Transcript BTY328: Viruses

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HIV/AIDS prevention and treatment
BTY328: Virology [email protected]
Monitoring the progress of HIV
infection and AIDS
Routes of HIV infection
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The three main transmission routes of HIV are
sexual contact, exposure to infected body fluids
(eg blood) or tissues, and from mother to fetus
or child during perinatal period.
It is possible to find HIV in the saliva, tears, and
urine of infected individuals, but no recorded
cases of infection- risk of infection is
negligible?.
Routes of HIV infection
HIV transmission
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Typical condom use reduces the risk of
heterosexual HIV transmission by approx. 80%
over the long-term, although the benefit is
higher if condoms are used correctly on every
occasion (upto 98-99%).
Where one partner is infected and with
consistent condom use, HIV infection rates for
the uninfected partner are below 1% per year.
Randomized controlled trials have shown that
male circumcision lowers the risk of HIV
infection among heterosexual men by up to
60%.
Needle stick injury
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Health care workers: needles, scalpels and
glass:-careful disposal of to prevent needlestick
injuries with contaminated items.
Intravenous drug : needle-exchange
programmes can reduce the infections caused
by drug abuse.
Estimated that 20% of infections in Africa are
do to iatrogenic effects (unscreened blood, poor
sterilisation of needles/equipment)
Mother to child transmission
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Transmission can occur mother to foetus
During breastfeding: Current recommendations
replacement feeding is acceptable, feasible,
affordable, sustainable and safe, HIV-infected
mothers should avoid breast-feeding their
infant. However, if this is not the case, exclusive
breast-feeding is recommended during the first
months of life and discontinued as soon as
possible.
Routes of HIV transmission and risks
Treatment
Since AIDS is asyndrome treatment is often of the
opportunistic infections.
An ideal drug would excise all HIV provirus from
cells DNA, or eliminate all HIV infected cells.
If HIV replication can be suppressed long enough,
all HIV infected cells will die off.
Several strategies for reducing viral host cell
invasion and replication...
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Nucleoside analogue RT inhibitors
(NNTRIs)
Drugs that resemble the 4 nucleosides used to
make DNA. e.g AZT
 nucleoside analogues are RT inhibitors that stop
further synthesis the viral genome.
the dideoxy- analogues stops RT from joining
next nucleoside by 3'-5' phosphodiester bond
these drugs have limited effectiveness as a
monotherapy because of the toxic side effects,
individually they do not delay the onset of AIDS,
and HIV becomes resistant to each one.
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Non-nucleoside analogue RT inhibitors
(NNTRIs)
In contrast to NRTIs, NNRTIs are not
incorporated into viral DNA but inhibit HIV
replication by binding to RT. e.g. Nivirapine
this blocks DNA polymerase and stops HIV DNA
replication
HIV has shown rapid resistance to these drugs
and the resistance can often lead to crossresistance
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Protease Inhibitors
eg. saquinavir, ritonavir, indinavir, nelfinavir etc
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HIV proteases required late in HIV replication
cycle to process precursor GAG and POL
polyproteins into mature HIV proteins.
The aspartyl protease of HIV cleaves GAG
(p55) and GAG-POL (P160) polyproteins into
structural GAG protein subunits and three viral
enzymes (RT, integrase and protease).
At least 15% of people have serious side effects
to protease inhibitors, another 15% do not
respond at all to protease inhibitors.
Fusion or Entry Inhibitors
Maraviroc and enfuvirtide
Fusion inhibitor T-20 has been licensed both in
the US and in Europe since 2003, but only for use
by people who have already tried other treatments
(requires injection).
A new type of entry inhibitor known as maraviroc
was licensed in 2007. This drug is known as a
CCR5 inhibitor as it blocks the CCR5 co-receptor
on human immune cells, preventing HIV from
attaching to the cells' surface.
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Other drugs in development
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Integrase inhibitors inhibit the enzyme integrase,
which is responsible for integration of viral DNA into the
DNA of the infected cell. There are several integrase
inhibitors currently under clinical trial- raltegravir
became the first to receive FDA October 2007.
Maturation inhibitors inhibit the last step in GAG
processing in which the viral capsid polyprotein is
cleaved, thereby blocking the conversion of the
polyprotein into the mature capsid protein (p24).
Because these viral particles have a defective core, the
virions released consist mainly of non-infectious
particles. Under investigation, bevirimat (first isolated
from Syzygium claviflorum, a Chinese herb. ) and Vivecon.
Combination therapy: HAART
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HAART allows the stabilization of the patient’s
symptoms and viremia.
Without treatment, the net median survival time
after infection with HIV is estimated to be 9 to
11 years, depending on the HIV subtype, and
the median survival rate after diagnosis of AIDS
(treatment is not available) ranges between 6
and 19 months.
HAART reduced the death rate from this AIDS
by 80%, and raised the life expectancy for a
newly-diagnosed HIV-infected person to about
20 years.
HAART can double life
expectancy of HIV+
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Without treatment, the net median survival time
after infection with HIV is 9 to 11 years, and the
median survival rate after diagnosis of AIDS in
resource-limited settings where treatment is not
available ranges between 6 and 19 months,
depending on the study.
HAART reduced the death rate from this AIDS
by 80%, and raised the life expectancy for a
newly-diagnosed HIV-infected person to about
20 years.
Evolving virusnew treatments needed
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Mutation of RNA viruses results in the rapid evolution
of drug-resistant viral quasi species. In an HIV-infected
person, about 10.3 x 109 virions are produced per day.
These have a half life of 5.7 hours and a fixed
mutation rate of 3 x 10-5 per base per replication cycle
in an HIV genome of 104 base pairs. This means that
at least one mutation may occur in each nucleotide of
the HIV genome in a day.
New treatments continue to be developed and
because HIV continues to evolve resistance to
treatments and estimates of survival time are likely to
continue to change……
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