Reversed Peptide Enhances HIV Infection

LOS ANGELES, May 11 -- A peptide that protects rhesus monkeys from HIV-1 infection does just the opposite when its structure is reversed, researchers here say.

The peptide, retrocyclin-111, is a synthetic analog of a naturally occurring peptide called retrocyclin-100, according to Shen Pang, Ph.D., of the University of California at Los Angeles School of Dentistry and a member of the UCLA AIDS Institute.

But while retrocyclin-100 protects cells against HIV-1, the reverse peptide actually promotes infections, Dr. Pang and colleagues reported in the April issue of AIDS Research and Human Retroviruses.

The unexpected finding -- although of no apparent value in AIDS research -- may one day be useful in gene therapy applications, Dr. Pang and colleagues said.

"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."

The researchers were trying to confirm directly that retrocyclin-100 and its analogues - members of a class of defensive proteins known as theta-defensins - bar the door to HIV-1.

Interestingly, humans have the genes for theta-defensins but do not express them because of a mutation that introduced a premature stop in the gene sequence.

One of the study's authors -- Robert Lehrer, M.D., also of UCLA - had previously shown by indirect means that the retrocyclin peptides had a protective effect.

For these experiments, the researchers used strains of HIV-1 genetically engineered to express a protein that glows green under fluorescent light and exposed four types of human cells to the virus in the presence of the various peptides.

As expected, retrocyclin-100 slowed infection. In a control culture of cervical cells, the virus formed 198 colonies after three days.

In contrast, in cells treated with one microgram per milliliter of retrocyclin-100, only about 10.5 colonies formed, or about 5% of those seen in control. The difference was significant at P<0.01.

When the experiment was carried out with retrocyclin-111, the virus formed 1,603.5 colonies, or about eight times the number seen in controls. The difference was significant at P<0.05.

The two peptides are cyclic and contain 18 amino acids. They are virtually identical in most respects except that the order of the amino acids is reversed, the researchers said.

It remains unclear why reversing the sequence reverses the effect.

"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," Dr. Lehrer said. "We would like to learn why it happens, but at the moment there's no explanation for this paradoxical result."

Many research teams are trying to find ways of using retroviruses, such as HIV or herpes simplex, in gene therapy, Dr. Pang said.

"So many people have tried to deliver genes into different kinds of cells," he said. "If you knew of some method that can enhance gene delivery, you would have a useful tool."