Structure and life cycle of hiv
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Structure and Life Cycle of HIV. Lecture 11 Life Cycle of HIV-1 (II) HIV Genome. Virus structure. Virus structure. HIV-1 Structure. HIV is a fairly complex virus, although by no means the most complicated known.

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Structure and life cycle of hiv

Structure and Life Cycle of HIV

Lecture 11

Life Cycle of HIV-1 (II)

HIV Genome


Virus structure

Virus structure


Virus structure1

Virus structure


Hiv 1 structure

HIV-1 Structure

  • HIV is a fairly complex virus, although by no means the most complicated known.

  • The ribonucleoprotein particle is encapsidated by a capsid made up of a capsid protein (CA).

  • The capsid environment also contains other viral proteins such as integrase and reverse transcriptase.

  • The capsid is in turn encapsidated by a layer of matrix protein (MA).

  • This matrix protein is associated with an envelope.


Viral attack

Viral attack

  • Following infection with any virus for the first time, the various components of the immune system go on 'red alert'.

  • Initially, the viruses inside susceptible cells multiply unchecked, but after a short time there is the first immune response. This is the T-cell response, made up of both 'killer' T-cells (CTLs) which destroy virus-infected cells, and 'helper' T-cells (CD4 T–cells).

  • The helper cells secrete an array of chemicals known as cytokines. Some of these molecules are involved in the control of inflammation; others have antiviral activity, and others stimulate B cells to produce antibodies against the invading virus.


Enter hiv

Enter HIV

  • Once infected by HIV a person is said to be HIV positive because they give a positive result to the test for antibodies to HIV. This condition generally persists throughout life.

  • Present on the surface of helper T-cells and macrophages are receptor proteins, notably CD4.

  • A glycoprotein on the surface of H|V, called gp120, binds to this receptor.

  • Following fusion of the viral and CD4 T-cell membranes, HIV becomes enclosed within the cell.

  • Here, the genetic material of the virus (RNA) is converted through the action of viral reverse transcriptase into DNA.

  • This 'proviral DNA' then becomes integrated into the host cell genome.

  • This DNA remains latent until genetic material of the host CD4 T–cell is replicated or translated into proteins.


The display system

The display system

  • Once produced, particular viral proteins will be cleaved by the cell’s enzymes into short peptides and transported into the endoplasmic reticulum.

  • Here, the peptides fit and bind on to a cell protein called HLA. The combined viral peptide and HLA molecule then become inserted in the CD4 T-cell membrane, so exposing the foreign peptide to the cells of the immune system .

  • Effectively, the HIV-infected CD4 T-cell is sacrificing itself to cytotoxic T-cells (CTLs), for the good of the whole organism.


Triggering immune response

Triggering immune response

  • The precise binding of the HLA molecule to a viral peptide is vital to stimulate a successful immune response.

  • Unfortunately, HIV is a highly variable virus with an enormous potential for mutation. Each time HIV reverse transcriptase makes a DNA copy of the viral RNA genome, it makes at least one error - one mutation.

  • So, on average, each one of the billion or so virus particles made every day by an HIV-infected individual will contain one mutation. Consequently, the virus may escape from both CTLs and activated (see Figure 5). If this is the case, HIV multiplying rapidly, destroying CD4 T–cells and progression to AIDS follows (see figure 4)


Structure and life cycle of hiv

קצת על חלבונים ...

  • חלבון הינו שרשרת של חומצות אמיניות.

  • במצב תקין, אותן חומצות אמיניות, מרחפות באופן חופשי בחלל התא (מחוץ לגרעין).

  • ב-DNA מצויות הוראות הייצור של כל חלבון, קרי: אילו חומצות אמיניות ובאיזה סדר ישורשרו על מנת ליצור את אותו חלבון.


Structure and life cycle of hiv

ובמושגים של הגוף ...

  • "ספר מתכונים" – זהו המידע התורשתי, ה-DNA.

  • "מתכון" – זהו כל אחד מהגנים שמרכיבים את ה-DNA.

  • "ספר" ה-DNA כתוב בשפה של 4 אותיות (A,T,C,G) הנקראות נוקליאוטידים (ח' גרעין).

  • כל מילה בשפה מורכבת משלוש אותיות. לדוגמא: ATACGAGCTGTT.

  • מתוך המידע שב-DNA הגוף צריך להרכיב חלבונים.

  • רוב המידע ב-DNA אינו מיועד להרכבת חלבונים, אלא למשל לצורכי בקרה (ויש הטוענים שחלקו הגדול אינו מכיל מידע כלל).


The central dogma

The Central Dogma


A revised central dogma

A revised central dogma


Structure and life cycle of hiv

מדנ"א לחלבון

שכפול

רנ"א-רנ"א פולימראז

שכפול דנ"א-דנ"א פולימראז

תעתוק

דנ"א-רנ"א פולימראז

תרגום

רנ"א מוביל

רנ"א ריבוזומלי

חלבון

רנ"א

דנ"א

תעתוק הפוך

Reverse transcriptase


Structure and life cycle of hiv

תהליך ייצור החלבונים

  • התהליך מורכב מכמה שלבים עיקריים:

    • שעתוק (Transcription) - העתקת הוראות הייצור של החלבון המבוקש. כלומר, העתקת הקטע הרלוונטי (גֶן) מה-DNA לסרט חדש של RNA.

    • שחבור (Splicing) - חיתוך האזורים הלא-רלוונטיים ואיחוד המקטעים.

    • תרגום ה"מתכון" (Translation) ויצירת החלבון.


Gene says hello

Gene says “Hello”

  • "Hi! I'm Gene.  I have a little time before I need to get back to work, so I'd be happy to show you around my world, the chromosome.


Meet gene

Meet Gene

  • "There are a lot of us Genes here, so it can get pretty confusing.  We are kinda the brains behind the whole operation.

  • Each of us Genes have only one job to do.  That's to remember exactly how to construct a single protein.


Gene introduces himself

Gene introduces himself

  • I, for instance, keep the blueprint for making insulin.  Insulin tells your body that the glucose (sugar) levels are too high and that your cells should begin using it to make fat.


Gene introduces his pal

Gene introduces his pal

  • A pal of mine, whose name is also Gene, and who lives on another chromosome, keeps the blueprint for making hemoglobin.

  • Hemoglobin is the protein that carries oxygen around in your bloodstream.


Gene has some free time

Gene has some free time

  • He's a pretty busy fella, all right.  Your body needs to make hemoglobin all the time.  But, me, I don't have to work every minute.  Your body doesn't need insulin except right after you eat.  So, I get some time off between meals.  That's why I can show you around our place.


Meet gene and polly

Meet Gene and Polly

  • "Let me introduce you to Polly.  Polly is not a Gene like me. She's not even DNA.

  • Polly is a protein: a special protein called an enzyme.

  • Her real name is "DNA Polymerase" but we just call her Polly."


Polly talks

Polly talks

  • Gene and I are made out of small pieces hooked together to make a long strand; like train cars are the small pieces that are hooked together to make a long train.  I'm made out of small pieces called 'amino acids'. 


Polly shows a nucleotide

Polly shows a nucleotide

  • Gene and the rest of the chromosomes are made from small pieces called 'nucleotides'.  Here, let me show you what a nucleotide is.


Polly shows a nucleotide1

Polly shows a nucleotide

  • Here you can see nucleotides being made from a base, a sugar, and a P (phosphate).  There are four factories like this, each making one type of nucleotide for me to use in making a new chromosome.  One factory makes a nucleotide with the name 'adenine' that we just call 'A'.  There are also factories for making 'thymine' ('T'), 'cytosine' ('C'), and 'guanine' ('G').


Dna genes

DNA - genes

  • "Gene here.  I'm back to tell you a bit about me and the rest of the Genes.  We Genes are stretches of DNA and we all have assigned places on the cell's chromosomes.  Oh, there's all sorts of other folks that have assigned places, but they're not Genes like us.  


Meet rna

Meet RNA

  • HOWDY, PARTNER!!!  How ya doin'? I'm RayNA!  Maybe ya heard of me!  Most people have, ya know!  I'll show ya how DNA is used to create proteins.  I, by the way, play a highly significant role in that process.  Those Genes and those proteins think they're such hot stuff!  They couldn't get along without me, I tell ya!


Structure and life cycle of hiv

RNA

  • What's that?  What am I?   Well, I'm RNA, don't ya know!

  • RNA is like DNA, but we're smaller and more mobile. Need to be mobile, don't ya know.

  • Look close at my arm and you'll see that I'm made of nucleotides like Gene and the rest of the DNA is. But my nucleotides are slightly different.


Protein synthesis

Protein Synthesis

  • Hey!  Look who came to meet us!  The ribosomes!  I'm always popular!


Ribosome

Ribosome

They always jump all over me like that!   It's just like coming home and having your puppy greet you at the door.  Do you see how the ribosome are split into a small part and a large part.  Each of those two parts is called a 'subunit' and is made up of many proteins and RNA.  It's a special RNA made expressly for the purpose of using in ribosomes, called 'ribosomal-RNA'.   I'm what they call 'messenger-RNA' because I carry the message of how to make a protein. 


Protein synthesis1

Protein Synthesis

  • "When the ribosome subunits jump onto my arm, they snuggle my arm between them and become a whole ribosome.  This is the beginning of protein synthesis.  They can translate the secret code of my nucleotide sequence to create a protein with the correct amino acid sequence.

  • Let's watch them make a protein, then I'll show you the secret code and how it works.


Structure and life cycle of hiv

The ribosome crawls along messenger-RNA like me, and translates my secret code into which amino acid belongs where.  Then it super glues the amino acids together.   The chain of super glued amino acids is called a protein.


Structure and life cycle of hiv

מבנה ה- HIV


Hiv 1 structure1

HIV-1 Structure

  • מורכב ממעטפת חיצונית הנתרמת על ידי תא המאכסן.

  • בעל קופסית חלבונית.

  • ה- HIV הוא רטרווירוס, בעל חומר תורשתי רנ”א אשר משתכפל על ידי יצירת דנ”א מתווך.


Hiv proteins

HIV proteins

Protease

Reverse Transcriptase


Genome organization

Genome organization

The virus has a diploid genome (2 copies of RNA genome per virus particle). The genome codes for at least three genes: gag, pol and env:

gag - codes for the core proteins, structural virion components

pol- reverse transcriptase

env- envelope glycoprotein


Structure and life cycle of hiv

LTR -Long terminal repeat - is a regulatory sequence at each end of the genome.

LTR - gag - pol - env – LTR

Their presence allows integration into the host chromosome and controls gene expression


The genome of hiv

THE GENOME OF HIV

Since HIV has a more complex life cycle that simple retroviruses such as RSV and it appears that HIV can control its replication in a more complex fashion, we might expect more genetic information but this is not so.

גודל לא קובע!


Structure and life cycle of hiv

HIV genome is 9749 nucleotides-- about the same size as any other retrovirus, for example Rous sarcoma virus (RSV).


Structure and life cycle of hiv

  • The genome of HIV is more complex than RSV, however, since it has extra open reading frames that clearly code for small proteins. Some of these are protein synthesis-controlling proteins.

  • The HIV genome has nine open reading frames but 15 proteins are made in all

  • The GAG gene and the GAG and POL genes together are translated into large polyproteins which are then cleaved by a virus-encoded protease that is part of the POL polyprotein.


Images

IMAGES


Structure and life cycle of hiv

43

  • GAG polyprotein is cleaved to into four proteins that are found in the mature virus: MA (matrix), CA (capsid), NC (nucleocapsid), p6

  • POL polyprotein is cleaved to: PR (protease), RT (reverse transcriptase), IN (integrase)

  • ENV gene is translated to a polyprotein (Gp160) which is then cleaved by a host cell protease that is found in the Golgi Body.

  • Gp160 is cleaved to: SU (Gp120) and TM (Gp41)


Frameshift

48

Frameshift

ב95% ריבוזום עוצר בקודון העצירה ורק gag נוצר. ב5% ריבוזום "קופץ" מעל אות הסיום למסגרת קריאה –1 כדי לתרגם pol בנוסף לgag.


Structure and life cycle of hiv

51

6 חלבונים נוספים(קטנים)

  • חוץ מ-9 חלבונים מקודדים ב 3 גנים עיקריים (פול, גג, אנב) יש עוד...


Structure and life cycle of hiv

  • In a addition to the nine protein derived from GAG, POL and ENV, there are six other proteins made by HIV. Three of these are incorporated into the virus (Vif, Vpr and Nef) while the others are not found in the mature virus: Tat and Rev are regulatory proteins and Vpu indirectly assists in assembly. The genes that encode these proteins are known by three letter names that are derived as follows:


Structure and life cycle of hiv

  • TAT: Trans-Activator of Transcription

  • REV: Regulator of Virion protein expression

  • NEF: Negative Regulatory Factor

  • VIF: Virion Infectivity Factor

  • VPU: Viral Protein U

  • VPR: Viral Protein R


Structure and life cycle of hiv

  • These genes encode small proteins. They overlap with the structural genes (especially ENV) but are in different reading frames. From the above diagram of the organization of the HIV genome, it can be seen that some are encoded in two exons (unlike the structural genes) and therefore their mRNAs can be derived by alternative splicing of structural gene mRNAs. This is rather important to the way in which the levels of these are controlled. Mutants in the TAT and REV genes show that their proteins are both necessary for virus production.


Structure and life cycle of hiv

גורמי התעתוק

קומפלכס התעתוק, המורכב מגורמי התעתוק התאיים, נוצר על גבי ה-LTR ומשפעל ביטוי לא יעיל של הגנים הנגיפיים. הRNA הנגיפי המתועתק במערכת זאת עובר מספר שחבורים תוך כדי מעבר לציטופלזמה.


Structure and life cycle of hiv

TAT

TAT gene product binds to a sequence in all of the genes of HIV and positively stimulates transcription. It is thus a positive regulator of protein synthesis, including its own synthesis.


Structure and life cycle of hiv

חלבון בקרת השחבור Rev

כמו Tat כך גם Rev משומר בכל Lentivuruses. חלבון Rev נקשר לאתר ייחודי ארוך קרוי RRE (Rev Responsive Element). האתר נמצא בתוך גן env באזור הכי שמור באבולוציה!


Structure and life cycle of hiv

REV

  • REV binds to an element only in the mRNA for structural proteins (GAG/POL/ENV) and regulates the ratio of GAG/POL/ENV to non-structural, controlling protein (TAT/REV) synthesis. When REV levels are high, structural protein synthesis rises and controlling protein synthesis falls. Thus REV inhibits its own production and that of TAT.

  • The normal result is homeostasis, low or non-existent virus production and latency in the resting CD4 cell.

  • There is an inherent problem in HIV's lifestyle. It uses genomic RNA as its messenger RNA. This RNA is unspliced and the nucleus has a mechanism to prevent unspliced mRNAs from leaving the nucleus and being translated. It is the function of Rev to overcome this problem.


Negative factor nef

גורם בקרה שלילי Negative factor (Nef)

The name, NEF, comes from negative factor.Originally, it seemed that virions that lacked NEF grew better than wild type. Now the consensus is for the opposite, that is that virus produced in the presence of NEF is a little more infectious than virus produced in its absence.


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