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Author Topic: hiv science how why imm sys war w/hiv -- part 2  (Read 3865 times)

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Offline bimazek

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  • Posts: 781
hiv science how why imm sys war w/hiv -- part 2
« on: January 10, 2007, 06:17:52 PM »
hiv science ----part 2

 Page 5
 macrophages and the
 numbers of CD4 cells
 remain stable but
 an individual from R5 to
 R4 is the precursor to
 developing immune
 The key is the ping pong
 effect among infection
 by the R5 strain, clinical
 latency, gradual mutation
 to R4 strain infecting
 naÔve T cells, loss of the
 epitope war*, loss of the
 ability to control viral
 replication, and
 development of AIDS
 *epitope war: battle of epitopes, typically those recognized by antibodies or T cells; the interaction
 between the expressed genome of HIV and our immune systemís ability to recognize and control it
 Acute HIV-1 Infection: HIV is controlled by the immune system but only for a period of time
 Clinical: Typical viral infection
 At the end of the virus
 Headache, retro-orbital pain, myalgias,
 pharyngitis, fever
 Nonpruritic maculopapular rash in first 1-3
 Adenopathy and malaise may last for
 several months or may not even be noticed
 Transient thrombocytopenia and CD4 T
 cell lymphopenia
 Rapid appearance of marked viremia with
 R5 strain infecting monocytes and memory
 CD4 T cells
 Results in acute CD4 T-cell lymphopenia
 Integration into memory CD4 T cells
 provides a long-lived reservoir where HIV
 can remain latent
 The virus is brilliantly clever in utilizing
 features of the immune system
 Structurally the initial virus strain has no,
 or very limited diversity, so infection
 apparently occurs only by one strain, even
 though what is transmitted from one person
 might be hundreds of different strains
 Anti HIV Immune Response
 With onset of CD8 response viremia falls from5X10
 /mL to <10
 /mL, sometimes undetectable
 CD4 count rises from400 to  800/ĶL
 A key concept that isnít fully understood: Degree of viral suppression and return of CD4
 levels (set point) varies and correlates with the length of the asymptomatic period; there have
 been attempts to treat with retrovirals and other means to manipulate the set point
 HIV species begin to diversify, viral variants appear reflecting successful attempts to escape the
 suppression of CD8 response, body brings in another CD8 type (concept of epitope war)
 The virus mainly persists in monocytes and macrophages
 Page 6
 Experimental infection
 with SIV (Simian) of
 intact and CD8 depleted
 monkeys illustrates role
 of CD8 T cells in
 controlling viremia
 CD8 Response to HIV-1
     Establishes asymptomatic phase of infection
     CD8 responds to HIV peptides by activation, clonal expansion, and differentiation to effectors
     2 Critical Events:
 1. Specific lysis of HIV-infected target cells (macrophages and CD4 cells) via perforin
 pathway and/or apoptosis via upregulation of fas ligand
 2. Strong inhibition of viral infectivity by release of chemokines (MIP-1a/Ŗ, RANTES) that
 bind to CCR5 and block coreceptor dependent entry of R5 HIV-1
     Lastly, release of IFN-? and secondarily TNF-a ?? LTR-driven transcription
     Excessive anti HIV CD8 response may result in diffuse infiltrative lymphocytosis syndrome
 (DILS) stimulating Sjogrenís syndrome
 T cell infiltration leads to dry eyes, loss of salivary gland secretions
 Disabling autoimmune disease with autoantibodies resembling those found in
 lupus patients
     DILS is usually associated with long term non-progression and a favorable outlook, but it is also
 associated with a type of B cell lymphoma that occurs early in the course of HIV infection,
 reflecting chronic cell stimulation (begin in lacrimal gland or salivary gland)
 Thwarted Immunosurveillance
 No expression of viral peptides
 Also inaccessible to Rx
 Reasons for failure of CD8 cells to totally eliminate HIV-1
 1. HIV may integrate into a region of the
 heterochromatin (e.g. in memory CD4 T cell) where
 it remains undetected and inaccessible to therapy for
 as long as that CD4 T cell is quiescent; activation of
 CD4 cell leads to reexpression of HIV
 2. Nef and vpu diminish MHC class I expression, thus
 avoiding infection surveillance, especially when in
 Extra credit: Nef is particularly clever since it decreases
 HLA-A and HLA-B, but not HLA-C and HLA-E, thus
 avoiding most NK cell surveillance; what goes on in the
 3. Dendritic cells are used as a  Trojan Horse
 Immature DCs typically located in the
 submucosa express a C-type lectin CD-SIGN
 HIV-1 envelope binds to CD-SIGN with high
 The virions are internalized and remain in acidic
 endosomal compartments while the DC matures
 Intact infectious virions are reexpressed on the
 surface when the CD enters the lymph node
 Page 7
 Why donít antibodies work?
 It takes too long for antibodies specific for a
 particular strain to develop
 The virus is evolving at a rate too great for
 the immune system to keep up with
 Immune Responses in Asymptomatic Phase: Depends on a relatively few CD8 clones
     Maintenance of <5-20 CD8 expanded memory/effector CTL clones, each comprising 1-5% of
 CD8 repertoire
     Clones each recognize different HIV peptides, great individual variation in number and particular
 peptide recognized
     Many clones = generally good outlook for long asymptomatic period ( 12 year), few clones =
 rapid progression of HIV infection (< 2 years)
     The number of clones and survival duration correlates with the viral  set point  established in the
 acute infection; set point reflects the adequacy of a personís immune system to respond to HIV
 Long term non progresors
     Subset of infected individuals that remain asymptomatic for  12 years
     Particular HLA types, e.g. HLA-B27, B57
     Low levels of plasma virions, CD4 counts  500/ĶL
     High CD8 counts, maybe  3000/ ĶL
     CTL response is against critical conserved region of HIV gag, env, pol that cannot readily be
 mutated without loss of viral function; This appears to be the key factor
     High chemokine release (RANTES, MIP)
 The particular peptide that is recognized in HIV by cytotoxic CD8 cells is critically important to
 whether the infection will be controlled
 If the recognized peptide encodes a region that is essential for HIV function, any mutation in that site will
 be lethal for the virus; for this to occur to conditions must be met:
 1) The correct peptide must be presented. The individualís class I MHC alleles are the major
 determinant of which peptide is recognized. They determine the particular peptides that are bound and
 2) The peptide must be recognized by a T cell clone. Not all bound peptides are equivalently
 recognized by T cell clones in the repertoire. Only a few bound peptides are  immunodominant,  and
 readily recognized.
 The T cell ligand is a combination of peptide and class I MHC, and it demonstrates the importance of
 polymorphism in the HLA molecule
 The environment formed by peptide binding properties of MHC molecules influences evolution of
 the HIV infection. HLA alleles influence the number of peptides in a protein that can be recognized
 (e.g. HIV envelope protein)
 Allele: HLA-B*27052
 Each allele is able to bind a number of different peptides
 Page 8
 Basis of outcome with HLA type
 HLA B35 Rapid Progression
 HLA B27 Slow progression
     PXXXXXY peptides recognized if any are
 in noncritical parts of HIV genome
 permitting mutations in MHC anchor
     Peptides are weak stimulators
     Rapid viral replication and evolution not
     RXXXXXX[KRYL] peptides recognized
 are often in critical parts of HIV genome
 and mutations not permitted in MHC
 anchor or TCR recognition residues
     Peptides give strong stimulation
     Viral replication and evolution greatly
 Immune Response
 Asymptomatic phase:
 Shifiting immunodominance in epitope war
 Near end of asymptomatic period
     Usually recurrent pattern of HIV escape
 from immunodominant CTL effect by
 mutation followed by regain of CD8
 control via next HIV peptide that can be
 presented by MHC I and recognized by
 TCR in hierarcy of HIV peptide
     During the progression of the infection in a
 person a huge number (swarm) of mutant
 forms arise (quasispecies)
     Ultimately return of high viral levels,
     Rate of viral infection and potential
 mutations increases. Definitive viral
 escape occurs when virus is no longer
 presented by MHC to available CD8 clones
     Continual generation of env mutations
     Selection against R5 variants by CD8
 CCR5 chemokines that blocks infection is
 finally bypassed
     Change in cellular tropism by env
 mutations leads to R4 phenotype
     Enhanced R4 tropism leads to more
 significant impairment of naÔve CD4
 compartment-This is the critical undoing
 of the immune response
 Loss of the  epitope war : 1) Viral control lost 2) Mutation to different tropic strain
 Reasons for CD4 T cell loss in HIV infection: During asymptomatic phase and transition to AIDS,
 there is an accelerated loss in number of CD4 T cells
     Activation of large numbers of mature and naÔve CD4 cells by cytokines, etc during antiviral
 response (bystander activation) leads to loss of repertoire by physiologic apoptosis because T
 cells arenít activated by signal 1 and 2 but rather, by an inappropriate mechanism
     Thymic derangement results in failure to generate new naÔve CD4 T cells to repopulate repertoire
     CD8 T cell killing of infected CD4 T cells
     ACDD by NK cells, etc to infected CD4 T cells
 Page 9
 Another reason for CD4 loss
 CD4 activation initiates HIV
 HIV replication initiates CD4
 T cell activation causes a marked
 increase in cyclin T1, NFAT and
 This links viral expression to T cell
 AIDS is the Consequence of progressive CD4 loss:
 T cell immune function progressively deteriorates reflecting the central role of CD4 T cells
     Loss of antigen-specific clonal responses (in vitro proliferation and skin test to various antigens,
 including those from immunizations)
     Loss of ability to generate new CD8 responses
     Loss of Mixed Lymphocyte Culture responsiveness
     Loss of PHA responsiveness
 Clinically, there is a hierarchy of infections developing as immune deficiency progresses to frank AIDS
 reflect differing roles of CD4 T cells
     Candida (Thrush)
     Salmonella-microbial persistence (Reactive arthritis?)
     Mycobacterium tuberculosis reactivation, Cryptosporidium
     Activation of latent herpes zoster
     EBV reactivation and development of polyclonal lymphomas, Kaposiís sarcoma (HHV-8)
     Pneumocystis carinii
     Progressive cytomegalovirus infections, M. avium complex
 Why has an HIV virus vaccine failed?
     Immunization with rENV should, in theory, produce neutralizing antibodies and perhaps CD8
     But neutralizing antibodies induced by immunization fail to protect
     A live attenuated virus has not yet proved achievable
     For a CD8 vaccine one major issue is providing HIV peptides able to bind divergent MHC class
 I of a large proportion of the population
     The second larger issue is immense heterogeneity of HIV, need many immunodominant peptides
 directed to critical regions of viral genome because no cross protection
     Some strains, mainly R4 tropic have evolved to circumvent MHC presentation by some common
 alleles. With high numbers of infected individuals, there is increasing chance of infecting a
 person with the same HLA by a strain evolved to avoid immunosurveillance
 There still is hope in that 1) HIV is a disease that one neednít acquire, and 2) some people are long-term
 survivors (e.g. Nairobi prostitutes constitute a minority of people who are repetitively exposed to HIV but
 donít acquire it-their immune systems can respond to the virus)

Offline thirtysomething

  • Member
  • Posts: 124
Re: hiv science how why imm sys war w/hiv -- part 2
« Reply #1 on: January 11, 2007, 09:56:52 PM »
really bad formatting ! If you continue posting articles in this zig-zag way, nobody's going to read it! Spend 5 more minutes and format the article  ;)


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