First man ‘functionally cured’ of HIV

Since HIV was discovered 30 years ago this week, 30 million people have died from the disease, and it continues to spread at the rate of 7,000 people per day globally, the UN says.
There's not much good news when it comes to this devastating virus. But that is perhaps why the story of the man scientists call the "Berlin patient" is so remarkable and has generated so much excitement among the HIV advocacy community.

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Scientists find gene that could help body cure itself of HIV

Scientists may have found a way for the body to cure itself of HIV.
In a series of tantalising experiments, they were able to harness the immune  system to such an extent that it defeated the virus and completely removed it  from the body.
While there have been advances in treating the condition, the virus’s  remarkable ability to outwit the immune system means that the recipe for a cure  has so far eluded even the world’s best scientists.
 

New hope: Scientists may have found a way to cure AIDS

 

The latest experiments were carried out in mice but the researchers believe  they raise the possibility of a cure, not only for HIV but for other long-term  infections, including hepatitis B and C and tuberculosis.
A lot of the work into finding a cure for these illnesses has focussed on  trying to use the immune system to gradually eliminate the virus or bacterium.
But the latest research, funded by the Australian and Canadian governments,  suggests that a short, sharp shock is far more effective.
Dr Marc (CORR) Pellegrini, of the Walter and Eliza Hall Institute  said:  ‘Viruses such as HIV and hepatitis B and C overwhelm the immune system, leading  to establishment of chronic infections that are lifelong and incurable.
‘Despite tremendous efforts, long-lived immune responses for some of these  viruses are ineffective, because the body is so overrun by virus that the  immune system just give up trying to battle the infection. 
‘Some people have coined the phrase “immune exhaustion” to explain the  phenomenon.
 

Breakthrough: the research centres on a gene called SOCS-3 which has a strong reaction to overwhelming infections (file photo)

 

‘Our approach is to discover some of the mechanisms that cause this immune  exhaustion, and manipulate host genes to see if we can boost the natural immune  response in order to beat infection.’
The breakthrough centres on a gene called SOCS-3.
When faced with an overwhelming infection such as HIV, the gene becomes highly  active and slams the brakes on the immune response, allowing the virus to  persist.
When the researchers boosted levels of a hormone called IL-7, the gene  ‘switched off’ and mice were able to gradually remove HIV from their bodies,  the journal Cell reports.
Dr Pellegrini said the research had provided ‘excellent ideas ‘for new  therapies that could target and boost host immune cells called T cells to fight  disease, rather than targeting the disease itself.
‘The findings could help to develop drugs that target some of these host  molecules, such as SOCS-3, and turn them off for very short, defined periods of  time to reinvigorate the T cells, allowing them to regroup to fight  infection,’  he said.
An estimated 86,500 Britons are living with HIV, including more than 21,000 who  are unaware of their infection.
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New Drug Strategy Shows Promise Against HIV

Experimental agent disrupts mechanism virus uses to enter cells, scientists say

 
WEDNESDAY, Dec. 22 (HealthDay News) -- Scientists are reporting early but promising results from a new drug that blocks HIV as it attempts to invade human cells.
The approach differs from most current antiretroviral therapy, which tries to limit the virus only after it has gained entry to cells.
The medication, called VIR-576 for now, is still in the early phases of development. But researchers say that if it is successful, it might also circumvent the drug resistance that can undermine standard therapy, according to a report published Dec. 22 in Science Translational Medicine.
The new approach is an attractive one for a number of reasons, said Dr. Michael Horberg, director of HIV/AIDS for Kaiser Permanente in Santa Clara, Calif.
"Theoretically it should have fewer side effects [and indeed had minimal adverse events in this study] and there's probably less of a chance of mutation in developing resistance to medication," said Horberg, who was not involved in the study.
Viruses replicate inside cells and scientists have long known that this is when they tend to mutate -- potentially developing new ways to resist drugs. "It's generally accepted that it's harder for a virus to mutate outside cell walls," Horberg explained.
The new drug focuses on HIV at this pre-invasion stage. "VIR-576 targets a part of the virus that is different from that targeted by all other HIV-1 inhibitors," explained study co-author Frank Kirchhoff, a professor at the Institute of Molecular Virology, University Hospital of Ulm in Ulm, Germany, who, along with several other researchers, holds a patent on the new medication.
The target is the gp41 fusion peptide of HIV, the "sticky" end of the virus's outer membrane, which "shoots like a 'harpoon'" into the body's cells, the authors said. The launch of this peptide is a first step in the virus's bid to inhabit host cells.
Although there are two other drugs on the market, maraviroc and T-20, which also prevent the virus from entering cells, they don't target fusion peptides. That makes this trial the first time that scientists have seen that fusion peptides are a worthwhile target in the fight against HIV/AIDS.
And given that fusion peptides also provide a point of entry for many other viruses, from measles to Ebola and hepatitis B and C, scientists theorize that the strategy could be turned against these illnesses as well.
The 18 patients with HIV in this small phase I/II trial took either 0.5, 1.5 or 5 grams of VIR-576 a day for 10 days via injection.
Those taking the highest dose saw a 95 percent reduction in their average viral load, the amount of HIV in the blood, without developing severe adverse effects.
"They were getting results that are similar to maraviroc and T-20 and certainly comparable to what's seen with intracellular drugs," Horberg said.
But the same factors that have limited the use of maraviroc and T-20 are also likely to get in the way here as well, namely the cost and the fact that they must be given by injection (because of the large size of the molecule), he warned.
The needle-vs-pill hurdle is something patients and doctors have to contend with in many settings, not just HIV, Horberg said. For example, "we all know that insulin works great [in diabetic patients] but the hard part is convincing patients to actually take it."
Hoping to get around the problem, the researchers are now searching for a smaller molecule to do the same job.
"The next big step is to use the structure of VIR-576 and its viral target (the fusion peptide) to generate small molecule inhibitors that act by the same mechanism but are orally available," Kirchhoff said. "We will start to test the first compounds next year, but how long it will take such drugs make it to the market is impossible to say."
"The bottom line is, yes, any time that you can find a new mechanism to attack the virus -- and certainly if you can prevent the virus from getting into the host cells -- that's a really good thing. But this isn't near prime-time," Horberg concluded.
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NIH-Led Scientists Find Antibodies that Prevent Most HIV Strains from Infecting Human Cells

Discovery to Advance HIV Vaccine Design, Antibody Therapy for Other Diseases
Scientists have discovered two potent human antibodies that can stop more than 90 percent of known global HIV strains from infecting human cells in the laboratory, and have demonstrated how one of these disease-fighting proteins accomplishes this feat. According to the scientists, these antibodies could be used to design improved HIV vaccines, or could be further developed to prevent or treat HIV infection. Moreover, the method used to find these antibodies could be applied to isolate therapeutic antibodies for other infectious diseases as well.

This image shows the atomic structure of the antibody VRC01 (blue and green) binding to HIV (grey and red). The precise site of VRC01-HIV binding (red) is a subset of the area of viral attachment to the primary immune cells HIV infects. View larger image Credit: NIAID VRC

“The discovery of these exceptionally broadly neutralizing antibodies to HIV and the structural analysis that explains how they work are exciting advances that will accelerate our efforts to find a preventive HIV vaccine for global use,” says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. “In addition, the technique the teams used to find the new antibodies represents a novel strategy that could be applied to vaccine design for many other infectious diseases.” Led by a team from the NIAID Vaccine Research Center (VRC), the scientists found two naturally occurring, powerful antibodies called VRC01 and VRC02 in an HIV infected individual's blood using a novel molecular device they developed that hones in on the specific cells that make antibodies against HIV. The device is an HIV protein that the scientists modified so it would react only with antibodies specific to the site where the virus binds to cells it infects.
The scientists found that VRC01 and VRC02 neutralize more HIV strains with greater overall strength than previously known antibodies to the virus.
The researchers also determined the atomic-level structure of VRC01 when it is attaching to HIV.  This has enabled the team to define how the antibody works and to precisely locate where it attaches to the virus. With this knowledge, they have begun to design components of a candidate vaccine that could teach the human immune system to make antibodies similar to VRC01 that might prevent infection by the vast majority of HIV strains worldwide. 
NIAID scientists Peter D. Kwong, Ph.D., John R. Mascola, M.D., and Gary J. Nabel, M.D., Ph.D., led the two research teams. A pair of articles about these findings appears today in the online edition of Science.
“We have used our knowledge of the structure of a virus—in this case, the outer surface of HIV—to refine molecular tools that pinpoint the vulnerable spot on the virus and guide us to antibodies that attach to this spot, blocking the virus from infecting cells,” explains Dr. Nabel, the VRC director.
Finding individual antibodies that can neutralize HIV strains anywhere in the world has been difficult because the virus continuously changes its surface proteins to evade recognition by the immune system. As a consequence of these changes, an enormous number of HIV variants exist worldwide. Even so, scientists have identified a few areas on HIV’s surface that remain nearly constant across all variants. One such area, located on the surface spikes used by HIV to attach to immune system cells and infect them, is called the CD4 binding site. VRC01 and VRC02 block HIV infection by attaching to the CD4 binding site, preventing the virus from latching onto immune cells. 
“The antibodies attach to a virtually unchanging part of the virus, and this explains why they can neutralize such an extraordinary range of HIV strains,” says Dr. Mascola, the deputy director of the VRC.
With these antibodies in hand, a team led by Dr. Kwong, chief of the structural biology section at the VRC, determined the atomic-level molecular structure of VRC01 when attached to the CD4 binding site. They then examined this structure in light of natural antibody development to ascertain the steps that would be needed to elicit a VRC01-like antibody through vaccination.
Antibody development begins with the mixing of genes into new combinations within the immune cells that make antibodies. Examination of the structure of VRC01 attached to HIV suggested that, from a genetic standpoint, the immune system likely could produce VRC01 precursors readily. The researchers also confirmed that VRC01 does not bind to human cells—a characteristic that might otherwise lead to its elimination during immune development, a natural mechanism the body employs to prevent autoimmune disease. 
In the final stage of antibody development, antibody-producing B cells recognize specific parts of a pathogen and then mutate, or mature, so the antibody can bind to the pathogen more firmly. VRC01 precursors do not bind tightly to HIV, but rather mature extensively into more powerfully neutralizing forms. This extensive antibody maturation presents a challenge for vaccine design. In their paper, Dr. Kwong and colleagues explore how this challenge might be addressed by designing vaccine components that could guide the immune system through this stepwise maturation process and facilitate the generation of a VRC01-like antibody from its precursors. The scientists currently are performing research to identify these components.
“The discoveries we have made may overcome the limitations that have long stymied antibody-based HIV vaccine design,” says Dr. Kwong.
The two research teams included NIAID scientists from the VRC, the Laboratory of Immunoregulation, and the Division of Clinical Research, all in Bethesda, Md.; as well as researchers from Beth Israel Deaconess Medical Center in Boston; Columbia University in New York; Harvard Medical School and Harvard School of Public Health in Boston; The Rockefeller University in New York City; and University of Washington in Seattle.

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References:
Wu X et al. Rational design of envelope surface identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science. DOI: 10.1126/science.1187659 (2010).

Zhou T et al. Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science. DOI: 10.1126/science.1192819 (2010).

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NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at www.niaid.nih.gov.
The National Institutes of Health (NIH)—The Nation's Medical Research Agency—includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov
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New Antibodies Found that Cripple HIV

New Antibodies Found that Cripple HIV
IAVI and affiliated researchers have discovered two powerful new antibodies to HIV that reveal what may be an Achilles heel on the virus. The findings are the result of a worldwide effort launched by IAVI in 2006 to find new antibodies that neutralize a wide variety of strains of HIV circulating in the world. The study was published in the journal Science.

HIV, the virus that causes AIDS, is the most mutable pathogen ever encountered by modern science. It changes at a furious rate, which helps it evade the body’s immune system. Today, countless variations of the virus infect people around the world. To be effective an AIDS vaccine would have to work against many versions of HIV.
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