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Basic Research
Understanding HIV and the Immune System
Following are links to the Kaiser Daily HIV/AIDS Report or other sources, and summaries from the CDC HIV/STD/TB Prevention
News Update.
Winter-Spring 2008 News
Exhaustion Of HIV-specific T Cells May Be Caused By
Chronic Exposure To Virus. ScienceDaily. Retrieved May 6, 2008, from
http://www.sciencedaily.com/releases/2008/05/080505211809.htm
Suppression of Human Protein Reduces HIV's Ability To Enter T Cells,
Replicate, Study Finds
http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=51825
Researchers Discover Genetic Circuit in HIV That Controls Whether Virus
Activates, Remains Dormant
http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=51040
Insight Into HIV's "On-Off" Switch Shows Promise For
Therapy, Understanding Cellular Decisions
17 Mar 2008
Researchers at the University of California, San Diego and Oak Ridge National
Laboratory have discovered how a genetic circuit in HIV controls whether the
virus turns on or stays dormant, and have succeeded in forcing the virus towards
dormancy, a finding that shows promise as an avenue for HIV therapy.
http://www.medicalnewstoday.com/articles/100845.php
Researchers Discover Protein That Could Lead to Development of HIV Vaccine,
New Treatments, Study Says
http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=50763
Gene Could Stop Progression of HIV, Study Finds
http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=50713
"Study Finds Anti-AIDS Drugs May Prevent HIV
Infection"
Voice of America , (02.05.2008) Jessica Berman
A study involving monkeys found that the use of two antiretroviral drugs, FTC (emtricitabine)
and tenofovir, prevented transmission of a primate version of HIV.
Lead researcher Walid Heneine of CDC and colleagues injected macaques with
single daily doses of FTC and then exposed them once a week for 14 weeks to
simian HIV (SHIV). Compared to untreated primates, FTC reduced the risk of
infection 3.8-fold. The scientists then gave the macaques oral doses of FTC and
tenofovir, resulting in a 7.8-fold lowering of SHIV infection risk.
In a third experiment, the monkeys were given daily shots of FTC and higher
doses of tenofovir prior to exposure to SHIV. According to Heneine, this
resulted in 100 percent protection, as did another regimen in which the macaques
received the FTC-tenofovir combination two to three hours before exposure and 24
hours after each weekly exposure.
“The findings from this intermittent study suggest that ultimately it is
possible to provide a promising new avenue for future research, where it opens
up the floor for a lot of more research for intermittent dosing,” said Heneine.
The study, “Prevention of Rectal SHIV Transmission in Macaques by Daily or
Intermittent Prophylaxis with Emtricitabine and Tenofovir,” was published in the
journal Public Library of Science Medicine (2008;5(2):e28
doi:10.1371/journal.pmed.0050028).
Protein In Tick Saliva Prevents HIV-1 From Attaching
To T Cells
16 Feb 2008
The HIV-1 virus cripples the human immune system by targeting white blood cells
called T cells that form the body's first line of defense in fighting
infections. A recent study by researchers from the University of Massachusetts
Amherst shows that a protein found in the saliva of deer ticks prevents the
HIV-1 virus from attaching to the surface of T cells, which is the critical
first step in the virus' attack strategy. Results were published in the February
2008 issue of Biochemical and Biophysical Research Communications.
Article URL:
http://www.medicalnewstoday.com/articles/97582.php
Molecule That Directs Immune Cells to Intestines Also Serves as Receptor for
HIV, Study Finds
http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=50321
NIAID Scientists Identify New Cellular Receptor for
HIV
A cellular protein that helps guide immune cells to the gut has been
newly identified as a target of HIV when the virus begins its assault on the
body's immune system, according to researchers from the National Institute of
Allergy and Infectious Diseases (NIAID), part of the National Institutes of
Health (NIH). NIAID Release (2.8.08)
Researchers Develop Technique That Prevents HIV From Reproducing, Philadelphia
Inquirer Reports
http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=50322
Researchers Examine Immune Cells Where HIV Can Lie Dormant, Possible
Treatments
http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=50184
Medscape News
VIRAL CELLULAR MECHANISMS
Tetherin Protein Blocks HIV Release From Infected Cells
US researchers have identified a membrane protein that acts as a
tether for HIV, preventing the release of virions from infected cells.
As it turns out, this protein, which the group named "tetherin," is
actually CD317, a previously discovered protein of unknown function.
Reuters Health Information
2008 |
Host Proteins Required for HIV Infection
Identified
A recently published study has identified 273
host proteins, or "HIV dependency proteins" (HDPs),
that are hijacked by HIV during the course of
infection.
Using a technique called RNA interference,
the study evaluated thousands of proteins. Some
of the proteins identified include Golgi
transport proteins (Rab6 and Vps53) that are
required for viral entry into cells, a
karyopherin (TNPO3) required for viral
integration into cells, and the mediator complex
(Med28) used by HIV during viral transcription.
Researchers intend to use the HDPs identified
in this study to determine potential targets for
future HIV therapies.
More information is available:
AIDSinfo At-A-Glance Volume 4 Issue 3
Researchers Identify 273 Human Proteins That Play
a Role in HIV Transmission, Progression
http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=49772
Amino Acid Mutations in Protein Might Make HIV Vulnerable to Immune System
Attack, Study Finds
http://www.kaisernetwork.org/daily_reports/rep_index.cfm?DR_ID=49674
See Fall 2007 Archives
Summaries and Reports
NIAID Scientists Identify New
Cellular Receptor for HIV
NIAID Release (2.8.08)
A cellular protein that helps guide immune cells to the gut has been newly
identified as a target of HIV when the virus begins its assault on the body's
immune system, according to researchers from the National Institute of Allergy
and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH).
“The identification of this new receptor opens up new avenues of investigation
that may help further elucidate the complex mechanisms of the pathogenesis of
HIV infection,” says NIAID Director Anthony S. Fauci, M.D., chief of the
Institute’s Laboratory of Immunoregulation (LIR) and senior author of the new
study.
Several other immune cell receptors bind to HIV. Most important among these, the
CD4 molecule, identified as an HIV receptor in 1984, functions as the principal
receptor for HIV. The CCR5 and CXCR4 molecules, discovered in 1996, serve as
co-receptors that HIV uses to enter its target cells. In the new study, which
appears online Feb. 10, 2008 in Nature Immunology, NIAID scientists identify a
cell adhesion molecule known as integrin alpha 4 beta 7 as another potentially
important receptor for HIV.
Early in the course of HIV infection, the virus rapidly invades and replicates
in gut-associated lymphoid tissue (GALT), the immune cells of the gut. Once
seeded with HIV, the gut is rapidly depleted of CD4+ T cells, the main target of
HIV, triggering the process that ultimately leads to AIDS.
“In the very early days of infection, it is in the GALT where most of the damage
caused by HIV occurs,” says Elena Martinelli, Ph.D., a lead author of the paper
and a fellow in Dr. Fauci’s laboratory. “The gut is where the virus really takes
hold. We found that integrin alpha 4 beta 7, whose natural function is to direct
T cells to the GALT, is also a receptor for HIV. It is very unlikely that this
is a coincidence.”
Dr. Martinelli, along with Claudia Cicala, Ph.D., James Arthos, Ph.D., and their
colleagues found that the gp120 protein, part of the HIV envelope, binds to
integrin alpha 4 beta 7 on CD4+ T cells, which promotes the formation of a
stable junction, or synapse, between neighboring cells.
“A synapse is a junction that allows two cells to adhere in a stable way,” says
Dr. Arthos. “Many viruses have found a way to trick cells into forming these
stable junctions. Now it appears that HIV can also trigger synapse formation.”
Specifically, a short piece of the HIV gp120 protein in a region known as the V2
loop recognizes the alpha 4 chain of the integrin molecule on host cells. This
stretch of the V2 loop is similar to part of the naturally occurring molecules
that bind integrin alpha 4 beta 7. Thus, it appears that HIV is mimicking the
natural molecular partners, or ligands, that normally bind to the receptor. The
authors note, however, that some HIV isolates react more strongly to integrin
alpha 4 beta 7 than others.
“The ability of a particular virus to bind to integrin alpha 4 beta 7 may
determine whether it will have a major impact in targeting the gut lymphoid
tissue,” says Dr. Fauci. “This finding could be a significant determinant in the
pathogenic mechanisms that lead to AIDS.”
As part of the natural homing process, integrin alpha 4 beta 7 binds to its
natural ligands and activates a protein known as LFA-1. According to Dr. Arthos,
HIV can co-opt this process by mimicking the cells’ alpha 4 beta 7 receptor
natural ligands. When HIV gp120 protein binds to the alpha 4 beta 7 receptor it
facilitates the formation of a synapse. Thus, HIV tricks an infected cell into
binding to an uninfected cell, enabling HIV to readily gain access to the
uninfected cell.
“While this study provides important new information concerning the various
mechanisms by which HIV debilitates the human immune system, it also raises new
questions and challenges that our laboratory and others will pursue,” notes Dr.
Cicala.
For more information on HIV/AIDS, see
http://www3.niaid.nih.gov/healthscience/healthtopics/HIVAIDS/overview.htm .
NIAID is a component of the National Institutes of Health. NIAID supports basic
and applied research to prevent, diagnose and treat infectious diseases such as
HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis,
malaria and illness from potential agents of bioterrorism. NIAID also supports
research on basic immunology, transplantation and immune-related disorders,
including autoimmune diseases, asthma and allergies.
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 http://www.nih.gov.
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Reference: J Arthos et al. HIV-1 envelope protein binds to and signals through
integrin alpha 4 beta 7, the gut mucosal homing receptor for peripheral T cells.
Nature Immunology DOI: 10.1038/ni1566 (2008).
'Good bacteria' in women give
clues for slowing HIV transmission
Public release date: 7-Feb-2008
University of
Rochester Medical Center
Beneficial bacteria found in healthy women help to reduce the amount of vaginal
HIV among HIV-infected women and might make it more difficult for the virus to
spread, boosting the possibility that “good bacteria” might someday be tapped in
the fight against HIV.
The findings come from physicians and scientists at the University of Washington
and the University of Rochester Medical Center, who worked together in an effort
to learn more about how HIV survives and spreads from person to person. The
study involving 57 women was done in Seattle and Rochester through the Women’s
HIV Interdisciplinary Network (WHIN), which is based at the University of
Washington.
The team studied the vaginal environment, examining the mix of bacteria that
reside there and taking into account several other factors. Physicians tracked
the level of HIV virus in the vagina as well as infection by common sexually
transmitted diseases like trichomoniasis, gonorrhea and chlamydia, and other
more common types of vaginal infections.
Physicians also monitored the levels of beneficial bacteria known as
Lactobacillus in the vagina, as well as hydrogen peroxide, which is produced by
the bacteria and hinders the virus. They also measured the level of HIV in the
women’s blood and the rate of progression of the disease overall.
The team found that women with hydrogen-peroxide-producing Lactobacillus in the
vagina had lower levels of HIV virus in genital secretions – what physicians
call the genital viral load. Physicians know that the lower the level of HIV in
the sexual tract, the less likely that the virus will be spread from person to
person through sexual contact.
Scientists have previously recognized from laboratory studies that Lactobacillus
might give women some natural protection against HIV. The bacteria, commonly
found in most women, bind to the virus and secrete hydrogen peroxide. The
bacteria are a close cousin of the Lactobacillus bacteria found in the small
intestine, a type of “good” bacteria widely found in yogurt.
While previous work in the laboratory has indicated that Lactobacillus might
help prevent HIV infection in women, the current study actually links, in women,
decreased levels of the virus in the vagina with the presence of Lactobacillus
that produce hydrogen peroxide there.
The team also found that the amount of the virus in the vagina varied in step
with the presence of Lactobacillus: Women who did not have the bacteria at first
but who had acquired it by a subsequent visit had their vaginal HIV levels drop,
while vaginal HIV levels increased in women in whom the good bacteria had
disappeared between visits.
The research was presented this week at the Conference on Retroviruses and
Opportunistic Infections in Boston by Jane Hitti, M.D., associate professor in
the Department of Obstetrics & Gynecology at the University of Washington School
of Medicine. Hitti has been working closely with Robert Coombs, M.D., Ph.D., the
principal investigator for the WHIN study and professor of Laboratory Medicine
and of Medicine at the University of Washington. Amneris Luque, M.D., associate
professor of Medicine and medical director of the AIDS Center at Strong Memorial
Hospital, and Susan Cohn, M.D., associate professor of Medicine at the
University of Rochester School of Medicine and Dentistry, also took part in the
study.
“These findings underscore the importance of maintaining a healthy,
Lactobacillus-dominant vaginal flora for HIV-positive women,” said Hitti. “I
hope that we can explore Lactobacillus replacement in the future for women who
do not have this bacteria, as a strategy to decrease the amount of HIV in the
vagina.”
“The research opens up some doors,” said Luque. “Sexual activity is the most
common mode of transmission of HIV. Perhaps we can make it less likely to spread
by somehow taking advantage of good bacteria as a natural way to stop HIV and
prevent transmission. These findings are striking, though preliminary, and
should be looked at further.”
Luque and Cohn both care for patients at Strong’s AIDS clinic, which provides
ongoing care for approximately 900 patients with HIV. The center is part of a
broader AIDS treatment and research effort at the University of Rochester
Medical Center. The University is the only institution in the nation to be part,
since inception, of two major national AIDS research efforts – the search for a
vaccine, and the testing of new treatments. More than 3,000 Rochester-area
residents have taken part in treatment and vaccine studies at the University’s
HIV/AIDS Clinical Trials Unit, funded by the National Institute of Allergy and
Infectious Diseases.
Cohn stresses the importance of HIV-positive women participating in clinical
research. “These women made a large contribution to knowledge about HIV and
reproductive health by participating in this study. Advances in the care of
HIV-positive women really depend on the dedication of study subjects.”
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