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Early-stage immune system control of HIV may depend on inherited factors
November 06, 2006Findings may provide important clues for vaccine development
How well an individual's immune system controls HIV during the earliest phases of infection appears to depend on both the specific versions of key immune-system molecules called HLA Class I that have been inherited, as well as on the fragments of viral protein those molecules display to the T lymphocytes that usually destroy infected cells. In a report in the November issue of PLOS Medicine, researchers from the Partners AIDS Research Center at Massachusetts General Hospital (PARC/MGH) report that specific HLA Class I/HIV viral fragment combinations are associated with a more powerful antiviral response, findings that may help develop vaccines against HIV.
"We found that only a limited number of viral protein fragments from HIV-1 are targeted by the immune system in early infection and that the versions of HLA Class I previously associated with slower HIV-1 disease progression also contribute more to this initial antiviral immune response," says Marcus Altfeld, MD, PhD, of PARC/MGH, the paper's lead author.
An essential aspect of the immune response involves educating T cells to recognize pathogens or other "non-self" proteins. This is done by means of human leukocyte antigen (HLA) receptors that sit on the surface of virtually every cell. Immune system cells that ingest bacteria or parasites digest those pathogens and display protein fragments on their surface membranes via HLA Class II proteins. Virally infected cells display viral proteins on HLA Class I molecules, which activate the CD8 cytotoxic T lymphocytes that usually destroy infected cells. Although the CD8 response against HIV is ultimately ineffective in protecting infection, several studies have suggested that it plays a key role in determining how quickly the disease progresses after initial infection.
HLA - also called major histocompatibility complex (MHC) - proteins are also the primary markers of tissues as "self." Unique to each individual, these are the factors that need to be matched as closely as possible in organ transplants, with perfect matches only possible between identical twins. Some studies have found that HIV patients with particular versions of HLA may be better able to control viral levels, but the diversity of HLA molecules - each person may have up to six different varieties of Class I proteins - has made investigating the role of HLA type in HIV infection challenging.
The current study was designed to determine the contribution of both HLA Class I and the particular viral fragments displayed on those molecules to the activation of HIV-specific CD8 cells. The researchers analyzed blood samples from more than 100 people recently infected with HIV, first determining their specific HLA types by DNA analysis. Then they focused on 173 HIV protein fragments known to bind to those HLA types to see if particular peptides were more powerful in activating the HIV-specific CD8 response.
The researchers found that, for many varieties of HLA, only a few HIV protein fragments were responsible for the activation of CD8 T cells early in infection. In addition, the same HLA types that had been previously identified in people who stay healthy for a longer period of time after initial infection were associated with a more powerful early-stage HIV-specific CD8 activity.
"While we can't say this for sure right now, it is looking like both the HLA Class I molecule and the specific viral sequences being displayed contribute to the strength of immune response against primary HIV infection," says Altfeld. "In addition, the combination of Class I molecules that an individual expresses, something that is genetically determined, seems to have a significant impact on the specificity and strength of that response.
"Identifying the HIV epitopes [viral fragments] that are particularly good at priming an early T cell response may be important to vaccine design, and the impact of an individual's genetic HLA Class I background implies that a successful vaccine would have to overcome genetic factors associated with a less protective response,\\\
Massachusetts General Hospital
An essential aspect of the immune response involves educating T cells to recognize pathogens or other "non-self" proteins. This is done by means of human leukocyte antigen (HLA) receptors that sit on the surface of virtually every cell. Immune system cells that ingest bacteria or parasites digest those pathogens and display protein fragments on their surface membranes via HLA Class II proteins. Virally infected cells display viral proteins on HLA Class I molecules, which activate the CD8 cytotoxic T lymphocytes that usually destroy infected cells. Although the CD8 response against HIV is ultimately ineffective in protecting infection, several studies have suggested that it plays a key role in determining how quickly the disease progresses after initial infection.
HLA - also called major histocompatibility complex (MHC) - proteins are also the primary markers of tissues as "self." Unique to each individual, these are the factors that need to be matched as closely as possible in organ transplants, with perfect matches only possible between identical twins. Some studies have found that HIV patients with particular versions of HLA may be better able to control viral levels, but the diversity of HLA molecules - each person may have up to six different varieties of Class I proteins - has made investigating the role of HLA type in HIV infection challenging.
The current study was designed to determine the contribution of both HLA Class I and the particular viral fragments displayed on those molecules to the activation of HIV-specific CD8 cells. The researchers analyzed blood samples from more than 100 people recently infected with HIV, first determining their specific HLA types by DNA analysis. Then they focused on 173 HIV protein fragments known to bind to those HLA types to see if particular peptides were more powerful in activating the HIV-specific CD8 response.
The researchers found that, for many varieties of HLA, only a few HIV protein fragments were responsible for the activation of CD8 T cells early in infection. In addition, the same HLA types that had been previously identified in people who stay healthy for a longer period of time after initial infection were associated with a more powerful early-stage HIV-specific CD8 activity.
"While we can't say this for sure right now, it is looking like both the HLA Class I molecule and the specific viral sequences being displayed contribute to the strength of immune response against primary HIV infection," says Altfeld. "In addition, the combination of Class I molecules that an individual expresses, something that is genetically determined, seems to have a significant impact on the specificity and strength of that response.
"Identifying the HIV epitopes [viral fragments] that are particularly good at priming an early T cell response may be important to vaccine design, and the impact of an individual's genetic HLA Class I background implies that a successful vaccine would have to overcome genetic factors associated with a less protective response,\\\
Massachusetts General Hospital
HIV Current Events and HIV News RSSMultiple health concerns surface as winter, vitamin D deficiences arrive
A string of recent discoveries about the multiple health benefits of vitamin D has renewed interest in this multi-purpose nutrient, increased awareness of the huge numbers of people who are deficient in it, spurred research and even led to an appreciation of it as "nature's antibiotic."
AIDS research reveals a lack of family-planning programs in Uganda
University of Alberta graduate student Jennifer Heys wants to make her message clear: there needs to be more education in Ugandan communities about contraception.
Many pregnant women avoid HIV screening in Africa
'Prevention is the best cure' is a common expression, but what happens if preventative measures are not used? A large proportion of pregnant Ugandan women are going out of their way not to be HIV tested, increasing the risk of mother-to-child transmission.
An atomic-level look at an HIV accomplice
Since the discovery in 2007 that a component of human semen called SEVI boosts infectivity of the virus that causes AIDS, researchers have been trying to learn more about SEVI and how it works, in hopes of thwarting its infection-promoting activity.
New findings suggest strategy to help generate HIV-neutralizing antibodies
New discoveries about anti-HIV antibodies may bring researchers a step closer to creating an effective HIV vaccine, according to a new paper co-authored by scientists at the Vaccine Research Center of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.
Research calls for better assessment of tests for tuberculosis, HIV/AIDS and malaria
A rapid and accurate diagnosis is the first step towards treatment in the fight against infectious disease.
No-entry zones for AIDS virus
The AIDS virus inserts its genetic material into the genome of the infected cell. Scientists of the German Cancer Research Center have now shown for the first time that the virus almost entirely spares particular sites in the human genetic material in this process. This finding may be useful for developing new, specific AIDS drugs.
Hoping for a fluorescent basket case
Although recent advances have raised hopes that a protective vaccine can be developed, acquired immunodeficiency syndrome (AIDS) remains a major public health problem.
Scientists explain binding action of 2 key HIV antibodies; could lead to new vaccine design
A very close and detailed study of how the most robust antibodies work to block the HIV virus as it seeks entry into healthy cells has revealed a new direction for researchers hoping to design an effective vaccine.
U.S. and European Experts Applaud Creation of New Transatlantic Task Force on Global Antibiotic Resistance Threat
Experts on both sides of the Atlantic applaud President Barack Obama and Swedish Prime Minister Fredrik Reinfeldt, representing the European Union (EU) Presidency, for establishing a transatlantic task force to address antibiotic resistance, an urgent and growing problem that threatens patient safety and public health worldwide.
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