||Researchers at the University
of Pennsylvania School of Medicine have developed
a drug resistance screening method that analyzes multiple
HIV variants at the same time, while also saving time and
||By combining two genetic tests, the
rapidly obtained gene sequences from multiple drug-resistant
HIV samples at once.
||Not only did the parallel analysis help
researchers to cut time, the new screening technique also
uncovered four rare, minor drug-resistant mutations in the
patient samples of HIV that had gone undetected by standard
|| The study appeared online this month
in Nucleic Acids Research.
(PHILADELPHIA) – A growing number of drug-resistant strains
of HIV are a threat to the effectiveness of current treatments
despite anti-HIV drug cocktails decreasing the number of HIV-related
deaths and improving the quality of life for HIV patients. Existing
methods of detecting drug-resistant forms of HIV are expensive,
time consuming, and often fail to identify small populations of
drug-resistant HIV. Now, researchers at the University
of Pennsylvania School of Medicine have developed a drug resistance screening method
that analyzes multiple HIV variants at the same time, while also
saving time and money.
By combining two genetic tests, Frederic D. Bushman,
of Microbiology, and colleagues, rapidly obtained gene sequences from
multiple drug-resistant HIV samples at once. The study appeared online
this month in Nucleic Acids Research.
“There is considerable interest in identifying minor drug resistant
variants prior to initiating new therapy, in order to allow treatment
with the most effective drugs,” explains Bushman. “Treatment
of HIV infection often fails because viruses mutate to resist drugs.
Under the pressure of drug treatment, small populations of resistant
viruses can quickly grow to become the majority, resulting in treatment
failure due to drug resistance.”
According to the Joint United Nations
Programme on HIV/AIDS (UNAIDS),
approximately 40 million people in the world are currently living with
HIV/AIDS. Commonly prescribed antiretroviral cocktails work to slow the
debilitating effects of HIV by disrupting the virus at various stages
in its replication. While combinations of antiretroviral drugs have proven
effective, quickly mutating forms of HIV can complicate treatment outcomes.
Researchers estimate that up to 50 percent of individuals being treated
for HIV in the US carry drug-resistant forms of HIV, caused by mutations
in the virus in response to drug treatment or by being infected with
a resistant form of HIV. The increased availability of antiretroviral
drugs to meet the HIV/AIDS needs of developing countries in recent years
will likely contribute to a global rise in drug-resistant strains of
“To overcome drug resistance, patients must be treated with drugs
to which the HIV virus is still susceptible,” says Bushman.
To tailor the most effective anti-HIV treatment for a patient, antiretroviral
resistance screenings are conducted before a patient begins or changes
drug therapy. In developing countries where HIV/AIDS is most prevalent,
resistance testing is rare due to the high costs of screening. In cases
where resistance testing is available, most screening techniques are
not sensitive enough to analyze small populations of drug-resistant strains
of HIV. While small populations of drug-resistant HIV may go undetected
by current screening methods, Bushman says that minor mutant forms of
HIV often impair a patient’s response to future drug therapy.
To increase the sensitivity of HIV screening techniques and decrease
the time and cost of each test, Bushman and others examined seven samples
of mutated strains of HIV, including three HIV samples from patients
who had experienced antiretroviral multi-drug resistance. DNA bar coding,
in which different DNA molecules are indexed using DNA sequence tags,
allowed Bushman and others to map multiple sequences of HIV mutants simultaneously.
Drug-resistant mutations were identified using a new DNA sequencing technique
called pyrosequencing, which allows researchers to determine millions
of bases of a DNA sequence in a single one-day experiment. By combining
the two methods, researchers were able to quantify and characterize hundreds
of thousands of HIV variants for drug resistance in a single test.
Not only did the parallel analysis help researchers to cut time, the
new screening technique also uncovered four rare, minor drug-resistant
mutations in the patient samples of HIV that had gone undetected by standard
screening measures. These small drug-resistant populations of HIV may
explain why some patients do not respond to antiretroviral treatment,
because the minor alleles can rapidly grow out, generating new populations
of drug-resistant viruses.
Bushman’s new screening technique may open up opportunities for
improved drug-resistance screening in the United States and around the
world. By rapidly gathering sequencing information about drug-resistant
HIV, decoding resistance in HIV and other viruses can potentially be
done at a fraction of current costs and time.
In the future, Bushman plans to apply his new method to optimize drug-resistance
testing in the US and the developing world.
“Thanks to DNA bar coding and pyrosequencing, clinicians should
be able to optimize treatment for their patients with much more relevant
information in front of them,” says Bushman.
Penn co-authors are Christian
Hoffmann, Nana Minkah, Jeremy
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