POZlife

POZLife: Life from the Infected and Effected point of veiw.

Cells Natural Defense Against AIDS

Posted by pozlife on May 3, 2006

Scientists here have discovered a previously unknown mechanism that
cells use to fight off the human immunodeficiency virus (HIV), the
cause of AIDS.

The findings indicate that two proteins that normally help repair
cellular DNA can also destroy the DNA made by HIV after it enters a
human cell. This HIV DNA is essential for the virus to survive and
reproduce.

The study was led by researchers at The Ohio State University
Comprehensive Cancer Center – Arthur G. James Cancer Hospital and
Richard J. Solove Research Institute (OSUCCC – James) and
published in the Proceedings of the National Academy of Sciences.

The findings could lead to a possible new strategy for treating HIV
infection and AIDS, one that might complement current therapies and
would probably be less susceptible to viral drug resistance – an
increasingly urgent dilemma for patients and doctors.

Currently, doctors treat people with AIDS using combinations of
drugs that target the virus itself. These drugs do not eliminate HIV
from the body, but they do block its ability to reproduce and spread,
and they restore most people with AIDS to good health.

In time, however, HIV can develop mutations that render those drugs ineffective.

“Our findings identify a new potential drug target, one that
involves a natural host defense,” says principal investigator Richard
Fishel, professor of molecular virology, immunology and molecular
genetics and a researcher with the OSUCCC – James. “HIV
treatments that target cellular components should be far less likely to
develop resistance.”

Fishel’s laboratory colleague and first author Kristine Yoder
discovered the role of the cellular repair proteins while trying to
answer a different question.

Before HIV infects a cell, it carries its genetic material in the
form of RNA, or ribonucleic acid. Once inside a cell, the virus makes a
copy of its genes in the form of DNA. This DNA copy – known as
cDNA – then travels to the cell nucleus. There, it becomes
inserted, or integrated, into the cell’s DNA. There it is known as a
provirus, and it will generate new HIV in an infected patient and
eventually cause AIDS.

The process of integration, which is absolutely required for a
productive infection, begins with the help of an enzyme, integrase,
which is supplied by HIV. But the job is finished by DNA repair enzymes
provided by the host cell.

Yoder originally wanted to identify which repair enzymes were involved.

During these experiments, Yoder learned that cells with high levels
of two proteins called XPB and XPD had lower levels of HIV provirus in
their chromosomes. Both proteins help the cell repair damaged DNA.

Yoder, Fishel and their collaborators then introduced mutations into
the genes for the two proteins, which crippled the proteins’ ability to
repair DNA. When cells with these mutations were then infected with
HIV, they showed higher levels of provirus in their chromosomes.

“When we weakened a DNA repair pathway, we got more integration of the provirus,” Yoder says. “This was a total surprise.”

Next, the researchers wanted to learn whether the normal cells used
in the study had lower proviral levels because they were making less
HIV cDNA or because the HIV cDNA was being destroyed before it
integrated.

To answer that question, the researchers used antiretroviral drugs
known as non-nucleoside reverse transcriptase inhibitors (NNRTIs).
These drugs prevent HIV from making the cDNA copy of its RNA genetic
material. The researchers exposed newly infected cells to the drugs and
then measured changes in the amount of cDNA over time.

These experiments showed that the cDNA was destroyed faster in cells
with normal XPB and XPD compared to cells with mutant XPB or XPD. Cells
with normal XPB protein lost half their proviral DNA after 4.6 hours,
while cells with low levels of the protein lost half after about 7.7
hours. Similarly, cells with normal XPD protein lost half the proviral
DNA after 3.5 hours, while cells with mutated protein lost half after
five hours.

These experiments also showed that the two proteins destroyed the HIV cDNA before it is integrated into the chromosome.

“Overall, our results indicate that these two DNA repair proteins
participate in the destruction of HIV cDNA in cells,” Fishel says.
“This process reduces the pool of HIV cDNA that can integrate into host
chromosomes, thereby protecting cells from infection.”

The researchers are now working to learn how the proteins destroy
the HIV cDNA. These studies could lead to drugs that might help the
proteins destroy more HIV cDNA and in shorter time.

Source : Ohio State Universit

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