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8.2 Transcription: From DNA to RNA 285

transcriptase is a remarkable DNA polymerase that can con- transcriptase incorporates one of the drug molecules rather than
struct a DNA polymer from either an RNA or a DNA template. a genuine nucleotide into a growing DNA polymer, the enzyme
In addition to its comprehensive copying abilities, reverse cannot extend the chain any further. However, the drugs are toxic
transcriptase has another feature not seen in most DNA poly- at high doses and thus can be administered only at low doses
merases: inaccuracy. As we saw in Chapter 7, normal DNA poly- that do not destroy all virions. Because of this limitation and the
merases replicate DNA with an error rate of one mistake in every virus’s high rate of mutation, mutant reverse transcriptases soon
million nucleotides copied. Reverse transcriptase, however, in- appear that work even in the presence of the drugs.
troduces one mutation in every 5000 incorporated nucleotides. Similarly, researchers are having trouble developing effec-
HIV uses this capacity for mutation to gain a tactical advan- tive vaccines. Even if a vaccine could generate a massive im-
tage over the immune response of its host organism. Cells of mune response against one, two, or even several HIV proteins,
the immune system seek to overcome an HIV invasion by multi- such a vaccine might be effective for only a short while—until
plying in response to the proliferating viral particles (virions). enough mutations build up to make the virus resistant.
The numbers are staggering. Each day of infection in every pa- For these reasons, the AIDS virus will most likely not suc-
tient, from 100 million to a billion HIV particles are released cumb entirely to drugs or vaccines that target proteins active at
from infected immune-system cells. As long as the immune sys- various stages of its life cycle. However, combinations of these
tem is strong enough to withstand the assault, it responds by therapeutic tools have nonetheless proven remarkably effec-
producing as many as 2 billion new cells daily. Many of these tive at prolonging an AIDS patient’s life. In 2013, AIDS patients
new immune system cells produce antibodies targeted against who received combination therapy had on average two-thirds
proteins on the surface of the virus. of a normal life span. Newer drugs added to the cocktail include
But just when an immune response wipes out those viral protease inhibitors that prevent the activity of enzymes needed
particles carrying the targeted protein, virions incorporating new to produce viral coat proteins, drugs that prevent viral entry into
forms of the protein resistant to the current immune response human cells, and inhibitors of the viral integrase protein.
make their appearance. After many years of this complex chase, A self-preserving capacity for mutation, perpetuated by
capture, and destruction by the immune system, the changeable reverse transcriptase, is surely one of the main reasons for
virus outruns the host’s immune response and gains the upper HIV’s success. Ironically, it may also provide a basis for its sub-
hand. Thus, the intrinsic infidelity of HIV’s reverse transcriptase, jugation. Researchers are studying what happens when the
by enhancing the virus’s ability to compete in the evolutionary virus increases its mutational load. If reverse transcriptase’s
marketplace, increases its threat to human life and health. error rate determines the size and integrity of the viral popula-
This inherent mutability has undermined two potential thera- tion in a host organism, greatly accelerated mutagenesis might
peutic approaches toward the control of AIDS: drugs and vac- push the virus beyond the error threshold that allows it to func-
cines. Some of the antiviral drugs approved in the United States tion. In other words, too much mutation might destroy the virus’s
for treatment of HIV infection—AZT (zidovudine), ddC (dideoxy- infectivity, virulence, or capacity to reproduce. If geneticists
cytidine), and ddI (dideoxyinosine)—block viral replication by could figure out how to make this happen, they might be able to
interfering with the action of reverse transcriptase. Each drug give the human immune system the advantage it needs to over-
is similar to one of the four nucleotides, and when reverse come the virus.

and RNA. Using these techniques, which we describe in in the DMD gene underlie the genetic disorder Duchenne
Chapter 9, they began to compare eukaryotic genes with muscular dystrophy (DMD). The DMD gene is 2.5 million
the mRNAs derived from them. Their expectation was that nucleotides—or 2500 kilobases (kb)—long, whereas the
just as in prokaryotes, the DNA nucleotide sequence of a corresponding mRNA is roughly 14,000 nucleotides, or
gene’s RNA­like strand would be identical to the RNA nu­ 14 kb, in length. Obviously the gene contains DNA
cleotide sequence of the messenger RNA (with the excep­ sequences that are not present in the mature mRNA. Those
tion of U replacing T in the RNA). Surprisingly, the regions of the gene that do end up in the mature mRNA are
investigators found that the DNA nucleotide sequences of scattered throughout the 2500 kb of DNA.
many eukaryotic genes are much longer than their corre­
sponding mRNAs. This fact suggested that RNA tran­ Exons and introns Sequences found in both a gene’s DNA
scripts, in addition to receiving a methylated cap and a and the mature messenger RNA are called exons (for ex-
poly­A tail, undergo extensive internal processing. pressed regions). The sequences found in the DNA of the
An extreme example of the length difference between gene but not in the mature mRNA are known as introns
primary transcript and mRNA is seen in the human gene (for intervening regions). Introns interrupt, or separate, the
DMD, which encodes the protein Dystrophin. Abnormalities exon sequences that actually end up in the mature mRNA.