World AIDS day - like other days dedicated to the awareness of certain diseases - brought a flurry of attention from political world.

In a joint statement released to the press, National Institute of Health officials Elias Zerhouni, Jack Whitescarver and Anthony Fauci (Fauci won this year's Lasker Award for Public Service "for his role in developing two major U.S. public health programs, in AIDS and biodefense") cite the grim numbers: More than 25 million dead, an estimated 33.2 million infected globally, with 2.5 million new infections and 2.1 million AIDS deaths last year.

But they also "applaud the heroic efforts of researchers and clinical trial participants who have devoted their time and energy to helping us find effective ways to prevent HIV/AIDS and [develop] new treatments to help those already infected."

In his own remarks, President Bush also tried to strike a positive note: "We mark this day with hope - for improving prospects of those living with the virus . . . for the unprecedented number of infections being prevented, and for new progress toward eradicating this disease," he said speaking at a Maryland church.

Meanwhile, recent advances in the basic science of HIV have moved hope and progress along as they usually do in the trenches: more continuously, but one small step at a time.

Knocking Down Syndecan-3 Can Prevent Transmission

One of those advances involves the use of microbicides, which have several advantages for use in the developing world, and their biggest advantages may not be medical. Their use can be controlled by women themselves, who control little else about their sexuality in many parts of the world.

HIV is thought to muscle its way into T cells, where it replicates, via dendritic cells that take up the virus at the body's mucosal surfaces. One protein long implicated in this process is DC-SIGN, which does not lead directly to HIV entry into cells - that job goes to two other receptors - but does bind the virus, helping it to reach a position where it can infect them.

In a paper to be published in the Dec 4, 2007, issue of the Proceedings of the National Academy of Sciences, researchers identify a second protein on dendritic cells that HIV can use to hijack those cells: a proteoglycan, or protein with a sugar molecule attached, known as syndecan-3.

In their paper, the scientists first identified syndecan-3 as a possible entry molecule for HIV and showed that it binds HIV and that such binding increases the infection of dendritic cells by HIV.

Either knocking down syndecan-3 via inhibitory RNA or removing it from dendritic cells with an enzyme-reduced HIV transmission, and getting rid of both syndecan-3 and DC-SIGN completely abolished the capture of HIV by dendritic cells and its subsequent transmission to T cells. The researchers concluded that "HIV-1 exploits both syndecan-3 and DC-SIGN to mediate HIV-1 transmission, and an effective microbicide should target both syndecan-3 and DC-SIGN on [dendritic cells] to prevent transmission."

CTLA-4 Receptors In Disease Progression

HIV's infection of T cells makes it especially devastating to the immune system. But T cells frequently show impaired function in chronic viral infections. In the November issue of Nature Immunology, researchers explored the mechanisms behind this weakening.

In their paper, the researchers described experiments showing that the inhibitory T-cell receptor CTLA-4 is up-regulated in HIV-specific helper T cells from patients with both acute and chronic HIV infection. Expression levels of CTLA-4 receptors increased as the disease progressed and were reversed only partly by highly active antiretroviral therapy.

Interestingly, when the researchers tested samples from HIV patients able to control the virus without highly active antiretroviral therapy - so-called "elite controllers," a rare patient type, but one that does exist - their helper T cells showed low levels of CTLA-4 receptors.

However, the interactions with PD-1, another co-stimulatory molecule, were what the authors termed "complex." Though helper T cells from most patients were correlated in how much PD-1 and CTLA-4 they expressed, the degree of co-expression varied widely between patients, and CD4 cells from "elite controllers" were more inconsistent in the relationship between PD-1 and CTLA-4 than those from more typical patients.

Perhaps mindful of unpleasant surprises other scientists have had when trying to harness co-stimulation, the authors are quite cautious in their conclusions. They wrote that their "results emphasize the need for cautious investigation of the CTLA-4 and PD-1 pathways in different in vitro and in vivo experimental systems as preparation for possible interventional studies in human subjects."

They nevertheless seem to believe that such interventional studies could pay off. According to the conflict-of-interest statement accompanying the article, co-author Gordon Freeman "has patents and patent application for CTLA-4, PD-1 and PD-1 ligands and their use to modulate immune responses."

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