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Author Topic: hiv science how why daily changes in imm sys war w/hiv evolv detail info clear  (Read 1765 times)

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Offline bimazek

  • Member
  • Posts: 781
      HIV is a retrovirus, whose infectious form is a packaged RNA genome
     When it enters the body it is reverse translated from RNA to DNA
 Components of the HIV Provirus: Hallmarks of the retrovirus
     LTR unit at either end that are the means with which it integrates; contains various promoter
 elements that response to a variety of post transcription factors such as NF?B and NFA; links the
 expression of the virus to the activation of the cell
 Canonical gag, pol and env: the three critical genes that define the existence of all retroviruses
     gag encodes protein (GAG) that packages RNA; it has zinc fingers and interacts with the RNA
 structure
     pol primarily encodes the reverse transcriptase (polymerase) plus a few other enzymes involved
 in processing that are critical for the life cycle
     env gives specificity or cellular tropism to the virus, enabling it to infect a particular cell
     nef is an important gene that encodes negative effector protein (p24); p24 interacts with both
 CD4 and MHC I molecules to subvert immune surveillance to make the cell express less MHC I
 and hence be less detectable to the immune system
 Early Events of HIV Infection
     Envelope interacts with membrane receptor
 complex thatís composed both of CD4 and
 a chemokine receptor
     Interaction first with CD4 then with the
 chemokine receptor has an unfolding effect
 on the membrane envelope that in effect
 harpoon a lipid rich region of the
 membrane and the virus enters
     Critical event: reverse transcription
 occurs at this point in the virusís life cycle
 and it makes itself into a cDNA copy thatís
 drawn into the nucleus on microtubles and
 integrates via LTRs into the host DNA
     The key to the retrovirus: reverse
 transcriptase has no proofreading function
 and thus creates a huge number of mutant
 forms that are integrated, then subject to
 the precise proofreading controls of
 genomic DNA
     There is virtually no likelihood of a
 mutation occurring with integrated virus
 but itís at the step of integration that the
 mutation occurs


 Page 2
 Host Response to HIV Infection: 2 Major Phases
 Y axis: CD4 T cells #/ĶL
 Flu-like illness
 Asymptomatic Phase
 Symptomatic Phase
 First Phase of Response:
     Vigorous CD8 response controls viral replication but doesnít eliminate the infectious virus, which
 is primarily but not exclusively located in monocytes
     Antibodies to HIV-1 are formed (these are the tools youíll use with PCR to diagnose the presence
 of an infection; antibodies signal infection not exposure) but they donít clear the infection and
 arenít protective
     2 Subdivisions to this phase:
 1. Minimal flu-like illness passes relatively unnoticed
 2. Clinical asymptomatic phase lasts 2-12 or more years in which the person is at a relative
 equilibrium with the virus
 Second Phase of Response:
     HIV-1 escapes CD8 response and mutations in viral envelope favor infection and destruction of
 CD4 cells
     A shift from a monocyte phase to a CD4 dominant phase results in extirpation of the CD4 cells
 and AIDS
 Host-Parasite Relationship of HIV
     Reverse transcriptase has no proofreading function and creates many mutations
     HIV must adapt and evolve in an environment determined by attributes of the hostís immune
 system (i.e. MHC alleles, TCR repertoire, polymorphism of viral entry receptors, chemokine and
 cytokine milieu, immune history)
     The outcome of infection depends on the biology of the host, the mutational capacity of HIV-1
 and whether the immune response targets critical HIV structures
     A good immune response is one that is able, fortuitously, to identify regions that the virus cannot
 mutate; if a personís immune response recognizes that particular peptide, you have a hold on the
 virus, and as long as the virus is unable to mutate, you can effectively control it with a CD8
 response


 Page 3
     If your immune system happens to see relatively expendable or irrelevant parts of the viral
 genome, the virus can quickly mutate around that
 Evolutionary History of HIV
     HIV is genomically highly diverse, reflecting MHC selection in each species
     The phylogeny is intricate, a given individual will likely be infected by only one of these strains
 of the virus but there multiple strains that differ somewhat in their actual biological characteristics
 and in their virulence
     By studying the molecular fingerprints one is able to go back in time and calculate because
 mutations provide a molecular clock
     Genetically similar HIV viruses are called clades; the dominant clade in the US is Clade-B, and it
 probably deviated from the main viral clades in the 1950s
     An earlier form of this probably existed in 1938
     In 1930, the virus first moved from chimpanzees into humans in at least 2 independent passages
     HIV-2 probably moved from the sooty mangabeys and macaque monkeys into humans
     We wonít discuss HIV-2, but it is relatively milder form that has the acute viral phase but the
 people remain for the most part in the asymptomatic phase
     HIV-2 is very uncommon in this country
 HIV Tropism
 Chemokine Receptors: Coreceptors for HIV Entry
 CCR5
 CXCR4
 Ligands
 RANTES, MIP-1a, MIP-1Ŗ
 Inflammatory
 chemokines produced in
 large quantities by
 activated CD8 and CD4
 immune response to HIV
 Compete with R5 HIV
 binding to membrane
 receptor complex,
 blocking progress of the
 infection
 As long as you have a
 vigorous immune
 response in which CD8
 cells either kill the target
 Stromal derived growth factor 1
 (SDF-1)
 Produced by stromal
 cells
 Competes with HIV
 binding, but not
 produced in
 inflammation or by T
 cells
   
 
 Tropism,  or cellular specificity of HIV strains,
 is based on envelope structure
     The viral envelope contains sequences that
 interact with a membrane viral receptor complex
 composed of CD4 and one of several chemokine
 receptors
     The sequence of a given viral envelope is specific
 for one of the chemokine receptor types
     The two main chemokine receptors, CCR5 and
 CXCR4, are distributed on different cell lineages
     Strains that bind CCR5:  R5  tropic
     Strains that bind CXCR4:  R4  tropic ( X4 )


 Page 4
 or release these
 cytokines, you can
 effectively block viral
 entry
 This is critical for the
 asymptomatic for the
 asymptomatic period
 Distribution
 Monocytes
 Dendritic cells
 Effector, memory or
 activated T cells
 NOT naÔve T cells
 Monocytes
 B cells
 YES naÔve T cells
 R4 preferentially infects
 naÔve/activated T cells
 Biology
 Responsible for migration of
 memory and effector T cells,
 monocytes and dendritic cells to
 sites of inflammation
 Essentially a signal to
 bring these cells together
 in a site of inflammation
 SDF-1 responsible for
 migration/homing of naÔve T
 cells to lymph nodes
 Other
 Several polymorphisms
 e.g. ?32 mutant that
 renders the CCR5
 receptor unexpressed; a
 cell with this mutation
 phenotype is incapable of
 binding HIV R5 strains
 (homozygote frequency
 1%, heterozygote 10%,
 gene is almost
 exclusively in N.
 European Caucasoids)
 Because R5 strains
 mainly replicate in
 monocytes, they used to
 be termed  MT-tropic or
 monocytotropic
 Because T cell lines only express
 CXCR4 coreceptors and respond
 to HIV infection by forming
 syncytia, earlier X4 strains were
 termed  syncytia inducing, T-
 tropic
 HIV strain early in infection and
 mutation of R5 to R4
 Early in infection R5 is almost
 always the sexually transmissible
 form of the virus
 Primary isolates from
 newly infected
 individuals are usu R5
 Mainly replicate in
 monocytes; infect
 activated and memory T
 cells at lower efficiency
 Much of the viral load in
 earlier phase of HIV
 infection is in the
 monocytes and
 The difference between the
 two strains is relatively
 subtle, on the order of 5
 amino acid sites
 In general R4 is more
 positively charged
 Mutation of R5 to R4
 results from a change in
 the V3 envelope loop
 sequence (comes down
 and interacts with CD4
 and the chemokine
 receptor)
 Evolution of tropism in
 4

Offline J220

  • Member
  • Posts: 587
Thanks for the interesting articles, but I suggest that you make a better effort at formatting the text in the post so it is easier to read. If you just copy from an html ocoument and paste it onto the text box it carries the html formatting, making it kind of a jumble. The title of your post also is a bit unclear. Just friendly suggestions. Regards, J.
"Hope is my philosophy
Just needs days in which to be
Love of Life means hope for me
Born on a New Day" - John David

 


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