A collaborative team led by a Northeastern University professor may have altered the way we look at drug development for

HIV by uncovering some unusual properties of a human protein called APOBEC3G (A3G). In an article published in Nature Chemistry, Prof. Mark Williams and his graduate student Kathy Chaurasiya, along with several collaborators, show how these unusual properties help us to fight HIV infection. APOBEC3G It is well known that in response to virus infection, the body makes specific antibodies to counteract the infection. However, we are also born with another way to fight infection, namely through the action of defense proteins that are always present in our system. These proteins provide the first line of defense against invading pathogens. For example, we are all potentially protected against HIV because we have an antiviral protein called A3G. However, HIV has evolved a strategy to circumvent the activity of this protein by tricking our cells into destroying our own A3G proteins. This is where Prof. Williams's research comes into play. A MULTI-FUNCTIONAL PROTEIN A3G moves along a DNA strand as part of its function as an enzyme, and when it reaches a particular one of the four bases in DNA, it chemically alters the DNA, causing HIV to mutate. This was originally thought to be the only way A3G blocks HIV infection. However, some researchers found that even when A3G could not chemically alter the DNA, it still inhibited HIV. To explain this, Prof. Williams's collaborator Dr. Judith Levin from NIH, together with postdoctoral fellow Dr. Yasumasa Iwatani, proposed that A3G forms a roadblock that prevents the virus from making a DNA copy of its genome, thereby stopping HIV replication. This would require A3G to be more slowacting, yet because the protein normally has to move fast to perform its chemical function, there seemed to be an apparent contradiction in the experimental results. Professor Williams' research resolves this paradox and shows that the A3G protein does not always have the rapid movement needed for chemical function. Instead, its activity changes over time. "First, A3G is a really fast protein," said Williams. "Then, gradually over time, it becomes a slow protein and remains bound to the DNA, blocking replication." CHALLENGING POPULAR OPINION Many researchers doubted that a protein could have both enzyme and roadblock functions. An enzyme is designed to act rapidly, so the idea of the A3G protein starting off fast, and then gradually slowing down seemed physically impossible. Professor Williams' collaborator Dr. Ioulia Rouzina from the University of Minnesota came up with the novel idea that when A3G proteins group together, they become slower over time. To test the idea, the Williams lab used an instrument called optical tweezers that allowed them to stretch single DNA molecules with A3G proteins bound. By measuring the change in DNA length over time as the proteins came on and off the DNA, they could show that the rates at which A3G bound to DNA became slower over time.

How does this happen? It was already known that A3G proteins bind to each other and form a multiprotein complex. "Once the complex is formed, the A3G proteins are no longer able to move rapidly along the DNA strand as needed for chemical modification of the DNA," said Williams. "This suggests that slow binding can also block HIV replication." IMPACT ON HIV RESEARCH The A3G protein has at least two mechanisms by which it can block HIV replication. We have known for over 10 years that A3G can, in principle, provide protection from HIV. However, finding a drug that can counter the anti-A3G activity of the virus has been elusive. This new work has the potential to develop alternative approaches to HIV therapy and development of drugs that can enhance the roadblock activity of A3G. This provides an alternate pathway for drug development that has not previously been pursued.

New research suggests that multivitamin supplements taken long-term, alongside a micronutrient called selenium, delay HIV progression in patients with early stages of the disease and reduce the risk of immune decline and illness. This is according to a study published in JAMA. Primary Care Guidelines for the Management of Persons Infected with Human Immunodeficiency Virus," an update on HIVMA's 2009 guidelines, will appear in print in January in Clinical Infectious Diseases. Reflecting changes in the HIV landscape, the guidelines note patients whose HIV is under control should have their blood monitored for levels of the virus every six to 12 months, rather than every three to four months as previously recommended. People with HIV are at increased risk for common health conditions, such as high cholesterol and triglycerides, due to the infection itself, ART or traditional risk factors such as smoking and eating unhealthy foods, and doctors must be vigilant about monitoring those levels. The guidelines include new recommendations for screening for diabetes, osteoporosis and colon cancer, and suggest patients with HIV infection should be vaccinated against pneumococcal infection, influenza, varicella and hepatitis A and B. A table outlining interactions between specific antiretrovirals and statins (the medications commonly used for lipid management) is also included. There also is a more robust section onsexually transmitted diseases, including a recommendation for annual screening of trichomoniasis in women and yearly screening for gonorrhea and chlamydia for all who may be at risk. The guidelines authors note that doctors should consistently discuss and counsel patients on their sexual history (current and past) and any risky behaviors, such as the use of illicit drugs, in a nonjudgmental manner and determine how patients are coping with living with HIV infection and if they have a sufficient support network.

Gilead Sciences, Inc. (Nasdaq: GILD) has announced results from a Phase 3 study, PHOTON-1, evaluating the investigational once-daily nucleotide analogue inhibitor sofosbuvir for the treatment of chronic hepatitis C virus (HCV) infection among patients co-infected with HIV. In the trial, 76 percent (n=87/114) of genotype 1 HCV treatment-nave patients receiving 24 weeks of an all-oral, interferon-free regimen of sofosbuvir plus ribavirin (RBV) achieved a sustained virologic response 12 weeks after completing therapy (SVR12). Patients who achieve SVR12 are considered cured of HCV infection.

Mutant protein discovered that blocks HIV infection and transmission

A mutant of an immune cell protein called ADAP (adhesion and degranulation-promoting adaptor protein) is able to block infection by HIV-1 (human immunodeficiency virus 1), new University of Cambridge research reveals. The researchers, who were funded by the Wellcome Trust, believe that their discovery will lead to new ways of combating HIV. Professor Chris Rudd from the Department of Pathology, who led the research, said: "One exciting aspect about this new target for HIV intervention is that we should be able to fight HIV without compromising the immune system's ability to battle infections." HIV infections cause a severe and selective depletion of T-cells, a type of white blood cell that plays a major role in the immune system. Infections result when the HIV virus enters T-cells of the immune system by binding to the surface receptor CD4. Once it enters the cell, it replicates or reproduces itself rapidly, and then spreads to other T-cells by releasing the virus. This spread can occur between an infected T-cell and an uninfected attached T-cell. The researchers found that an ADAP mutant is able to interfere with HIV-1 infection by targeting two events, by reducing the replication of the virus, and the contact between infected and uninfected T-cells. Professor Rudd added: "The ADAP mutant is potent in its interference of HIV-1 transmission because it targets simultaneously two critical events, viral replication and the spread of the virus from one T-cell to another. One therapeutic possibility is the reconstitution of infected individuals with T-cells expressing the mutant that are relatively resistant to HIV infection and which can react against the virus." According the World Health Organisation, there are currently 35.3 million people living with HIV. Although the number of new HIV infections has dropped, it remains a major global public health issue. In the past three decades, it has killed more than 25 million people