense Against HIV
Researchers Find A Peptide That Enhances HIV Infection
UCLA AIDS Institute researchers have discovered that reversing the order of chemical residues on a protein backbone actually changes a peptide that defends against viruses, bacteria and other foreign invaders, so that it paradoxically facilitates infection with HIV.
The findings, published in the April issue of AIDS Research and Human Retroviruses, could pave the way for the use of such peptides in gene therapy using retroviruses as carriers.
“Although it may seem counterintuitive to value or even study a peptide that increases the ability of HIV-1 to enter a broad range of human cells, retroviral vectors are currently being explored as vehicles for gene therapy,” the authors wrote. “In this area, at least, agents that enhance retroviral uptake could contribute to an emerging field of medicine.”
“So many people have tried to deliver genes into different kinds of cells,” said study co-author Shen Pang, adjunct associate professor at the UCLA School of Dentistry and a member of the UCLA AIDS Institute. “If you know of some method that can enhance gene delivery, you would have a useful tool.”
DEFENSINS ARE ENDOGENOUS, peptide antibiotics that contribute to host defense against bacteria, fungi, and viruses. Retrocyclin-1 (RC-100) is a circular peptide that has been shown in previous studies to inhibit the infection of CD4 cells with HIV. RC-111 is also cyclic and has the same amino acid sequence as retrocyclin-1. In both peptides, the amino acids are strung like 18 beads along the molecule’s backbone. The amino acids in RC-111, however, are in reverse order.
The researchers had initially wanted to quantify previous research by Dr. Robert I. Lehrer, distinguished professor of medicine in the division of infectious diseases at the David Geffen School of Medicine at UCLA and a co-author of the present study. Unexpectedly, the researchers discovered that while retrocyclin-1 inhibited infection of CD4 cells with HIV-1 by about 95 percent, the RC-111 variant enhanced viral infection five-fold.
There are three structural varieties of peptides, also known as defensins — alpha, beta and theta, Lehrer said. Humans have only alpha and beta; monkeys have all three.
“Here’s a peptide whose normal structure allows it to protect against viruses, yet if you make the same peptide and place its amino acids in a reverse order, that lets the virus in,” Lehrer said. “We would like to learn why it happens, but at the moment there’s no explanation for this paradoxical result.”
Still, the findings seem to show promise in gene therapy.
In addition to Pang and Lehrer, study researchers were Rose Q. Wang, Wei Wang, Junying Zheng, Sina Tabibian, Yimin Xie, Jun song, Alan J. Waring, Robert Chiu, Otto O. Yang and Irvin S.Y. Chen.
Grants from the National Institutes of Health and the U.S. Department of Defense funded the study.
Established in 1992, the UCLA AIDS Institute is a multidisciplinary think-tank drawing on the skills of top-flight researchers in the worldwide fight against HIV/AIDS, the first cases of which were reported in 1981 by UCLA physicians. Institute members include researchers in virology and immunology, genetics, cancer, neurology, ophthalmology, epidemiology, social science, public health, nursing, and disease prevention. Their findings have led to advances in treating HIV, as well as other diseases, such as hepatitis B and C, influenza, and cancer.
AIDS RESEARCH AND HUMAN RETROVIRUSES
Volume 23, Number 4, 2007, pp. 508–514
© Mary Ann Liebert, Inc.
Paradoxical Effects of Two Theta-Defensins on HIV Type 1 Infection
QIUWEI WANG,1 WEI WANG,2 JUNYING ZHENG,1 SINA TABIBIAN,1 YIMING XIE,3 JUN SONG,1 ALAN J. WARING,2 ROBERT CHIU,1 OTTO. O. YANG,3 IRVIN S.Y. CHEN,3 ROBERT I. LEHRER,2
and SHEN PANG1
Retrocyclin-1 (RC-100) is a cyclic octadecapeptide whose primary structure is based on the sequence of an
expressed human theta-defensin pseudogene. RC-111 has the same amino acid sequence as RC-100 and is also cyclic, but its residues are placed in reverse order along the peptide’s backbone. We quantified the effects of RC-100 and RC-111 on HIV-1 infection using HIV clones that expressed green fluorescent protein. Whereas 0.2 microg/ml of RC-100 inhibited infection of CD4-positive cells by approximately 80%, its retroanalogue significantly enhanced infection of the cells. RC-100 and RC-111 also demonstrate their effects in HIV infection of CD4-negative cells. Whereas 40 ng/ml of RC-111 significantly enhanced infection of CD4-negative cells by HIV-1, RC-100 demonstrated significant inhibition of HIV infection with a concentration of approximately 10 microg/ml. RC-111ox, an acyclic variant of RC-111 with a beta-hairpin structure, also enhanced HIV-1 infection, but did so less effectively than cyclic RC-111. The divergent actions of RC-100 and RC-111 show that topology and polarity of theta-defensin peptides can determine their effect on HIV infection. The ability of RC-111 to enhance HIV-1 infection might prove useful in developing peptides that can enhance gene delivery by HIVbased lentiviral vectors.