July 25th HIV/AIDS lecture continued

*** review.***

The rise of AIDS:

#1 cause of death in Africa, #4 worldwide in the US - charting the causes of death in the 25-44 age range: Men (top) note: since 1994 AIDS is the leading cause of death
Women

********

–What caused the virus to spread beyond small, contained outbreaks to become epidemic and then pandemic?

 roads and planes and more travel and movement.

Structure of HIV-1 (Box p. 726)

Genome: ______2____ identical (duplicate) strands of ___RNA_________.

Enzymes:

1-Reverse transcriptase

2- Integrase

3- protease

3 surrounding layers:

Capsid

Layer of ____matrix (tegument)_______________ proteins

Envelope (plasma membrane taken from ______peplomers_________________)

http://www.youtube.com/watch?v=9leO28ydyfU

*** see video posted on blackboard***

2 proteins make up peplomers:

–Head = gp 120

–Stalk = gp 41

HIV-1 Life Cycle (Fig. 25.19)

1- ATTACHMENT  (Fig. 25.20)

Viral - gp-120 attaches to host cells CD-4 receptor site and co-receptor.

CD-4 cell types:
1. -T helper,
2.- Macrophages:includes fixed cells such as  Dendrite Kuppfer, microglial cells;
3.smooth muscles

***

2. Penetration
* Fusion of host cell and viral envelope (gp-41); * Uncoating
* Fusion inhibitor drugs: block penetration of virus (gp-41 interference)
*** list of drugs: Fuzeon, Selzentry ...

******stop and draw two steps on big chart************



 
*** she labels the drug targets: fusion and penetration inhibitors**** she drew step 1 and 2****

3. Reverse Transcription step

target drug::::: AZT (*** remember this one, oldest drug, approved for pregnant mothers) , dd1, ddC, d4T, 3TC (7 drugs + 7 combinations)

 Nucleoside reverse transcription inhibitors (chapter 10)

 * Base analogue- drugs replace nucleotides in DNA (roadblock)
             -AZT, dd1, ddC, d4T, 3TC (7 drugs + 7 combinations)

 * mistake because viral enzyme are fast and sloppy

Fig. 10.7 common nucleoside (base analogue) antiviral drugs




Non-nucleoside reverse transcriptase inhibitors
      * affect reverse transcriptase enzyme directly
      * 4 drugs, 1 combination


4. Incorporation
  * Integration of viral DNA into genome using integrase
  * Integrase inhibitor drugs block incorporation


 
*** my youtube channel for Microbiology: Microbiology Youtube channel

I'll add more videos when I get a chance.

*** stop and draw two steps on diagram.....draw host DNA, Reverse transcriptase enzyme makes viral DNA from viral RNA....viral DNA becomes double stranded and attach to host DNA.. becomes provirus... step 3: reverse transcription label... step 4. incorporation label...put drug targets on for those two steps: protein inhibitors * nucleoside RT inhibitors * non-nucleoside RT inhibitors *D0 integrase inhibitors*****break*****

5. Synthesis (no drug targets)
 transcription of incorporated viral DNA into viral RNA
Newly made strands produced are used to :
1. genome copies for new viruses
2. mRNA to be translated into proteins

Protiens MADE:

Gp-120 and gp-41 proteins (peplomers parts) are produced in cytoplasm and immediately go to cell membrane
protease and integrase enzymes
other proteins made in large multi-proteins to be cut into small proteins with protease later
    - Final enzyme reverse transcriptase
   -capsid building blocks = capsomers
   - stabilizing proteins = matrix proteins

6.  Assembly
   * components move to cell surface
    * (completed after release)

7. Release by budding
-Envelope and peplomers wrapped around proteins and genome

6B Maturation (finish assembly) (9 drugs + 1 combination)

* Protease Inhibitors block:
      - cutting multi-protein into individual:
                - capsomeres
                - matrix proteins
               - enzymes






*** add to picture.... regular transcription.. viral RNA is going to be conserved and used as genome copies... some are to be translated by ribosome into viral proteins.....you will make peplomer proteins separately (gp140 and gp41)integrase separately, protease separately, the rest made in a long protein containing: capsomers, matrix proteins, reverse transcriptase enzyme......synthesis starts where you make the RNA and when you make the proteins.......NO new drugs to add to synthesis step... now move on to Assembly... peplomer proteins go into the membrane.. genome , protease, integrase, multiprotein gather down near section where peplomer proteins go.....this is stage 6, assembly, nothing unusual.. no drug targets.....7. release through budding....cell surface will have surface molecules, peplomer proteins, genome copies inside, protease, integrase inside, and then the multiprotein which has reverse transcriptase, capsomers and matris.....this is step 7.. no drug targets for budding but where you will see the final drug target is when protease cut the multiprotein into various places and folding occurs and the entire virus is done.. matrix right under envelope to stabilize it... then capsid inside of that and then genome and protease and integrase and reverse transcriptase.....drug target E: protease inhibitor***

Sample test question: 1. which viral enzyme is used first after it is made? protease
2. which viral enzyme is used first in the new host cell? reverse transcriptase

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Progression of HIV Disease    Fig. 25.21

Stage one: occurs ___weeks_____ after infection

Symptoms are : flu-like, swollen lymph nodes.

What is happening to CD-4 cells are killed after 6 hours but replaced by stem cells from your bone marrow

Immunocompentence is still high.

Stage two:  occurs _months___ after infection

 - no symptoms

 - CD-4 cells replaced (may have swollen lymph nodes but some people have it normally)

Stage three:  occurs __years___ after infection

Symptoms are: immune response failing (CD-4 replacement decreased)

********(babies infected by mom, will be at this stage by the time they are 2 years old)

 - opportunistic infections begin: (most common)
      * Pneumocystis carmi pneumonia (eukaryotic parasite, does not respond to antibodies or antiviral)
      * repeated severe, or systemic yeast infections
      * Cryptosporidium diarrhea ( a liter of fluid an hour, cloridine resistant)
      * Herpes inflections (simplex, zoster (shingles), CMV (causes blindness))

**** Table 25.5 ***

Stage four: (also called __AIDS__) occurs __years (often 15 or more)____ after infection

What is happening to CD-4 cells: drops below 200 cells/microliter

Symptoms include: opportunistic disease and other unusual diseases appear:
    * Prior opportunists: more common and sever
    * M. tuberculosis/ M. aviium complex (MAC) (acid fast)

    * cancers (Kaposi's sarcoma) Fig. 18.25
    * wasting disease (your body digest your own tissues)

Why HIV/AIDS is unusual:

Why no vaccine: 
            -HIV evolves rapidly (many strains and types) 
            -Ethical testing of vaccine?

Transmission depends upon many factors:
          - viral load of the body fluids varies
         - body fluid has cells? 
        - case of entry of virus into bloodstream 
                * trauma (rape, or anal) 
                * presence of other sexually transmitted diseases

Transmission of HIV
(Ranked in order of likelihood of infection)