What is HIV?
o Life cycle of HIV
1. HIV encounters host cell (helper T cell)
2. HIVs gp120 surface protein binds to CD4 and then to
coreceptor (CCR5 or CXCR4) on surface of host cell
3. HIV virion fuses with the host cell
HIVs RNA genome and enzymes enter the host cells
cytoplasm
4. HIVs reverse transcriptase enzyme synthesizes HIV DNA
from HIVs RNA template
5. HIVs integrase enzyme splices HIVs DNA genome into
host cells genome
6. HIVs DNA genome transcribed into HIV mRNA by host
cells RNA polymerase
7. HIVs mRNA is translated into HIV precursor proteins by
host cells ribosomes
8. New generation of virions assembles at the membrane
of the host cell
9. New virions bud from the host cells membrane
10. HIVs protease enzyme cleaves precursors into mature
viral proteins, allowing the new virions to mature
How does the Immune System React to HIV?
o Dendritic cells capture the virus and present bits of its proteins
to nave helper T cells
Once activated, nave cells divide to produce effector
helper T cells
o Effector helper T cells stimulate B cells displaying the same bits
of viral protein to mature into plasma cells, which make
antibodies that bind and in some cases inactivate the virus
Also activate killer T cells that destroy host cells infected
with the virus
Effector T cells are short lived but some become long lived
memory helper T cells
How does HIV cause AIDS?
o Macrophages, effector helper T cells and memory helper T cells
vulnerable to HIV because of CD4 and CCR5
o Acute phase HIV virions enter the hosts body and replicate
explosively, so concentration of CD4 T cells plummets
o Chronic phase- patient has few symptoms but HIV continues to
replicate
Concentration of virions in the blood stabilizes for a while
but eventually rises again and concentrations of CD4 T
cells falls
o A model for how HIV causes AIDS
HIV infects CD4+ T cells in gut, induces immune activation,
replicates most efficiently in activated CD4+ T cells
(immune system activation causes effector T-cell
proliferation)
Proliferation of T cells gives HIV more target cells
Steady supply of target cells allows HIV to replicate
prolifically
HIV directly and indirectly induces immune activation and
replicates in activated immune system cells
When the ongoing battle damages the immune system to
the point that it can no longer produce enough T cells to
function properly, AIDS begins
Why does HIV therapy using just one drug ultimately fail?
o AZT is similar in structure to T that it fools reverse transcriptase
to pick it up and incorporate it into growing DNA strand and cant
add more nucleotides
o Populations of virions within individual patients change to
become resistant to AZT and populations evolve
Evolution by Natural Selection
o 1. Replication errors produce mutations in reverse transcriptase
genes that vary in their resistance to AZT
o 2. Mutant virions pass their reverse transcriptase genes and AZT
resistance to offspring, so resistance is heritable
o heritable traits that lead to survival and abundant reproduction
spread in populations. Heritable traits that lead to reproductive
failture disappear. This is evolution by natural selection
Understanding evolution helps researchers design better therapies
o By reducing genetic variation for resistance in virion population,
cocktail of drugs that target different points in HIVs life cycle
limit evolution of resistant strainshas dramatically improved
patient survival
o HAART = highly active antiretroviral therapy
Evolution of HIV strains resistant to multiple drugs
o Sometimes HIV populations evolve resistance even in patients
taking multidrug cocktails
Risk is highest in patients who fill most but not all of their
prescriptions
After Human populations evolving as a result of HIV pandemic?
o For a population to evolve, it must harbor genetic differences
among individuals
o A missing coreceptor
In human populations, some individuals carry alleles that
make them resistant to infection with HIV
32 allele mutant form that has a 32-base-pair deletion in
DNA
o HIV is too new a human disease to have triggered substantial
evolutionary change in human populations
o Humans carry a loss-of-function mutation in the retrocyclin gene
that appears to increase our susceptiblity to HIV. An allele with
the back-mutation might be protective, but no such allele is
known.
Where did HIV come from?
o HIV-1 and HIV-2 transmitted to humans from different sources
HIV-2 originated in sooty mangabeys
HIV-1 transmitted to humans from chimpanzees
o Monkey SIV causes little to no disease but causes disease in
humans and chimps
