Elusive secret of HIV long-term immunity
Discovery offers hope of new, shorter HIV treatment if drugs are started right away
16-OCT-2013 - CHICAGO - Scientists have discovered a critical new clue about why some people are able to control
the HIV virus long term without taking antiviral drugs. The finding may be useful in shortening drug treatment for everyone else with HIV.
These rare individuals who do not require medicine have an extra helping of a certain type of immune protein that blocks HIV from spreading
within the body by turning it into an impotent wimp, Northwestern Medicine® scientists report. The new finding comes from analyzing
cells from these rare individuals and HIV in the lab.
Scientists have been trying to solve the mystery of why 1 percent of people with HIV -- called "controllers" -- have enduring control
of the virus without medications, in some cases for life. The controllers' early defense against HIV is quickly extinguished by the
virus, so how do they have long-term immunity? The Northwestern discovery represents what scientists have long sought: a second
line of defense deep in the immune system backing up the short-lived early defense.
This discovery suggests a novel approach involving much earlier treatment that could potentially make every HIV-infected person
into a controller for the long term by protecting the reserves of this defensive immune protein. The goal would be for them to
eventually be free from anti-retroviral drugs.
Currently most HIV patients need to take powerful anti-retroviral drugs every single day for life. If the medicines are stopped,
the virus quickly reactivates to harmful levels even after years of treatment.
"Preserving and even increasing this defense in cells may make more HIV-infected persons into controllers and prevent HIV
from rebounding to high and damaging levels when anti-HIV medications are stopped," said Richard D'Aquila, M.D., the
director of the Northwestern HIV Translational Research Center. He is the senior author of the study, which will
be published Oct. 16 in the journal PLOS ONE.
Changes in sexual practices could make the problem worse: An unintended consequence of the success of public campaigns to limit the
spread of HIV has led some to embrace the notion that oral sex is "safe," Dr. Kimberlin wrote, despite the fact that oral sex also
carries risks, including significant risk of transmission of HSV-1 from the mouth to the genitals. Another serious potential
consequence of increased susceptibility to genital herpes caused by HSV-1 is the risk of genital transmission of the virus
from mother to baby during delivery, Dr. Kimberlin wrote. Both HSV-1 and HSV-2 can pose significant problems for newborn
infants, who lack a mature immune system capable of fighting these viruses. Up to 30 percent of infected babies will
die from this infection if they have the most severe form of the disease, Dr. Kimberlin noted.
D'Aquila also is the Howard Taylor Ricketts Professor of Medicine at Northwestern University Feinberg School of Medicine and a
physician at Northwestern Memorial Hospital.
D'Aquila and colleagues now are working to develop a medicine that would boost this defensive immune protein called APOBEC3G,
or A3 for short.
The Missing Second Defensive Line
Much is known about how the immune system of controllers initially fights the virus. But HIV quickly escapes from that first line
of defense by mutating and evading the adaptive immune system. How these individuals control HIV long term without medications to
keep from developing AIDS has been under study by many researchers. It seemed there must be a second defensive line in the immune system.
Turning HIV Into a Wimp
In the new study, D'Aquila and his team have found that controllers, long after they have acquired HIV, have a more abundant supply
of the critical immune protein A3 in specific white blood cells called resting memory T cells. This is where the virus lies
silently in an inactive form and roars back when anti-retroviral drugs are stopped. In controllers, though, their bounty of
A3 means that any new HIV made from those cells inherits a helping of A3, which turns the new viruses into harmless wimps
that can't infect other cells.
You Can't Fool A3
The feisty A3 is a critical part of the newly characterized intrinsic immune system, and it resides in many cells of the immune
system including resting T cells. Unlike the adaptive immune system, which fails to recognize the virus once it mutates its
pieces, the intrinsic immune system can't be fooled.
"The intrinsic immune system recognizes the basic guts of the virus -- the nucleic acids -- that HIV can't change and then damages
those nucleic acids," D'Aquila said.
D'Aquila theorizes that the controllers' first line of defense slows down the ability of HIV to destroy all the A3.
"Perhaps starting anti-HIV drugs very soon after HIV is caught, rather than the current practice of waiting until later to start,
would work like the controllers' first line of defense," D'Aquila suggested. "If we preserve A3, it could minimize HIV's spread
through the body as this protein seems to do in controllers."
Otherwise, D'Aquila theorizes, all reserves of the protein are wiped out if HIV replicates unchecked for several months.
Babies and Other Controllers
D'Aquila pointed to several recent examples of early treatment sometimes resulting in lasting control of HIV in humans that are
consistent with this theory.
In January 2013, a baby was born to an HIV-positive woman in Memphis who didn't take preventive medicines that are routinely given
to these women. The baby got infected, and doctors began anti-HIV drug treatment within 36 hours of birth. After some treatment,
the baby is now off anti-HIV medicines and appears to be cured of HIV.
Two studies published earlier this year show the protective effect of starting the medicines within three to four months after
infection for a relatively short course, resulting in a lower level of HIV in the blood and better control of the virus for
some who stopped the anti-retroviral medication.
A group of patients in a European study were started on anti-HIV drugs very early after infection. Their medications were stopped
after three years but some continued to have a suppressed virus at such low levels it did not cause any damage.
Earlier Detection Just Got Easier
"Early-as-possible detection -- much easier with our new technology -- and early drug treatment will be the future of HIV
therapy," D'Aquila said. He added that the Affordable Care Act mandates that insurance companies pay for routine HIV
testing, which they did not always cover in the past.
D'Aquila Helped Developed Personalized Approach to HIV Medicine
D'Aquila is a leading HIV scientist who began investigating AIDS in 1982, the first year it was identified. He was a senior
resident in Philadelphia when the early cases appeared at the hospital where he was working. D'Aquila began investigating,
calling other area hospitals to see if they had seen similar cases. He discovered there were lots of them. The same month,
Morbidity and Mortality Weekly Report sounded the first alarm that a new disease had erupted.
Over the last 30 years, D'Aquila has helped develop anti-HIV medicines and resistance testing for HIV -- the latter is
the first widely used clinical application of DNA sequencing in personalized medicine. Since the 1990s, HIV patients have
their virus sequenced to determine which medicines are going to work best for them at that time -- a result of research
done by D'Aquila and others.
D'Aquila was also a leader and virologist for many NIH-supported clinical trials in the AIDS Clinical Trials Group. His laboratory
studies were also among the first to characterize effects of resistance mutations on HIV's replicative fitness and to show that
resistant virus persisted in HIV's latent reservoir.
The new study was done in collaboration with MariaPia De Pasquale and Yordanka Kourteva, formerly at Vanderbilt University
School of Medicine, where D'Aquila did the experiments.
Northwestern's Worldwide HIV Research Leadership
Northwestern Medicine scientists and clinicians are leaders in many other aspects of HIV research. They are investigating how
the virus is acquired through heterosexual intercourse, how an individual's genes affect risk for HIV and how HIV damages the
brain. They're also doing clinical testing of new HIV medicines and potential vaccines and improving the disastrous impact
of HIV on global health. They also are addressing the health and wellness of LGBT adolescents and young adults through HIV prevention.
The research represents several pillars of Northwestern's Strategic Plan by discovering new ways to treat disease in the
biomedical sciences and translating those discoveries into ideas and products that make the world a better place for everyone.
The study title is: Lower HIV provirus levels are associated with more APOBEC3G protein in blood resting memory CD4+ T lymphocytes
of controllers in vivo.
Read the article at: http://dx.plos.org/10.1371/journal.pone.0076002
Funding for the research was from grant P30 AI 54999 from the National Institute of Allergy and Infectious Diseases, National Cancer
Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Heart, Lung and Blood Institute,
National Institute on Drug Abuse, National Institute of Mental Health and the National Institute on Aging. Other funding was from
grant UL1 RR024975-01 from the former National Institute for Research Resources. (The funding of those programs is now done by
the National Center for Advancing Translational Sciences.) The institutes are all part of the National Institutes of Health.
NORTHWESTERN NEWS: http://www.northwestern.edu/newscenter/
Contact: Marla Paul
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