---
# System prepended metadata

title: Virology(RNA virus)
tags: [共筆]

---

# Virology(RNA virus)
###### tags: `共筆`


<h2 id="Picorna">Picornavirus</h2>

### Picornaviridae family
* <a href="#Enteroviruses">Enterovirus (腸病毒)</a>
    * <a href="#Poliovirus">Poliovirus (小兒麻痺病毒)</a>
    * Coxsackie A & B
    * Echovirus
* Hepatovirus
    * Hepatitis A virus (A型肝炎病毒)
* <a href="#Rhinovirus">Rhinovirus (鼻病毒)</a>

### Property
* Naked, small, <font color="limegreen">icosahedral capsid</font>
* <font color="red">**+ssRNA**</font>
* Resistant to pH~9, detergents, mild sewage treatment & heat
    > 可以經由**糞口傳染**
    > Except: Rhinovirus在酸中不穩定、最適生長溫度為33度
    * Most viruses are <font color="red">cytolytic</font>.
* Viral RNA is translated into <font color="red">polyprotein</font>.
### Life cycle
#### Genome structure
* 5' Noncoding Region
    * VPg
        * Covalently linked to the 5’ end of the genome
        * 留下的**primer**
    * <font color="red">IRES (internal ribosome entry site)</font>
        * 促進mRNA轉錄(不需要CAP)
* Capsid Proteins
* Nonstructural Proteins
    * **Protein processing** (Cut **polyprotein**)
    * Host shutoff
        * Polio2A ^pro^ cleaves **eIF4G**, <font color="red">inactivating most cellular translation</font>.
            > Polio mRNA用IRES而非5'-cap initiate translation
            > Causes **cell death**
    * RNA replication
* 3' Noncoding Region (3'-poly(A) tail)
#### RNA replication
* <font color="red">Cell membrane-associated replication</font>
* Viral **RNA polymerase (RdRP)**
* Host factors: accessory proteins

![](https://i.imgur.com/iQrmY50.png =600x)

---

<h3 id="Enteroviruses">Enteroviruses</h3>

* 腸病毒(Enteroviruses)++不常造成腸胃道疾病(Enteric disease)++
* **糞口傳染(fecal-oral route)**: 上呼吸道與口咽(Oropharynx)黏膜 -> Intestines
1. 於口咽部複製、亦會感染在小腸黏膜**培氏斑塊**(**Peyer’s patch**)的淋巴球
3. Primary viremia: blood stream
4. Target tissue (**tissue tropism** &cytolytic capacity )
    * Skin: 
        * <font color="red">Hand-foot-and-mouth disease(手口足症)</font>
        * <font color="red">Rash, herpangina(疱疹性咽峽炎)</font>
    * Muscle
        * Myocarditis(心肌炎)
        * Pericarditis(心包炎)
    * Brain
        * Encephalitis(腦炎)
    * Meninges
        * Meningitis(腦膜炎)
    * Liver
        * Hepatitis(肝炎)
5. Secondary viremia
* Viral, rather than immune, **pathologic effects** are responsible for causing disease symptoms.

<h3 id="Poliovirus"> Poliovirus</h3>

* Asymptomatic illness (>90%)
* Abortive poliomyelitis, the **minor illness** (5%): nonspecific febrile illness (高熱病)
* Nonparalytic poliomyelitis or **aseptic meningitis**(無菌性腦膜炎) (1-2%): back pain(背痛) and muscle spasms(肌肉痙攣)
* Paralytic polio, the **major illness** (0.1% to 2.0%)
#### Vaccine
* Sabin (沙賓)
    * **口服，活病毒**
    * **Life long immunity**
    * Risk of **vaccine-associated poliomyelitis**
    * Not safe for immunodeficient patients.
* Salk (沙克)
    * 注射，死病毒
    *  Lack of induction of secretory Ab.(=>會被感染但不會有臨床症狀)
    * Need boost for life long immunity.

<h3 id="Rhinovirus"> Rhinovirus</h3>

* Most important cause of the <font color="red">**common cold**</font>
* Optimal replication temperature is 33°C or lower.

---


<h2 id="Corona">Coronavirus</h2>

### Property
* Enveloped, <font color="orange">helical symmetry capsid</font>
* <font color="red">+ ss RNA genome</font> ~30 kb(gene很大的RNA病毒), **5’ capped** and **3’ polyadenylated**
* **Glycoprotein**: <font color="red">**可以容忍腸胃道環境**</font>，以**糞口傳遞**
* Zoonotic (人畜共通)
* Structure
    * N: Nucleocapsid
        * Binds to viral RNA
    * M (E1): Membrane
    * S (E2): Spike
        * **Receptor binding and fusion**
    * E: Small envelope
    * HE: Hemaglutinin esteras
        * Involved in **release of virus** from cell
### Life cycle
#### Genome organization
* 5’-Pol-S-E-M-N-3’
* Gene 1:  ORF1a & ORF1b
    * Non-structural proteins
        * ORF1a: Viral proteases
        * ORF1b: Polymerase RNA helicase 
* Gens 2 to 7: subgenomic mRNAs
    * Structural proteins
#### Transcription
* <font color="red">**Ribosomal frameshift**</font>: ORF1a & ORF1ab
* Sub-genomic mRNAs share the same 5’ leader sequence and 3’ overlapping sequences
    > A <font color="red">nested set</font>

![](https://i.imgur.com/6Rf6xUw.png =500x)

#### Entry
* Receptors for **spike proteins** of ++SARS-CoVand SARS-CoV2++ are <font color="red">**Angiotension-converting enzyme 2 (ACE2)**</font>. (in **upper and lower respiratory tracts**)
* Spike protein **needs to be processed** before fusion can occur. 
    > by **Cellular proteases**

![](https://i.imgur.com/uQshERJ.png)

### Disease mechanisms
* Human coronavirus infects and kills epithelial cells of the upper respiratory tract. (replicates best at 33~35°C)
* SARS-CoV & MERS-CoV replicate at 37°C, kill cells and <font color="red">initiate inflammatory responses</font> in the lung
* The **glycoprotein** helps this enveloped virus <font color="red">**survive the gastrointestinal tract**</font>.

### MERS-CoV
*  **Pneumonia & Renal failure**
*  Case–fatality rate: 34.4% 
*  Majority of these cases were reported from **Saudi Arabia**.
*  Occur more readily in the **immunocompromised individuals** or those have another **comorbidity**(合併症).
*  Receptor: Dipeptyl peptidase 4 (DPP4)
*  Natural reservoir: dromedary camels

### SARS-CoV-2 (cause of Covid-19)
* Beta-coronavirus
* Cause <font color="red">ARDS (acute respiratory distress syndrome)</font>
#### Transmission for SARS-CoV2
* Respiratory droplets, contact
* <font color="red">R~0~</font> (R naught, the basic reproduction number)
    *  the average number of people who will catch a disease from **one contagious person**
    * Reduce R0
        * (social) distancing
        * Isolating infected 
        * Immunization, preventive antiviral  treatment
        * Test, isolation, contact trancing 
#### Anti-viral drugs
![](https://i.imgur.com/iZo9FAB.png =500x)
* Remdesivir (a nucleotide analogs)

---

<h2 id="Calici">Calicivirus</h2>

* Naked <font color="limegreen">icosohedral capsid</font>, <font color="red">+ssRNA</font>, with a 5ʹ-terminal VPg and 3ʹ-terminal poly(A) 
* Causes <font color="red">acute gastroenteritis</font>(急性腸胃炎)
    *  因為小腸上皮細胞被破壞
* Replication is similar to coronaviruses

### Norovirus (諾羅病毒)
* **Norwalk virus (Norwalk agent)**
* Resistant to environmental pressure, detergents, drying and acid
    > 要用漂白水消毒
* 由受汙染的水或食物**糞口傳染**
* Cause outbreaks of <font color="red">**gastroenteritis**</font>, **vomiting**
* Disease <font color="red">++resolves after 48 hours++</font>, without serious consequences.

---

<h2 id="Paramyxo">Paramyxovirus</h2>

* <font color="red">-ssRNA</font>, enveloped <font color="orange">helical nucleocapsid</font>
* Infection induces <font color="red">**syncytia**</font> (**cell-cell fusion**, ++multinucleated giant cell++)
### Structure
* Surface glycoprotein
    * Larger glycoprotein (HN, H, G) (**viral attachment protein**)
        * H: Measles virus
        * HN: Parainfluenza virus 1~4
        * G: Metapneumovirus
    * Smaller glycoprotein (F) (**fusion protien**)
* Ribonucleoprotein (RNP)
    * Virion-associated polymerase
        * L (large-polymerase)
        * P (Phosphoprotein)
    * <font color="orange">Helical nucleocapsid</font> (**RNA plus NP protein**) 
* <font color="red">Neuraminidase</font> can facilitate **release** (by removing **sialic acid**)
* F protein needs to be ++cleaved into F1 and F2++ (Hydrophobic fusion peptide) by a **cellular protease** before it can function in membrane fusion.
    > Cause cell-cell fusion (<font color="red">**syncytia**</font>)
### Life Cycle
* Transcription begins at the exact **3’ end**.
* RNA上每段基因間都有<font color="red">**intergenic gap**</font>：有RNA二級結構，RdRP有兩成的機率無法解開而++掉下來++
* 當RNA被N protein bind住：不會產生Gap => RNA replication
    > <font color="red">High level of N leads encapsidation.</font>

![](https://i.imgur.com/neDz30g.png =500x)

* F protein facilitates fusion between membranes at ++physiological pH++ -> **direct fusion**
* <font color="red">在membrane組裝</font>

![](https://i.imgur.com/KitL3Ka.jpg =400x)


### Pathogenesis and epidemiology
|Virus|Disease|Tansmission|
|---|---|---|
|<a href="#Measles-virus">Measles virus</a>|Maculopapular rash (<font color="red">rubeola</font>)<br>Complications:<br>&nbsp; Otitis(耳炎), Croup(哮吼), Encephalitis|<font color="red">呼吸道->淋巴組織散佈</font><br>**Life-long immunity**|
|<a href="#Parainfluenza-virus">Parainfluenza virus</a>|Mild cold-like symptom|**上呼吸道**感染<br>鮮少造成viremia|
|<a href="#Mump-virus">Mump virus</a>|Parotitis (腮腺炎)<br>Orchitis (睪丸炎)<br>Meningoencephalitis(腦膜腦炎)|呼吸道上皮-><font color="red">腮腺</font>|
|<a href="#Respiratory-syncytia-virus">Respiratory syncytia virus</a>|**Fatal acute** respiratory tract infection<br>Common cold -> pneumonia|Highly contagious<br><font color="red">Lower respiratory tract</font>|

---

<h3 id="Measles">Measles virus</h3>(麻疹病毒)

|3C & P (cough, conjunctivitis, coryza, and photophobia) -> Koplik’s spots -> SSPE|
|---|

1. Inoculation of <font color="red">respiratory tract</font>
2. Cell-associated (monocyte and lymphocytes) viremia (<font color="red">Lmphatic spread</font>)
3. Wide dissemination
    * **Conjunctivae**
    * Respiratory tract
    * Urinary tract
    * Small blood vessels
    * Lymphatic system
    * CNS
5. <font color="red">T-cell response</font> to virus-infected epithelial cells => **Rash**
    * <font color="red">**Koplik’s spots**</font> (柯氏斑點)
7. Rarly cause Encephalitis (occurs in 3 ways)
    * <font color="red">**SSPE: Subcute sclerosing Panencephalitis**</font> (亞急性硬化性泛腦炎)

* Virus causes ==<font color="red">immunosuppresion</font>==.
    > Prompt to other infections
    > Can last after recovery
* Highly contagious, transmitted by **respiratory droplets**.

---

<h3 id="Parainfluenza">Parainfluenza virus</h3>

* ++Limited to respiratory tract++
* **Coldlike sypmtoms, bronchitis (支氣管炎), croup(哮吼)**
* Protective immunity is short duration => **會被重複感染**
---

<h3 id="Mump">Mump virus</h3>(腮腺炎病毒)

* Inoculation of <font color="red">respiratory tract</font> -> Viremia -> Systemic infection
* **Parotid gland** (腮腺): Loacl inflammation, swelling (腫脹)
* Pancreas (胰臟): Juvenile diabetes
* Testes (睾丸): Orchitis (睪丸炎)
#### Measles-Mumps-Rubella Vaccine

---

<h3 id="Respiratory syncytia">Respiratory syncytia virus</h3>

* ++Respiratory tract local infection++, causes common cold to pneumonia.
* Pneumonia results from **cytopathologic** spread of virus (including <font color="red">syncytia</font>)
* **呼吸道狹窄**(Narrow airways) in ++infants++ : **formation of plugs** of mucus, fibrin, and necrotic materials

---

<h2 id="Rhabdovirus">Rhabdovirus</h2>

### Properties
* Rhabdo -- Rod
* Enveloped <font color="red">helical nucleocapsid (bullet shape)</font>, simplest, non-segmented <font color="red">-ssRNA</font> virus
* Similar genetic organization, transcription, and replication to those of ++Paramyxoviridae and Filoviridae++.
* Contains genera:
    * ++Vesiculovirus++ (vesicular stomatitis virus, VSV, most intensively studied) 
    * ++Lyssavirus++ (**rabies** (狂犬病), rabieslike viruses in animals)

### Life cycle
1. <font color="red">**Receptor mediated endocytosis**</font>: **G protein (glycoprotein)**
    > Fusion occurs at **acid pH** (enodsome) => 不會有syncytia現象
2. L (RdRp) and P synthesizes mRNA (five monocistronic fragments). 
3. Translation:
    * G is translated by ++ER-bound ribosomes++
    * M (Matrix protein), N(nucleocapsid protein), P, and L (RNA polymerase) L are translated by ++free ribosomes++.
4. **High level of N** blocks polyadeynlation and mRNA cleavage 
    => full length +RNA.
* There is ++no early/late division++.

![](https://i.imgur.com/IpXMWX8.png =500x)

### Rabies
####  Transmission route 
* <font color="red">Zoonosis</font> (animal to human)
* Animal bite
    * US: bats
    * Asia: stray dogs
    * Taiwan: badgers (鼬獾)

#### Disease mechanism
1. Virus <font color="red">raplicates in the muscle</font>, with no symptoms (**Incubation phase**)
2. After weeks to month, the virus infects the peripheral nerves and travels up the CNS to the brain (**Prodrome phase**, 前驅期)
    > 發燒、頭痛、喉嚨痛、疲倦、噁心
4. Infection of the brain (**Neurologic phase**)
    > <font color="red">Classic brainstem encephalitis (典型的腦幹腦炎)</font>：
    > 腦神經異常、咽部肌肉收縮的疼痛 => <font color="red">恐水症</font>(hydrophobia)
#### Treatment
* **Post-exposure prophylaxis**(預防): due to ++long incubation time++
    * Clean wound
    * Vaccination
    * **Human rabies immune globulin (HRIG)**
        > 在非疫區，原則不必打疫苗或HRIG，但要打破傷風
* Once symptoms develop, treatment virtually always **unsuccessful**.
#### Diagnosis
* <font color="red">**Negri bodies**</font> (內基小體): aggregation of viral nucleocapside in neurons 

---


<h2 id="Orthomyxo">Orthomyxovirus</h2>

### Properties
* Ortho - standard; myxo - mucus
* <font color="red">**Segmented** -ssRNA virus</font>, <font color="orange">helical symmetry</font>, enveloped
* <font color="red">==Replicate in the nucleus==</font>
* Influenza:
    * Influenza A: human and other mammalians (**zoonosis**)
    * Influenza B: **human only**
    * Influenza C: mainly human, swine in China
#### Structure
* <font color="red">Hemagglutinin (血球凝集素, HA)</font>: **Attachment protein**, **Fusion protien** (binding to ++sialic acid++)
* <font color="red">Neuraminidase (神經胺酸, NA)</font>: Preventing clumping(結塊) and **facilitating release** ( cleaves the ++sialic acid++)
    > **Only Influenza A has subtypes**: 18 HA and 11 NA subtypes
* <font color="red">M2</font>: Ion channel, important for <font color="red">**uncoating**</font>
* RdRP: PA, PB1, and PB2
* RNA: **8 segments** (**helical RNP => RNA+NP**)
### Life cycle
#### Transcription
* <font color="red">RNA splicing</font> for **M2 and NS2**
* <font color="red">Cap snatching(stealing)</font>: 
    *  Influenza virus RdRP (PA) has intrinsic **cap-dependent endonuclease** => steal host mRNA CAP => as a **primer**
* Genome is ++transcribed into mRNA++ in the <font color="red">**nucleus**</font>

![](https://i.imgur.com/Tx7Z6fJ.png =700x)

### Pathogenesis
* Systemic symptoms: **interferon** and **cytokine** response
* Local symptoms: **epithelial cell damage** (ciliated and mucus-secreting cells)
* <font color="red">Reye syndrome (雷氏症候群)</font>: 幼兒 + 流感 + <font color="red">**Aspirin**</font> => ++嚴重肝和腦的疾病++
* Complications: <font color="red">Bacterial superinfection</font>
### Epidemiology
* Spread by inhalation of **small aerosol droplets**
* Virus likes a **cool, less humid atmosphere** => winter
* High-risk: **Elderly & immunocompromised people**
* Major causes of influenza virus- associated death.
    * **Bacterial pneumonia**
    * **Cardiac failure**
### Serology
* **Antigenic drift** (抗原漂變)
    * RNA-dependent RNA polymerase has **no proof-reading activity** -> **mutation prone**
* **Antigenic shift** (抗原轉移)
    * Only for <font color="red">influenza A</font> viruses.
    * **“New” HA or NA proteins** =>宿主從來沒被這個HA或NA感染過
    * May cause **pandemics**
    * <font color="red">Reassortment</font> (segmented viruses)
        > 兩種型態的病毒同時感染相同細胞時，RNA片段被錯誤包裹到其他病毒

### Avian influenza viruses
* No/limited human to human transmission
* H5N1 / H7N9
* Receptor:
    * Human influenza viruses: sialic acid–a-2,6-Gal(++上呼吸道++)
    * Avian influenza viruses: sialic acid-a-2,3-Gal(++下呼吸道++)

### Prevention/Treatment
#### Durgs
|藥物|藥品名|機制|補充|
|---|---|---|---|
|Rimantadine<br>Amantadine|Flumadine(R)<br>Symadin(R)|M2 inhibitor|Type A only<br>**抗藥性高**|
|Zanamivir<br>Oseltamivir|Relenza(R)<br>Tamiflu(R) (**克流感**)|NA inhibitor|Types A and B<br>僅能**緩解症狀**|
|Baloxavir marboxil|Xofluza(R) (紓伏效)|inhibit **cap-dependent <br>endonuclease** activity|Types A and B|
#### Vaccine
* ‘Best guess’ of main antigenic type
    * A型: H1N1, H3N2
    * B型: Yamagata, Victoria
* 三價流感疫苗：2A+1B；四價流感疫苗：2A+2B
* **Sub-unit vaccine** for children
    **Reassortant live attenuated vaccine** for healthy persons 
    
---

<h2 id="Reo">Reovirus</h2>(呼腸孤病毒)

* Orthoreovirus (正呼腸孤病毒)
* Orbiviruses (球狀病毒) / Coltiviruses (科羅拉多壁蝨熱病毒)
* <a href="#Rotavirus">Rotavirus(輪狀病毒)</a>

### Property
* <font color="red">**Double-layered capsid**</font> =>對於++環境抗性非常高++
    > Virion is resistant to detergents, acidic pH, drying.
* Naked <font color="limegreen">icosahedral symmetry</font>
* <font color="red">ds-RNA **segmented** genome</font> (10-12 fragments)
* Family has members that infect a **broad range of hosts** from fungi to humans
### Structure
* <font color="red">ISVP</font> (Intermediate/Infectious subviral particle) 
    * Proteolytic **cleavage of outercapsid** (in GI tract) activates the virus for infection 
        -> produces an **ISVP (infectious)**
    * DsRNAs are **never exposed to cytoplasm**.(因為dsRNA會引發很強的免疫反應)
![](https://i.imgur.com/X8ATsJX.png =500x)


### Life cycle
### Entry
* **Receptor mediated endocytosis**
* **Acid-dependent** proteolytic cleavage (ISVP -> core)
#### Transcription
* Complete transcription system, including **RdRP**, **5’ capping** and **poly (A) addition**
#### Replication
* Early phase:  mRNAs are synthesized and capped **inside intact cores** and **extruded through channels into the cytosol**
    > by ++virion enzymes++
* Late phase: Synthesis of double-stranded genome RNAs occurs **within core-like subvirion particles** 
* 病毒複製發生於<font color="red">**細胞質**</font>
* Double-stranded RNA **remains in the inner core** 
* Gene segments can be <font color="red">reassorted</font> during coinfection of cells by different strains

![](https://i.imgur.com/mekGwwV.png =500x)

---

<h3 id="Rota">Rotavirus</h3> (諾羅病毒)

* The ++most common cause++ of <font color="red">**severe diarrheal disease**</font> in **infants and young children** worldwide.
* <font color="red">NSP4</font>
    > **Inner capsid protein**
    > Enterotoxin: **mobilize calcium** and causes **diarrhea**
* <font color="red">Reassortment</font> of the 11 gene segments  -> **Wide variety** of rotavirus strains 
    * 11 different VP7 antigens (outer capsid)  (**G-types**) 
    * 11 different VP4 antigen (outer capsid spike protein) (**P-types**)

#### Vaccines 
* Live, attenuated virus will replicate in the gut
#### Epidemiology
* Transmitted by **fecal-oral route**.
* Rotavirus vaccine is available.
    * **Live, attenuated virus** will replicate in the gut

---

<h2 id="Retro">Retrovirus</h2>

### Classification (based on disease)
* <font color="red">Lentiviruses</font>
    > Slow viruses causing **AIDS** and **neurologic disorders** (**HIV-1, 2**)
* Endogenous viruses (HERV)
    > may take up 1% of human genome
### Property
* Enveloped with <font color="red">**two copies (diploid)**</font> of <font color="red">+RNA</font> genome 
* Have virion associated **RNA-dependent DNA polymerase** (reverse transcriptase) and **integrase** enzymes.
* Replicate through a **DNA intermediate** (<font color="red">provirus</font>).
* Provirus **integrates randomly into the host genome**.
### Genome structure
* Gag (Group-specific antigen)
    * Capsid protein (CA): <font color="limegreen">icosahedral</font> or conical(圓錐) core
    * Matrix protein (MP), Nucleocapsid protein(NP)
* Pol(DNA polymerase):
    * **RTase**
        * RNA-dependent DNA polymerase (**Reverse transcripase**)
        * DNA-dependent DNA polymerase
        * **RNase H**
    * **Integrase**
    * Protease
* Env (Envelope proteins)
    * Surface protein (SU), Transmembrane protein (TM)
* Genome = **mRNA**
* ++5'-CAP & 3' poly (A) tail++
* 5’ and 3’ ends: **Repeated sequence** ( R )
* U5 and U3: **Unique regions**
### Life cycle
#### Entry
* Attach: SU (HIV: **gp120**)
* Fusion: TM (HIV: **gp41**)
    * Receptor: <font color="red">**CD4**</font>
    * Co-receptor: <font color="red">**CCR5**</font> (M-tropic) or <font color="red">**CXCR4**</font> (T-tropic)
#### cDNA synthesis
* Primer: <font color="red">**tRNA**</font>
* RT:
    * **RNase H activity** (remove RNA from RNA/DNA)
    * **DNA polymerase activity**.
    * Very **error prone** -> variants
    * <font color="red">LTR (long-terminal repeat)</font> is **duplicated at both ends** of the cDNA: U3, R, U5.
![](https://i.imgur.com/ziuKYAk.png =400x)
#### Integration
* A copy of cDNA is integrated into the cellular genome at a **random site**
#### Transcription
* **LTR** contains **promoter** and **enhancer** sequences
    > U3作為promoter
* <font color="red">RNA splicing</font>
    * Gag/Pol: <font color="red">Polyproteins</font> -> proteolytically by **viral protease**
    * Env
#### Translation (gag-pol fusion)
* Gag/Pol polyprotein
    * Suppression of termination (Gamma retrovirus genus)
        > About 5-10%, UAG is <font color="red">miss-read</font> as CAG (Gln)
    * Alternative reading frames (HIV-1)
        > About 5 % of <font color="red">ribosomes shift</font>
#### Assembly
* The virus **assembles at the plasma membrane**.
* Virus <font color="red">**matures after budding**</font> from the cell after protease (PR) cleaves Gag and Gag-pro precursors.
* HIV can also spread from cell to cell through <font color="red">syncytia</font>.

![](https://i.imgur.com/OQzV43E.png =500x)

---

<h3 id="HIV">Human immunodeficiency virus (HIV)</h3>

### Property
* **Lentivirus** genus
* Infect <font color="red">CD4^+^ T cells, macrophages, and dendritic cells</font>.
* Receptor: <font color="red">CD4</font>
    Coreceptor: <font color="red">CXCR4</font> (T-tropic), <font color="red">CCR5</font> (M-Tropic)
    > **SDF-1** in mucosal membrane blocks **CXCR4** virus infection
    > People with **CCR5-Δ32** are **resistant** to HIV infection. 
* AIDS (Acquired Immune Deficiency Syndrome)

### HIV infection
1. HIV binds to **DC-SIGN**
2. Active replication in **lymphoid tissue**
3. Massive **viremia** leads to the wide dissemination of virus 
4. Persistent infection (reservoir)
5. Immune response down regulates virus replication (**Asymptomatic**)
6. Large **viremia**
7. <font color="red">**Severe immunodeficiency**, **AIDS dementia**</font>
* M-tropic (CCR5, ++non-syncytia-inducing++) **switch to** T-tropic (CXCR4, ++syncytia-inducing++)
    > due to ++changes in cytokine pattern++ and/or ++mutation of Env gene++
* The infection rapidly destroys CD4 T-cells.
    * HIV-induced cytolysis
        *  HIV budding
        *  <font color="red">Syncytia</font> (cell-cell fusion) 
        *  **Cell permeability ↑**
        *  Apoptosis
    *  <font color="red">**Pyroptosis**</font>: a **highly inflammatory form** of programed cell death, ++caspase 1-dependent++
### Progression of AIDS-related diseases
![](https://i.imgur.com/Uowv0XH.png =400x)
* **AIDS-related complex (ARC)**: Weight loss and malaise, diarrhea, night sweats, and fatigue
* **Opportunistic** infection and **recurrent infection** (bacteria, herpes, JC, EBV..)
* **Malignancies** (惡性腫瘤) (HHV8-associated **Kaposi’s sarcoma**)
* <font color="red">AIDS-related dementia</font>: Infected macrophage and microglial cells **secrete neurotoxic substances**
#### Disease mechanism
* HIV primary infects **CD4 T cells** & cells of the **myeloid lineage** (包含**微膠細胞(Microglial cells)**)
* Virus mutant: CCR5(M-tropic) -> CXCR4(T-tropic)
* Lytic infection of virus causes CD4 T cell **apoptosis or pyroptosis**
* Causes **syncytia formation**
* HIV-1 infecZon leads to increase incidence(發生率) of **malignancy(惡性腫瘤)**
    > <font color="red">EBV, HHV8 (KSHV), HPV</font>
#### Transmission of HIV
* Inoculation in blood
* Sexual transmission
* Perinatal (圍產期) transmission
    > 分娩前後=>藉由++剖腹產++避免經由產道感染
#### Anti-HIV drugs
* Different classed of anti-HIV drugs
    * Nucleoside analog inhibitor (RTase)
    * Nonnucleoside RTase inhibitor
    * Protease inhibitors
    * Integrase inhibitor
    * Binding and fusion inhibitor
* **No vaccine** and no cure for AIDS. 
* <font color="red">HAART</font> (highly active antiretrovirus therapy, triple therapy) (雞尾酒療法)
    * The treatment cannot be discontinued
### Oncogenic retroviruses
* 帶有oncogene
* 在感染後幾天內便會develop tumor
* 不會感染人類
### Long-latency retrovirus
* Caused by virus-encoded regulatory protein controlling transcription
* Efficiency of tumor formation is very **low**
* Takes **long time** for tumor to develop 
#### Human T-cell lymphotropic (leukemia) virus (HTLV-1)
* Encodes a protein (**tax**) that transactivates gene expression
    * for growth-stimulating cytokines (IL-2, 3, GMCSF, IL-2 receptor) and LTR-dependent transcription activities.

---