Much like a drug can be truly dead or "biotech dead," there's a question as to whether viruses are actually alive. Unable to replicate by themselves, they co-opt the machinery of the cells they infect for their nefarious aims.

But HIV takes this principle one step further; according to a paper in the Sept 30, 2007 early online edition of Nature Medicine, it also co-opts the cell's machinery for not replicating.

Such nonreplication is the main reason HIV cannot be eradicated. Highly active antiretroviral therapy, or HAART, has been a triumph of Western medicine, turning what was a universally fatal disease in the 1980s into a chronic illness. HAART, which consists of a combination treatment of three to four different drugs, can keep viral load in the blood at undetectable levels, allowing HIV-infected individuals to keep going indefinitely.

Or at least as long as they stay on HAART. The treatment does not actually eradicate the virus, but instead drives it into what's known as latency. "The virus is hiding in the T cell, and so . . . the antiviral drugs cannot cure the infection," Hui Zhang, associate professor of medicine at Thomas Jefferson University's Jefferson Medical College, told BioWorld Today.

The virus can survive years of antiretroviral therapy that way, biding its time. But "once you stop HAART, the virus will come out and replicate again," Zhang explained. Latent infection, he added, has become "the biggest headache" in HIV treatment.

In the Nature Medicine paper, senior author Zhang and his colleagues from Thomas Jefferson University and Sun Yatsen University in Guangzhou, China, described a new mechanism by which HIV manages to lie low, as well as "a new way to drive it out of hiding."

The scientists wanted to test whether microRNA is one of the many cellular that HIV co-opts for its own purposes, and first used computational approaches to predict where cellular miRNA might bind to HIV. They identified five miRNAs that were enriched in resting, as opposed to activated, helper T cells and potentially could bind to HIV sequences.

The five suspect gene sequences were then engineered onto a marker protein, and the scientists tested whether microRNAs could inhibit expression of the engineered marker protein. They found that the miRNAs inhibited protein production in resting, but not in activated, T cells. Further experiments confirmed that the same was true for actual HIV.

When the researchers used antisense technology to prevent the miRNAs from inhibiting HIV, they found that while each individual miRNA had little effect, inhibiting all five in combination led to a more than tenfold increase in HIV protein levels.

HIV messenger RNA levels were not significantly affected, suggesting that the miRNA normally inhibits translation of proteins from mRNA.

The scientists note in their paper that the miRNA-binding sequences they identified are concentrated on an untranslated region of the HIV genome that is part of almost all HIV messenger RNA. For that reason, the miRNAs that bind them "can inhibit the translation of almost all HIV-1-encoded proteins - including Tat and Rev, which are key in the transcription and translocation of viral RNA."

The work suggests that such inhibiting of the miRNA could be used to bring HIV out of latency, allowing the immune system to deal with it.

"By using an inhibitor, we can induce the cell to produce [HIV], and the immune system will recognize and kill it," Zhang said. "That is the therapeutic use for this mechanism."