HIV's lair

HIV researchers may be looking in all the wrong places. Whereas most human studies examine immune cells in the blood, studies more than 6 years ago in simian immunodeficiency virus (SIV)-infected macaques showed that immune cells in the intestine take the brunt of SIV infection. Saurabh Mehandru et al. and Jason Brenchley et al. now report that this is also the case in humans, finding that HIV infection severely depletes CD4+ T cells in the intestine at all stages of infection.

CD4+ T cells (red) in a healthy intestine Credit: Reprinted with permission of J. Exp. Med.

Two factors have been invoked to explain the depletion of these cells in macaques: most CD4+ T cells in the intestine express the HIV coreceptor CCR5 and they are highly activated because of exposure to environmental antigens. These cells might support high levels of HIV replication because of high rates of transcription.

To extend the macaque findings to humans, researchers had to obtain consent for intestinal biopsies and were able to catch a rare glimpse of infection in several patients within weeks of HIV infection.

The investigators report in the September 20 Journal of Experimental Medicine (200, 749–459, 761–770) that intestinal CD4+ T-cell depletion surged during the first stages of infection. In contrast with a previous study on one patient, the CD4+ T-cell count in the intestine did not bounce back with highly active antiretroviral therapy (HAART) treatment, suggesting that that this deficit may not be as readily reversed with antiretroviral treatment as abnormalities in the peripheral blood.

The biological consequences of early depletion of CD4+ T cells in the intestine are unclear. But the researchers point out that constant killing of effector cells could prompt continual replacement and eventually deplete the source, CD4+ T-cell clones in the mucosa. Such depletion could accelerate the decline of the immune system.

Efforts to specifically inhibit T-cell activation in the gastrointestinal tract, as well as drugs to interfere with HIV entry, could help clear the virus, say the researchers. Only 2–5% of lymphocytes reside in the peripheral blood; most are in the gastrointestinal tract.

Fish fix

About half of the dry weight of the brain is lipid. One such lipid, docosahexanoic acid (DHA), is present in high levels in fish and seems to protect against Alzheimer disease in epidemiological studies. In the 2 September Neuron (43, 633–645) Frédéric Calon et al. test this omega-3 fatty acid in a transgenic mouse model of Alzheimer disease. At 17 months—middle-age in mouse years—DHA in the animals' diet was sharply curtailed. The DHA-deprived transgenic mice, when compared with their well-fed siblings, had poorer memory, lower levels of DHA in their brains and more neuronal damage. DHA mediates its protective effects, at least in part, by maintaining signaling of the phosphatidyl inositol-3 (PI3) kinase pathway. Among other tasks, PI3 kinase signals to Akt and keeps a lid on caspases, death-promoting enzymes. Caspases were overactive in the brains of DHA-depleted mice, and seemed to promote damage in postsynaptic structures. Omega-3 fatty acids are particularly vulnerable to oxidative damage, a hazard in the Alzheimer-affected brain.

Asthma edges ahead

In patients with asthma, the number of eosinophils in the airway is directly associated with disease severity. These cells spew cell toxins and substances that contract the airways. But the role of these cells in asthma is controversial—for instance, antibody to IL-5, which depletes eosinophils, has not eased symptoms of asthma in clinical trials. Now two research groups, using different methods, eradicate these cells in mice. The work, in the 17 September Science, shows that eosinophils indeed contribute to asthma—but the studies also raise yet more controversy.

Alison Humbles et al. (305, 1776–1779) created mice with a targeted deletion in the promoter of GATA-1, and so interfered with eosinophil development. These mice, when provoked to have asthma attacks, accumulated mucus and had hypersensitive airways. But they were largely spared another aspect of asthma, airway remodeling. That outcome is similar to the results seen in humans treated with antibody to IL-5. James Lee et al. (305, 1773–1776) expressed a toxin from a promoter active in eosinophils, killing these cells. But, in contrast to Humbles et al., they found that the mice were protected from airway hyperresponsiveness.

The research groups used two different strains of mice, note Marsha Wills-Karp and Christopher Karp in an accompanying Perspective. The researchers should now test each approach in both strains, they suggest.

Cancer's weak moment

Life is stressful for a cell in a solid tumor, where nutrient and oxygen fluctuations and confusing signals to survive and proliferate all seem to put on the pressure. To counteract stress, tumor cells turn on chaperone proteins that are part of the 'unfolded protein response' and that ease the folding of proteins and other vital functions. In the September Cancer Cell (6, 275–284), Marco Arap et al. take advantage of stressed out cancer cells. The investigators killed tumors by targeting GRP78, a component of the unfolded protein response that is expressed on the surface of tumor cells. After designing peptides that bound particularly tightly to GRP78, the investigators hooked the peptides to a cell death–inducing sequence. The researchers found that this chimeric peptide could suppress growth of mouse tumors and human prostate and breast tumors grafted into mice.

Mitochondria's secret weapon

The identity of a major source of dangerous reactive oxygen species in mitochondria has been disclosed. In the September 8 Journal of Neuroscience, Laszlo Tretter et al. (24, 7771–7778) and Anatoly Starkov et al. (24, 7779–7788) incriminate the Krebs cycle enzyme α-ketoglutarate dehydrogenase (α-KGDH). The results could lead to insight into how reactive oxygen species contribute to damage in conditions ranging from Parkinson disease to atherosclerosis.

Researchers have long known that impairing the ATP-generating respiratory chain complexes in the mitochondria contributes to formation of reactive oxygen species. But it was clear that there also were other sources. The investigators pinned down α-KGDH by several means—showing, for instance, that the isolated enzyme could produce H2O2. The amount of H2O2 produced hinges on the ratio of NADH to NAD+. When NADH levels are high, the enzyme favors production of H2O2 instead of NADH. The researchers invoke a deadly cycle: damage to the respiratory chain—by H2O2, for instance—increases the NADH/NAD+ ratio, and could prompt α-KGDH to produce more H2O2.

Written by Charlotte Schubert