HIV/AIDS Research Advances: Vaccines, a Cancer Drug vs HIV, and a Vaginal Ring

Research into HIV and AIDS does not always translate into clinical practice immediately, but it paves the way for advances and also defines strategies not worth pursuing. Here are some of the key HIV-related studies reported over the past few months.

Vaccine news. The frustrations surrounding the search for a vaccine against HIV are well known. But researchers are still on the case. A study published this month in the Proceedings of the National Academy of Sciences  highlights a new way of delivering a potential vaccine that could be particularly beneficial in developing countries where the epidemic is worst.

Researchers from King’s College in London used funding from the Bill and Melinda Gates Foundation to develop a dime-sized disk with an array of sugar microneedles that dissolve after puncturing the skin. They used a dried version of a live, modified adenovirus-based candidate HIV vaccine. The vaccine remained stable and effective at room temperature in a mouse model, triggering a reaction in specialized dendritic cells in the skin. The overall immune response was the same as that observed with the fluid version of the compound, which requires a syringe and refrigeration.

In other vaccine-related research, a study published online in Science Translational Medicine  in January 2013 found that three injections of a vaccine developed  with inactivated, virus-infected, monocyte-derived dendritic cells from the patients themselves significantly reduced viral load for up to 12 weeks in 55% of participants (12/22), and for up to 24 weeks in 35% (7/20). In the control group, which received unmodified dendritic cells, just one of 12 experienced a viral load reduction at 12 weeks, and none at 24 weeks. There were minimal adverse effects.

However, the researchers noted, patients stopped taking their ART for several weeks prior to the collection of the cells, which could have allowed the virus to replicate during that period.

Hitting the virus with a cancer drug. Today’s arsenal of anti-retroviral therapies is powerful and can drive the virus into hiding, but with few exceptions the virus remains, requiring that patients remain on ART for the rest of their lives. A study published in the December 2012 issue of the Journal of Leukocyte Biologyevaluated the potential of the bromodomain inhibitor JQ1, currently under investigation as a cancer drug, in HIV. The compound targets bromodomain-containing 4 (BRD4), a negative regulator of HIV replication. The experiment showed that the drug rooted out latent HIV and reactivated the virus, which could then allow traditional ART to eradicate it. Although this was an in vitro study, the authors of an editorial [http://www.jleukbio.org/content/92/6/1127] in the same journal wrote that it “may very well open up new approaches for reactivating latent HIV-1 and ultimately curing the infection.”

Delivering a preventive drug vaginally. High rates of nonadherence with oral medications, particularly for drugs designed to prevent rather than treat chronic medical conditions like HIV, is common. This is one major concern with tenofovir (TVF), approved last year to prevent HIV in high-risk individuals. However, TVF is also the only topical prophylactic shown to prevent sexual transmission of the virus. In October, researchers announced at the 2012 American Association of Pharmaceutical Scientists  meeting that a 90-day vaginal ring can deliver the drug in gel form safely and effectively. Unlike vaginal rings used to deliver hormonally based drugs, this one can deliver water-soluble drugs such as TFV. The ring has only been tested in an animal model so far, but clinical trials are expected. In addition, the researchers developed a ring that can co-deliver TFV and the hormonal contraceptive levonorgestrel.

HIV-associated neurocognitive disorders (HAND). About half of HIV-infected individuals will eventually develop HAND. Researchers have long associated its development to viral-related damage because, given the inability of most ART to penetrate the brain/blood barrier, the brain is a key reservoir for the virus. However, in recent years a few drugs have been able to breach the barrier, including efavirenz (EFV). Now a study published in the December 2012 issue of the Journal of Pharmacology and Experimental Therapeutics  suggests that EFV, which several cognitive-related adverse effects, may also be to blame.

Researchers evaluated the effects of purified metabolizes of EFV and EFV itself on dendritic rat cells. All induced neuronal damage in a dose-dependent manner, they reported, with the 8-hydroxyefavirenz (OH)-EFV metabolite considerably more toxic than either EFV or the 7-OH-EFV metabolite.

The researchers also found that concentrations of EFV and 8-OH-EFV in the cerebral spinal fluid of 13 HIV-infected patients with dementia who were taking the drug were within the range that damaged the cells in vitro. "Some people do seem to have this attitude that HIV is no longer a death sentence," said the lead author in a press release. "But even with anti-retroviral treatments, people infected with HIV have shortened lifespans and the chance of cognitive decline is high. It's nothing you should treat lightly."

Other research, published in the February 2013 issue of The FASEB Journal,  highlights the disruptive effective of the virus on neurosteroids and its role in HAND. Researchers exposed human neurons to supernatants from HIV-infected macrophages and observed suppressed neurosteroid enzyme expression. However, treatment with the neurosteroid sulfated dehydroepiandrosterone (DHEA-S) reduced expression of inflammation-related genes and, when used in an animal model of HIV, increased CD4+ T cell levels. This prevented neurobehavioral deficits and neuronal loss, compared to a control group.