Secrets of a deadly virus: seven potential ways to stop HIV
Steps in the life cycle of HIV offer clues to stopping its spread
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.
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.
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.
The double-stranded version of the viral DNA is transported into the nucleus with the help of cellular proteins.
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.
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.
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