Immune response to HIV differs, even in identical twins, discovered
A study, published in the Journal of Virology, showed that the body's defenses against the virus are random rather than genetically determined.
The researchers followed the cases of male twins who were infected shortly after their 1983 births in Los Angeles by blood transfusions administered from the same donor at the same time. Infected with the same strain of the virus, the twins continue to live in the Los Angeles area and grew up exposed to the same environmental forces.
Yet their T-cell receptors ( TCR ) reacted differently in each twin, showing that the body's defense response was random--and unpredictable.
TCRs play an important role in the immune system by binding viruses and other antigens to receptors on their surface, killing the invader. HIV escapes this action by changing shape so that it does not fit into those receptors.
" These boys are as similar as two humans can be, yet we see differences in how they fight the virus," said Paul Krogstad, one of the researchers. " That's one more thing that makes it difficult to develop a vaccine for everyone."
When a virus invades a body, the cellular immune response targets small parts of proteins in the virus. This targeting mechanism itself is genetically determined. ". The virus tries to escape that immune response by mutating and changing shape.
The twins' targeting of the HIV was remarkably similar 17 years after infection yet their overall TCR characteristics were highly divergent. The finding, demonstrates that the interaction between their immune systems and the virus was random and unpredictable--indicating that a "one size fits all" vaccine may not be possible.
" If the goal is to develop a vaccine, our findings suggest this may not be so straightforward," said Otto Yang, at UCLA, and the study's lead researcher.
According to the UCLA researchers, the results of this study have broader implications, and could apply to other viruses such as cytomegalovirus ( CMV ), a herpes virus that causes opportunistic infections in immunosuppressed individuals, and hepatitis C, the latter being similar to HIV in both its changeable and chronic nature.
TRAF3 protein is a key part of the early immune response to viruses
A protein called TRAF3, with a previously unknown job in immune cells, is actually a key part of a mechanism that triggers release of anti-virus molecules called type I Interferons ( IFNs ) as part of the body's rapid response against these invaders.
The discovery of TRAF3's role helps to explain how immune cells called macrophages use sensing devices called Toll-like receptors ( TLRs ) to orchestrate just the right response to different types of infections.
TLRs are on the outer membranes of macrophages and respond to germs by triggering the production of proteins called cytokines.
Various cytokines regulate different biological functions that are important during immune responses, such as inflammation and protection against viruses. In addition, some cytokines contain anti-inflammatory activities, which curb potentially harmful inflammation.
The researchers showed that TRAF3 is not only essential for production of type I Interferons, but also for production of IL-10, a protein that prevents inflammation.
In fact, the team showed that cells lacking the gene for TRAF3 can't produce IL-10 and instead over-produce proteins that cause inflammation.
A report on these results appears in the Nature.
" The discovery that TRAF3 is also recruited to Toll-like receptors was important," says Hans Haecker, the first author of the paper and at the St. Jude Department of Infectious Diseases. " It filled in an important piece of the puzzle of the front-line immune response to viruses that we didn't even realize was missing. Further research using this simple system will help solve the mystery of how macrophages can pick and choose among different strategies for combating specific infections." Haecker was at the Technical University of Munich and the University of California, San Diego, when he worked on this project.
Researchers already knew that TLRs use proteins called adapters to help them recruit small armies of signaling molecules that trigger the right response by the immune cell to invaders, such as viruses.
They also knew that a protein called MyD88 was one of the adaptors that help to recruit these armies; and that one of the first proteins in the signaling army recruited to MyD88 was the protein TRAF6. But what was unclear was the exact series of steps that occurred during the recruitment of the full army of signaling molecules by TLRs.
Therefore, the team developed a novel strategy to study how TLRs recruit their armies of signaling molecules.
The team inserted into macrophages an artificial gene that coded for the TLR adaptor MyD88 fused to a molecule called gyrase B.
In the presence of a drug called Coumermycin, gyrase B, these molecules bind together in pairs. This 'pair forming' activity of gyrase B triggered a similar formation of pairs of the MyD88 molecules that were fused to gyrase B.
This reaction, which produced pairs of MyD88-gyrase B complexes, then triggers recruitment of the rest of the army of proteins that form the macrophages's signaling pathway, according to Haecker.
During these studies the researchers discovered that TRAF3 as well as TRAF6 is recruited to such adaptors.
In addition to demonstrating that TRAF3 was recruited by MyD88 to generate type I Interferons, the researchers showed that TRAF3 can be recruited by another important adaptor, called TRIF, which is used by some TLRs. This demonstrated that TRAF3 has a general role in controlling the TLR-dependent type I Interferon and IL-10 response.
Results of the study suggest that the specific type of immune response triggered by TLR signaling depends on the relative amounts of TRAF6 and TRAF3 initially recruited, and the different signaling proteins each of those proteins subsequently recruit to the growing army.
The TLR system is part of the body's innate immune response. Innate immunity is a primitive type of defense that does not use antibodies. Instead, immune cells that are part of innate immunity act as an early-warning system that attempts to stop infections quickly so that the other, more complex immune responses don't have to be called into play.
HIV inserts into human genome using LEDGF, a DNA-associated protein
A study from researchers at the University of Pennsylvania School of Medicine, has shown that a human DNA-associated protein called LEDGF is the first molecule found to control the location of HIV integration in human cells.
This study, published in the journal Nature Medicine, describes the first clear target for modulating where viruses insert into the human genome, which has implications for better design of gene-therapy delivery. Retroviral vectors are often used to introduce therapeutic genetic sequences into human chromosomes, such as in the delivery of Factor VIII for hemophilia patients.
HIV integrates into active transcription units on chromosomes within the nucleus of human cells. These units are sites that lead to efficient expression of the viral genome. Most HIV-infected cells in a patient will have a very short life span, a day or less. " We surmise that this strategy helps the virus make hay while the sun is shining, as it were, producing lots of viral copies during a short time, so that the virus can maximize production of daughter virions," says Frederic Bushman, at Penn.
This study demonstrates the first piece of a mechanism that dictates where HIV integration takes place. Previous studies at other institutions showed that LEDGF binds tightly to HIV integrase, the enzyme that's important for the integration reaction. Now, Penn researchers showed in this study that the way LEDGF binds to HIV integrase and to specific sites on chromosomes suggests that HIV targets integration using a molecular tether.
Retroviruses contain RNA in their particles. They enter a cell and convert RNA into DNA by the enzyme reverse transcriptase and then integrate that DNA copy into the DNA of the host, using the integrase enzyme. The new viral particles are made by transcription of the viral genome, as with any cellular genes. If the cell divides, the viral DNA is copied and inherited, along with cellular human genes.
Bushman and his team made cells that were depleted of LEDGF and found that integration was less frequent in transcription units and in genes regulated by LEDGF. " This implies that LEDGF is part of the machinery that helps dictate the placement of retroviral integration sites within chromosomes," says Bushman.
Bushman notes that finding that LEDGF is part of the cellular apparatus necessary for HIV replication is important to the field of gene therapy. Controlling where gene-therapy vehicles insert in the human genome could help make the delivery of new therapeutic sequences safer. The new findings about LEDGF suggest that engineered tethering interactions might some day allow control over integration site selection during gene therapy. According to Bushman, this finding is of particular importance in light of recent cases where integration of gene-therapy vectors near cancer genes contributed to the development of leukemia in gene-therapy patients.
Children with HIV-infection benefit from zinc supplements
A trial, published in The Lancet, found that Zinc supplements are a safe, simple, and cost-effective method of reducing illness in children infected with HIV.
Previous studies have shown that Zinc supplements can reduce the incidence of diarrhoea and pneumonia in children in resource-poor settings.
However, the HIV virus requires zinc for its structure and function, and zinc activates lymphocytes that are target cells for HIV-1 replication.
For these reasons the safety of Zinc supplementation in children with HIV-infection has been uncertain.
To study the affect of Zinc supplementation, William Moss, at the Johns Hopkins School of Public Health, Baltimore, and colleagues recruited 96 children, aged between 6 months and 5 years, from Grey's Hospital in Pietermaritzburg, South Africa.
The team randomly assigned children to receive Zinc supplements or a placebo daily for 6 months.
The investigators found that Zinc supplementation did not result in an increase in blood HIV viral load. However, children receiving Zinc had less diarrhoea. The authors state that Zinc supplementation should be used as an adjunct therapy for children with HIV-1 infection.
Moss states: " Few interventions are available to reduce morbidity in children with HIV-1 infection in resource-poor countries. Although UNAIDS, WHO, and their partners are committed to providing antiretroviral therapy to 3 million people by the end of 2005, antiretroviral therapy and prophylaxis for opportunistic infections are not accessible for many children. Consequently, more than half these children die before the age of 3 years, most commonly of respiratory tract infections and diarrhoeal diseases…Zinc supplementation could be a simple and cost-effective intervention to reduce morbidity and mortality in children with HIV-1 infection…Programmes to enhance Zinc intake in deficient populations with a high prevalence of HIV-1 infection can be implemented without concern for adverse effects on virus replication."
Mother-to-child transmission of HIV
Without intervention, between 25% and 35% of the children born to HIV-positive mothers will themselves be infected. In about 50% of the cases, transmission from mother to child occurs during labor and delivery.
Researchers don't yet understand how exactly that transmission happens, but they have found that some treatments can prevent most cases. However, to many HIV-positive pregnant women in developing countries, these treatments are not available or acceptable.
A study by Jesse Kwiek and colleagues of the University of North Carolina, published in the journal PLoS Medicine, implicates placental microtransfusions in HIV transmission.
Placental microtransfusions cause exchanges of small amounts of blood between the mother and the baby.
They occur in most pregnancies once labor starts, because the contractions cause small areas of rupture in the placenta. However, the overall amount of blood exchanged differs from delivery to delivery.
Until recently, it was not possible to measure the extent of these microtransfusions for a particular delivery, but now researchers have developed an assay based on umbilical cord blood that can do this. In this study, the researchers made use of this new assay to ask whether there is a link between the extent of placental microtransfusions and the likelihood of HIV transmission
Kwiek and colleagues studied a group of mothers and children in Malawi.
All of the mothers were HIV-positive, and some of them transmitted the virus to their children.
This transmission occurred either during the pregnancy or around delivery, and the researchers knew the timing for each case.
They also knew how the children were born: approximately three quarters by vaginal delivery and one fifth by emergency caesarean section.
The researchers determined the level of placental microtransfusions from the umbilical cord blood and then looked for correlations between HIV transmission and the level of microtransfusions.
They found no correlation for the cases where HIV was transmitted during pregnancy. For cases of transmission around delivery, however, higher levels of microtransfusions were associated with a higher risk of HIV transmission for vaginal deliveries.
If a connection between microtransfusions and transmission is confirmed by other studies, it might help to improve the timing of short-term prophylaxis regimens and possibly lead to the development of new strategies for preventing mother-to-child transmission of HIV.