New classes of HIV inhibitors raise promise for future treatments
HIV experts discuss the most intriguing research
HIV researchers acknowledge it’s difficult to stay ahead of a virus that can remain deadly after major mutations, but they’re hopeful a variety of new antiretroviral strategies will improve the long-term outlook for HIV patients.
"On the close horizon are new classes of inhibitors of HIV," says Warner C. Greene, MD, PhD, director of the Gladstone Institute of Virology and Immunology and professor of medicine and microbiology and immunology at the University of California, San Francisco.
Some potential new treatments target the very early stages of HIV’s interaction with CD4 cells. Other possibilities include the study of strengthening the body’s own antiviral fighter APOBEC 3G, which is deactivated by an HIV protein. Also, investigators have begun to look into theories regarding the immune system’s complicity in producing AIDS and how this knowledge might lead to new avenues of treatment.
"The drugs on the market are effective, but the virus becomes resistant over time, so it’s important to have multiple drugs," says Peter Prevelige, PhD, professor of microbiology at the University of Alabama, Birmingham.
"The more targets one has, the better one can deal with inevitable resistance, so a lot of interest in the pharmaceutical and research community is to identify new targets, and the most recent are the fusion inhibitors," he says.
Greene and other researchers explain what some of these new treatment possibilities are and how they might work:
- CCR5 inhibitors.
One such new class being investigated is the CCR5 antagonist, which appears to have a very good response in some clinical trials, Greene says.
Discovered in 1996, the CCR5 and CXCR4 chemokine coreceptors for HIV were thought to hold promise as a target for treatment when it was found that 1% of Caucasians lack cell surface expression of CCR5, which in turn made them highly resistant to HIV infection.1
However, investigators have feared that a CCR5 receptor inhibitor, which is designed to produce the same effect that was found in nature in that small population, may cause the virus to shift to using the CXCR4 receptor, Greene notes.
"And when viruses shift to that, they become more pathogenic — there are a lot more CXCR4 target cells," he adds.
Fortunately, early clinical trials suggest this shift is not occurring, so a CCR5 inhibitor may prove successful on its own, Greene says.
"CCR5 inhibitors are deep into clinical trials and showing great effectiveness," he adds, predicting that a CCR5 inhibitor drug might make it to market within the next two years.
- Attachment inhibitors.
Another new area of study involves attachment inhibitors, which are much further behind in the pipeline than CCR5 inhibitors, Greene explains.
For example, an attachment inhibitor might block the insertion of CD4 residues into the gp120 pocket, disrupting the high-affinity interaction of the two proteins and, therefore, inhibiting HIV.1
"The attachment inhibitors haven’t generated as much interest," Greene notes. "They’re lagging a little behind the CCR5 antagonists, but it’d be nice to be able to use both of those drugs."
- Fusion inhibitors.
"These are the first of a class of drugs looking at the entry of the virus," says William Powderly, MD, professor of medicine and the head of the department of medicine at the University College Dublin (Ireland).
"There are a lot of drugs being developed in this class, and they offer potential for not only usefulness in patients who are resistant to existing drugs, but obviously in the future, the option to be a first-line therapy," he says. "The current infusion inhibitor is not one that would be offered to people as a first-line therapy."
Fusion inhibitors attend to the third part of the process in which HIV binds to CD4 cells, Greene says. Through a change, the virus fuses to target cells, and the fusion facilitates the virus’s ability to microinject its contents into the cytoplasm of the host cell, he explains.
"That fusion process is mediated by a protein called gp41," Greene adds.
T20 peptide inhibitor of gp41 Env-mediated fusion has been approved by the Food and Drug Administration (FDA) for treatment of HIV. Since the drug only can be administered through subcutaneous injection, it’s not widely used, he says.
Effective, just not convenient
"It’s not very convenient, but it’s effective," Greene says. "What I’d like to see are small molecules that could be engineered into drugs and taken by mouth and would do the same thing, but so far none have been identified."
This is an area that needs increased research emphasis, he notes.
"With the attachment inhibitors, the chemokine receptor antagonist and the fusion inhibitors, in essence, you have a new triple drug cocktail," Greene says. "All of these are blocking the earliest sequential steps in the viral life cycle as it tries to get into the cell in the first place — it’s pretty exciting that this could be done."
- Assembly inhibitors.
"Generally, people are interested in coming up with compounds that inhibit virus assembly," says Andrew H. Kaplan, MD, an associate professor of medicine at the University of North Carolina, Chapel Hill.
"That’s an area that hasn’t been aggressively pursued," he notes. "We’re talking about things that would disrupt the process of virus assembly, and those aren’t near clinical use, but people are thinking about those questions."
- Integrase inhibitors.
Although the development of integrase inhibitors has proven more difficult than expected, there has been progress, Greene says.
After the virus fuses and undergoes reverse transcription, which is where a lot of the inhibitors of the drugs pass on the reverse transcriptase, the virus makes its double-stranded DNA version of the single-stranded RNA, he explains.
This is integrated into the nucleus and then it integrates into the host chromosome, establishing what is called the HIV pro-virus, Greene adds. "Then there’s a viral enzyme called integrase which mediates that reaction," he says.
Investigators have spent a long time looking for integrase inhibitors, which is the third enzyme target of HIV: reverse transcriptase, protease, and integrase, Greene says.
Finally, some pharmaceutical companies have developed compounds that show promise, although there may be some toxicity issues. "So the integrase inhibitors are much further behind, but there is progress being made there." he adds.
- APOBEC 3G.
"Most HIV biologists would regard APOBEC-3G as the single most exciting drug target since the discovery of chemokine receptors," Greene says.
"So this is really hot in HIV molecular biology now," he adds. "We’re searching for small molecules even as we speak."
Still, it will be a long time before this early investigation leads to an HIV medication, Greene notes. APOBEC 3G is a very potent anti-HIV factor that already exists within the human body, he says. The reason APOBEC 3G has not prevented the AIDS epidemic is because HIV uses its protein called viral infectivity factor (VIF) to target APOBEC 3G and get rid of it, Greene explains.
"VIF binds to APOBEC 3G and targets its antiviral enzyme for destruction," he adds. "That raises the question of whether we could come up with small molecules that interfere with VIF binding to APOBEC 3G." Investigators now are exploring this possibility, Greene says.
- Immune system.
The HIV field is experiencing an emerging new thought about how HIV kills t-cells, he says.
"It turns out that most of the CD4 t-cells that are dying in HIV infection are not the cells that actually are infected with HIV, but are bystander cells," Greene explains. "So this has led to the notion that, in fact, a lot of the cell death, and therefore, the disease, is caused by immune response against HIV."
This new concept in HIV biology could lead to novel new treatments, if it proves to be true as investigators further study the idea.
"It sounds strange, but maybe what you really want to do is to somehow convince the immune system to ignore HIV, to allow it to kill a few CD4 t-cells because the body can quickly replace those," Greene notes. "But perhaps the vigorous immune response against HIV — this activation — is really what’s driving the pathogenesis.
" A lot of research work will need to be done to secure the hypothesis, he notes.
"The mechanism by which t-cells are chronically destroyed over time in HIV infection still is unclear," Powderly continues. "It may be part of an accelerated destruction of t-cells that ordinarily goes on, and that’s mediated by the immune reaction or by the virus’s reaction to being infected."
However, this debate is a straw man in terms of the epidemic because what drives the process is HIV replication, he adds.
"If you control HIV replication, you get t-cell recovery and recovery of the immune system, and it’s the virus that’s responsible for the process," Powderly says. "It’s the mechanism by which that happens that still is controversial and unclear."
1. Greene WC. The brightening future of HIV therapeutics. Nature Immunology 2004; 5(9):867-871.