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Failure of the immune system leads to any number of infections collectively known as AIDS-related illnesses.

In AIDS, fungi, parasites, bacteria, and viruses can rage unchecked through the bloodstream. Many of these pathogens are commonly found in the environment and are normally contained by our immune systems. They are, however, poorly controlled in HIV-infected people. These infections are called opportunistic because they arise when enough of the T cells that would normally fight them off have been killed.

Mosier studies the viral dynamics of several opportunistic viruses that are common co-infections and he has found ways of controlling some of them.

Epstein–Barr virus (EBV), Kaposi’s sarcoma herpesvirus, and cytomegalavirus can be controlled by transplanting CTLs that are specific for these viruses into patients. Transplanting EBV-specific CTLs, for instance, will prevent them from causing lymphomas and will clear the EBV from the system.

"They last for many months and are very effective at eradicating infection," says Mosier.

However, the same sustained and effective response is not found with HIV-specific CTLs. Infusing them into a patient does have an immediate antiviral impact, but the effect is short-term and is lost within about three days.

The Biology of a Coreceptor

Besides studying the basic viral dynamics of HIV, Mosier is actively involved in searching for novel compounds to use as antiviral therapeutics. His target is the C–C chemokine receptor 5 (CCR5).

CCR5 is a seven trans-membrane spanning protein of 332 amino acids that inserts into the cell membranes of human CD4+ T helper cells with the N-terminus and three external loops exposed to the outside and the C-terminus and three internal loops, which are responsible for signaling, on the inside.

The idea to explore CCR5 as a possible target for therapy and vaccines came shortly after the molecule was recognized as a co-receptor for HIV entry. This recognition came from studies with cells of certain individuals who seemed to be protected from infection despite having had multiple high-risk exposures to the virus.

It turned out that CCR5 is a coreceptor to which HIV virions need to bind after they bind to CD4 receptors on a cell, and the expression of this coreceptor is rate limiting for transmission of the virus and its expansion from cell to cell.

The resistant individuals all had a 32-base pair knockout mutation in CCR5 gene that left their CD4+ T cells with no coreceptors. Later data showed that individuals who were heterozygous for the mutation had lower CCR5 expression levels, less cell-to-cell infection, and brighter clinical prognoses.

"Since the virus has to use this receptor," says Mosier, "one might be able to block the interaction and prevent infection."

Possible agents would either bind to CCR5 and prevent it from functioning as a coreceptor, interfere with the folding of CCR5, or downregulate the expression of the CCR5 gene.

Mosier believes that the most effective therapy in the short-term will be the chemokine receptor blockers—molecules like the natural CCR5 human peptide ligand RANTES, which binds to the same loops of CCR5 as HIV.

Mosier calls RANTES a good lead candidate for a therapeutic blocking agent, and he has already seen that some of its synthetic analogues are 1,000-fold more potent at blocking HIV cell entry. As a drug, RANTES or a RANTES-like compound would probably be added to the current regiments of drugs rather than used as a single agent. "They will be part of a larger cocktail," says Mosier.

However, these RANTES compounds would be unlike current regimens, which are largely available in pill form. RANTES is a 68-amino acid long peptide, so it would not be orally bioavailable because enzymes in the stomach would digest it. Drugs based on RANTES would have to be injected in the same way people with Type 1 diabetes inject insulin.

He also says that he has obtained some encouraging data about the slow recovery of CCR5 when challenged with these agents. A large dose of the coreceptor blocking agents can "strip" the CCR5 receptors off the cell walls completely for over 24 hours.

"You might be able to get away with once-a-day dosing," he says.

As with any antiretroviral therapy, though, the greatest danger is that HIV will mutate. Since HIV has no proofreading mechanism, it copies itself with such notoriously low fidelity that it makes a mistake every time it makes a copy of itself. Because of the large number of copies it makes, the chances of spontaneous mutants with drug resistant properties are great—perhaps even guaranteed.

Mosier’s basic research has provided an effective model to test out HIV’s response to possible agents. He can grow human T cells with a mutant form of CCR5 that has the C-terminal end chopped off. These mutants can still bind to the HIV virions, but they cannot signal inside the cells and do not get internalized. Then, by comparing wild type to mutant viral constructs, he can observe what changes in the HIV genome allow it to enter the cell through another route.


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Human cells (shown in red) in the spleen of a hu-PBL-SCID model.












“Since the virus has to use this [CCR5] receptor, one might be able to block the interaction and prevent infection.”

Donald Mosier





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