Envelope glycoproteins

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					Envelope glycoproteins
• gp120
   Is a surface glycoprotein attached to the viral
     membrane it recognizes specific receptors on
     the surface of the target cells.

• gp41
  Mediates fusion of the host and viral membranes
     and thereby allowing the virus to enter the
     host cell
HIV core
• The core of the virus is encased in a cone-
  shaped structural protein, p24 or capsid
• Core consists of:
   • two single-stranded RNA molecules that
     form the RNA genome of the virus, and
   • three enzymatic proteins,
       reverse transcriptase
       integrase
       proteases
HIV genome

Most retroviruses have three common genes,
  referred to as the gag-pol-env genes.
• Gag encodes the proteins that form the core
  of the virion.
• Env encodes the envelope glycoproteins and
• Pol encodes the viral enzymes (reverse
  transcriptase, proteases and integrase)
HIV genome
• HIV-1 is however more complex than other
  retroviruses and contains additional genes,
  the HIV regulatory genes
• These genes code for proteins involved in
  regulation of gene expression
• Some play a role in the HIV disease
  progression

  * tat, rev, nef, vif, vpr, and vpu are regulatory genes
Cellular receptors for HIV

HIV targets the vital defense mechanism
Two receptors are required for the virus to gain
  entry into the host cell:
      • CD4 receptor
      • co-receptor (chemokine receptor)
Cellular receptors for HIV
Cells expressing the CD4 receptor
• CD4 T lymphocytes
• Monocytes
• Macrophages
• Langerhans cells in the mucous membranes and skin
• Glial cells in the central nervous system (astrocytes,
       microglia, follicular dendritic cells)
• Chromaffin cells in the intestine
Other cells
• Cervical cells
• Retinal cells
• Renal epithelia
Cellular receptors for HIV
Chemokine co-receptors

The chemokine receptors are regular receptors for
  small molecule chemical messengers called
  chemokines.
They mediate fusion between HIV and its target
  cells.
• CCR-5 found on both T lymphocytes and
  monocytes
• CXCR-4 found on T lymphocytes

  * normally functions as receptors for chemokines in the
  body.
HIV tropism

• Co-receptors also determine the cellular
  tropism of HIV-1
• T lymphocyte cells are the main X4 co-
  receptor cells
• T-tropic HIV-1 strains bind to the X4 co-
  receptor cells (mainly T cells)
• M-tropic HIV-1 strains bind to the R5 co-
  receptor cells like the macrophages
Replication cycle of HIV
Replication cycle of HIV
Attachment and fusion
• Binding of viral gp120 to target host cell CD4 receptor.
• gp41-mediated fusion of host and viral membrane then
   follows leading to internalization of virus. Co-receptor
   is vital in this stage.
• Reverse transcription of viral RNA to viral DNA
   catalyzed by RT enzyme occurs.
Replication cycle of HIV
Integration
• Viral DNA translocates to the nucleus and is integrated
   to host cell genome by the enzyme integrase forming
   proviral DNA.

Transcription
• Integrated proviral DNA may remain inactive in the
   nucleus or lead to viral RNA and mRNA transcription
   on cellular activation.

Translation
• HIV mRNA is translated to viral proteins
Replication cycle of HIV
Assembly
• Assembly of HIV proteins, enzymes and genomic RNA
   at the cell plasma membrane forms the viral particle.

Viral budding
• Budding of immature virion occurs and the core
   acquires its external envelope
• The third viral enzyme, protease cleaves the gag-pol
   precursor proteins during or just after budding
   yielding a mature, infectious virion

       * Potential for therapeutic intervention exists
  at all the different stages of the life cycle
Immunopathogenesis of HIV
Normal immune system consists of two arms:
  • innate (ancient) immune system and
  • adaptive (acquired) immune system

Innate immunity – non-specific, includes: Non-killer
  cell lymphocytes, dendritic cells, monocytes,
  macrophages, neutrophils, eosinophils, basophils,
  tissue mast cells

Adaptive immunity – characterized by: antigen-
  specific responses to a foreign antigen.
  Divided into:
   – cellular and
   – humoral immunity
Immunopathogenesis of HIV
Adaptive immunity consists of cellular and
  humoral immunity.
• T cells are the main mediators of cellular
  immunity (CD4 and CD8 T cells).
• B cells are the principal effectors of the humoral
  immunity and lead to specific antibody
  production once activated.
• CD4 T cells are the primary regulatory cells of
  both cellular and humoral immunity.
Immunopathogenesis of HIV
• Together, innate and adaptive immunity protect the
  host from infections by multiple organisms.

• HIV entry into the body initiates a complex chain of
  immunopathogenic mechanisms that lead to a vicious
  cycle of disease progression.

• Finally, profound immunosuppression characteristic
  of advanced HIV disease occurs.
Factors affecting HIV pathogenesis

Host factors
• cell-mediated immunity
     (CD4, CD8, B cells, NK cells,
     macrophages and Langerhans cells)
• humoral immunity
• genetic factors
Viral factors
Other factors
CD4

               WBC

 Neutrophils         Lymphocytes

                     CD4+    CD8+
  Cell-mediated immune response
CD4 T lymphocytes
Depletion and dysfunction of CD4 T cells with persistent
  HIV infection is central to the pathogenesis of HIV
  disease. CD4 T cells are the primary regulatory cells of
  both cellular and humoral immunity.

CD8 T lymphocytes
Cytotoxic CD8 T lymphocytes (CTL) – HIV–specific CTLs
  when activated, are cytotoxic to HIV infected CD4 cells
  and also to uninfected CD4 cells (innocent bystanders).
  CTLs appear early in primary HIV infection and play a
  major role in reduction of initial viraemia
Suppressor CD8 T lymphocytes – cause a non-cytolytic
  suppression of HIV replication
Cell-mediated immune response
B cells
Multiple functional abnormalities occur. Polyclonal
  activation, autoantibody production and
  hypergammaglobulinaemia

Non-Killer cells
Involved in the killing of HIV-infected cells

Monocytes and macrophages
These cells are not easily killed by HIV infection (low
  cytopathic effect) and are also targets of HIV.
  Therefore they act as reservoirs of HIV, an obstacle
  in eradication of HIV with treatment
Cell-mediated immune response
Dendritic and Langerhan cells
First cells to appear at inflamed mucosal sites. Carries
   the bound virus from inflamed site to the lymphoid
   organs rich in CD4 cells. Vital in initiating the above
   T- cell responses.
Humoral immune response
• HIV-specific antibody production by B cells is
  important in reducing the viraemia in primary infection
  stage
• Antibodies can be detected within six to twelve weeks
  by ELISA or Western blot
• No clear definite function of these antibodies, some
  have a protective function while others enhance
  progression of HIV infection
 Other mechanisms
Autoimmune mechanisms
• Production of antibodies against self (auto-antibodies).
   Several auto-antibodies have been detected in HIV-
   infected patients.

Apoptosis (programmed cell death)
• HIV infection may lead to abnormal activation of this
   process.

Anergy:
• Immunological unresponsiveness in HIV-infected patients
   due to inappropriate or wrong signaling of CD4 cells.
Lymphoid organs in HIV infection

• Plays a major role as a reservoir of HIV.
• Viral particles trapped within the FDCs
  network in lymph node germinal center.
• Persistent viral replication occurs, even
  during the clinical “latency” period facilitating
  further infection of CD4 T cells by trapped
  virus.
Lymphoid organs in HIV infection
• Expanding network of FDCs and chronic,
  persistent viral replication leads to follicular
  hyperplasia which presents clinically as
  enlarged lymph nodes.

• In advanced HIV disease, degeneration of
  FDCs network and involution of lymph node
  germinal center occurs and trapped HIV
  virions are released into circulation causing
  massive ↑ in plasma viremia in late disease
Genetic factors in HIV pathogenesis

• Some host genetic factors may influence the
  pathogenesis and course of HIV disease
• This is associated with different clinical
  conditions and different clinical courses of the
  disease, such as:
Genetic factors in HIV pathogenesis

• Long-term nonprogressors or slow progressors:
  CCR5 homozygous mutations are associated with ↓
  susceptibility to infection while its heterozygous
  mutation delays progression of disease.
• Rapid progression:
  HIV-infected patients with homozygous mutations of
  certain co-receptors (CX3CR1), showed rapid
  progression to AIDS. Also those with human
  leukocyte antigen, HLA B35.
• Exposed yet uninfected:
  They remain negative despite repetitive sexual
  exposure to HIV in high risk environment. In vitro
  tests have shown this to be due to co-receptor
  mutations.
Viral (HIV) factors
• Viral escape from immune response by mutations
• Viral attenuation:
      • E.g. a deletion in the nef gene (a regulatory gene), slows
                the rate of disease progression
• Viral tropism:
      • Progression from M-tropic to T-tropic viruses associated
               with ↑ pathogenicity and progression of disease
• Viral subtypes – different subtypes (M,N,O) have
  different virulence and transmissibility
Co-factors contributing to HIV
pathogenesis
Can be endogenous or exogenous factors

  Cytokines
  Chemical messengers like TNFα and β, IL-1 and IL-6
  (pro-inflammatory) are ↑ in HIV-infected persons and
  enhance HIV replication.

  Co-infection
  Of cells with HIV and other viruses like CMV, HSV
  type1, EBV, HTLV 1 and others can up-regulate the
  expression of HIV. Other microbes such as
  Mycobacterium tuberculosis and Mycoplasma also
  have a similar effect.

				
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