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In Novel Strategy Against AIDS, Einstein Researchers Genetically Engineer Immune Cells Into Potent Weapons For Battling HIV Infection
By outfitting immune-system killer cells with a new pair of genes, scientists
at the Albert Einstein College of Medicine of Yeshiva University transformed them into potent weapons
that destroy cells infected with HIV, the virus that causes AIDS. Their novel strategy of genetically
engineering immune cells to redirect their infection-fighting ability toward killing HIV-infected cells could
lead to an entirely new approach for combating AIDS and other viral diseases. The findings appear in the
March issue of the Journal of Virology.
After someone is infected with HIV, a subgroup of their immune cells known as CD8 cytotoxic T
lymphocytes, or CTLs, recognize cells infected with HIV and kill them before they become HIV-producing
factories. This CTL activity initially keeps the infection in check. But then-largely because these CTLs
may not bind tightly enough to the infected cells or because HIV mutates so rapidly-the virus typically
evades and ultimately overpowers the immune system, leading to an increase in viral load that, in the
absence of drug therapy, results in AIDS. However, a very small percentage of HIV-infected people known
as elite controllers manage to suppress HIV infection for many years.
"Certain of the CTLs of elite controllers may be genetically equipped to bind tightly to HIVinfected
cells and destroy them and thereby suppress the infection indefinitely," says Dr. Harris Goldstein,
senior author of the study and Director of the Einstein/Montefiore Center for AIDS Research. "Our idea,"
says Dr. Goldstein, "was first to identify the elite controllers' "super" CTLs and to isolate the genes that
enable these cells to bind tightly to HIV-infected cells and kill them efficiently; then we would transfer these
genes into CTLs that do not recognize HIV-infected cells and convert them into potent killers of those
cells."
After infecting a cell, HIV instructs it to make viral proteins. Tiny bits of these proteins, known as
peptides, are displayed on the surface of the infected cell-the cell's way of signaling the immune system
that it is infected. Detecting virus-infected cells so they can then be eliminated is the job of CTLs and the
protein molecules, known as T-cell receptors, that jut from their surface.
If a CTL's T-cell receptor has the right amino acid sequence, it will recognize the HIV peptide on the
infected cell as foreign--prompting the CTL to multiply and attack the infected cell. But all too often, this
battle between activated CTLs and HIV-infected cells ends badly. Why, then, are super CTLs of elite
controllers so effective in killing HIV-infected cells?
The explanation, the Einstein researchers postulated, is that these CTLs express T-cell receptors that
either have a knack for recognizing viral peptides that tend not to mutate, or they bind extremely tightly to
HIV-infected cells, enabling the elite controllers to keep their HIV infections under control.
A CTL's T-cell receptor, which is as unique for each CTL as a person's fingerprint, consists of two
"chains," alpha and beta. To obtain the blueprint for making exceptionally potent HIV-specific T-cell
receptors, the researchers isolated the genes that code for each of the two "chains" from the potent HIVspecific
CTL. Then, as a way to efficiently insert both genes into "naïve" CTLs (from people not infected
with HIV), they developed an efficient delivery system in which the genes were combined and packaged
inside a special type of virus, called a lentivirus. The lentiviruses then inserted these genes into the
chromosomes of naïve CTLs obtained from a naïve donor's blood and reprogrammed them into potent HIVspecific
CTLs.
"We demonstrated that these genetically reprogrammed CTLs have very strong activity in terms of
killing HIV-infected cells in both test tubes and an animal model," says Dr. Goldstein. In some of the animal
studies, for example, the researchers injected mice with both HIV-infected human cells and with
reprogrammed naïve CTLs into which the HIV-recognizing T-cell receptor genes had been inserted using
the lentiviral delivery system. One week later, when the researchers looked for HIV-infected human cells in
the animals, they found that the infected cells had virtually been eliminated.
Dr. Goldstein notes that this study was done using genes for just a single CTL T-cell receptor. "To
make this strategy even more effective, we're now in the process of isolating a "cocktail" of CTL receptor
genes that are specific for many different HIV peptides-an approach analogous to today's combination
drug therapy for treating HIV infection," says Dr. Goldstein. "Ultimately, we'd like to remove CTLs from
patients, convert them into potent HIV-specific CTLs by inserting a variety of HIV-specific CTL receptor
genes, and then re-infuse these fresh, genetically reprogrammed CTLs back into patients. By reinforcing the
immune system in this way, we hope to turn the tide of battle against HIV in favor of people infected with
the virus."
Besides Dr. Goldstein, other Einstein researchers involved in the study were Aviva Joseph, Jian Hua
Zheng, Antonia Follenzi, Teresa DiLorenzo, Kaori Sango, Jaime Hyman, and Ken Cheng. Other researchers
were Bruce Walker, Alicja Piechocka-Trocha and Christian Brander of Harvard Medical School and the
Howard Hughes Medical Institute; Erik Hooijberg of VU University Medical Center of Amsterdam, The
Netherlands; and Dario Vignali of St. Jude Children's Hospital, Memphis, Tennessee. The research was
supported by the National Institutes of Health.
Albert Einstein College of Medicine
În roman strategie împotriva SIDA, Einstein cercetãtori inginer genetic, celule imune în potent arme pentru lupta infecþiei cu HIV - In Novel Strategy Against AIDS, Einstein Researchers Genetically Engineer Immune Cells Into Potent Weapons For Battling HIV Infection - articole medicale engleza - startsanatate