September 18, 2024

Secrets of a deadly virus: seven potential ways to stop HIV

Steps in the life cycle of HIV offer clues to stopping its spread

Illustration by Dominic Doyle

Step 1:
The viral envelope protein, gp120, which is highly coated in sugars, docks to the CD4 receptor and a co-receptor on the surface of the T cell. This causes the envelope protein to change shape, allowing a previously hidden part of it, gp41, to “spring open” and seize the cell membrane like a grappling hook.

Step 2:
The viral envelope fuses with the cell membrane, and discharges the genetic core of the virus into the cell. A new class of “fusion inhibitors” can block entry of HIV by binding to gp41. Other entry inhibitors are being developed. A cellular factor recently identified in monkeys, called TRIM5-alpha, may block un-coating of the viral shell or capsid after entry. TRIM5-alpha could lead to a new way to prevent HIV replication in humans.

Step 3:
Using nucleotides, or building blocks of DNA, from the cytoplasm, the viral enzyme reverse transcriptase (pictured here as a zipper) produces a DNA copy of the single-stranded viral RNA, then a second DNA copy. Drugs that inhibit the reverse transcriptase enzyme are a major part of existing anti-retroviral therapy.

Step 4:
The double-stranded version of the viral DNA is transported into the nucleus with the help of cellular proteins.

Step 5:
Another viral enzyme, integrase (pictured here as needle and thread), “sews” the double-stranded viral DNA into the cellular genome, at which point it is called a “provirus.” Drugs are being developed to block the integrase enzyme. In resting or “memory” T cells, the HIV provirus can remain silent for years. In T cells that are dividing as part of the immune response against HIV, the virus “commandeers” cellular machinery to transcribe thousands of copies of the viral RNA from the integrated provirus.

Step 6:
After transport to the cytoplasm, some of the RNA is translated – using the cell’s protein-making machinery – into large polyproteins. Other cellular proteins transport the polyproteins to the cell membrane, and help construct a new virion. One of these proteins, called Tsg101, seems to be important in budding. “If you reduce the levels of Tsg101 in the cell, you see a lot of virions on the surface of the cell. They’re trying to pinch off but they can’t quite release,” says Chris Aiken, Ph.D., associate professor of Microbiology and Immunology at Vanderbilt.

Step 7:
During the assembly process, the viral enzyme protease (pictured here as a pair of scissors) cuts itself from one of the polyproteins, and cleaves structural proteins necessary to form a functional viral core. Drugs that inhibit the protease are an important part of current antiretroviral therapy. At Vanderbilt, two recent discoveries may lead to ways to inhibit viral particle assembly and maturation. Paul Spearman, M.D., and his colleagues have found evidence of an as-yet-undetermined cellular factor that can inhibit particle assembly and release, but which is overcome by the viral protein U (Vpu). Identifying this novel cellular factor could lead to a new way to block HIV. Meanwhile, Aiken and his colleagues are investigating a compound called DSB for its ability to prevent the protease from making an important cleavage in the polypeptide, thereby delaying virion maturation and reducing HIV's ability to infect cells. “It’s a completely novel mechanism of action for a drug,” Aiken says. “And it’s very potent; it seems to be very selective. Things like that are out there. They will just need some decision makers in industry to say, ‘Let’s go after this.’”