Watching HIV mature into an infection

Amanda D. Francoeur, amanda.francoeur@laurin.com

HIV, the virus that causes AIDS, now can be seen maturing from its inactive form into an active infection. The process, which has never been seen before, could provide researchers with the information they need to develop advanced therapeutic treatments that would intervene with the disease’s progression and slow the infection.

Dr. Chun Tang, assistant professor of biochemistry in the school of medicine at the University of Missouri-Columbia, and fellow researchers at the National Institutes of Health in Bethesda, Md., used paramagnetic relaxation enhancement, a sensitive nuclear magnetic resonance method, to visualize the process. “It’s very sensitive to the minor species and small population,” Tang said.

Researchers now can use paramagnetic relaxation enhancement to watch an HIV-1 protease become an active infection. During the maturation process, two subunits of the same small chain (blue and green peptides) combine to create a precursor. Once the precursor is active, the tail (yellow strand) is cleaved, and the virus continues to infect other cells.

The researchers focused on an HIV-1 protease – the primary enzyme responsible for releasing the mature HIV-1 viral particles that cause AIDS. At first, the enzyme is inactive, and the virus is harmless to its host. “There must be two equivalent halves to form an active enzyme,” Tang said. During the maturation process, the protease becomes active and gains infectivity through introduction to another protease protein. The two proteins attach to each other to create a homodimer, a biological entity consisting of two equivalent subunits, through hydrogen bonding. Both subunits consist of 99 amino acids.

Once the halves merge, a tunnel develops between them. There are three main catalytic residues – aspartic, threonine and glycine amino acids – that form within the tunnel to make the dimer active. The “tail” of the precursor, a flanking amino acid residue, inserts itself into the tunnel and makes transient contact with both subunits. The tail is then cleaved by hydrolysis in two major locations for the protease to mature, thus allowing the virus to infect new cells.

An estimated 1.3 million people in North America were living with HIV infection in 2007, according to data compiled by the United Nations and the World Health Organization. The process of finding treatment is very difficult, as the viral enzyme constantly changes to gain drug resistance. However, according to Tang, visualizing the maturation process may allow researchers to enhance peptide treatments that could block the HIV-1 dimer and inhibit the protease from becoming active.

Nature, Oct. 2, 2008, pp. 693-698.