Respons Imun terhadap Infeksi Virus: Perang Molekuler yang Kompleks dan Multi-lapis

Gambaran Umum: Pertahanan Berlapis terhadap Virus

graph TD
    A[Virus Entry] --> B{First Line of Defense}
    B --> C[Physical/Chemical Barriers<br/>Skin, Mucosa, pH, Enzymes]
    B --> D[Innate Immunity<br/>0-4 jam]

    D --> E[Interferon Response<br/>JAK-STAT Pathway]
    D --> F[Natural Killer Cells<br/>Missing Self Recognition]
    D --> G[Complement System<br/>Alternative Pathway]

    E --> H[Antiviral State<br/>ISGs Expression]

    H & F & G --> I[Adaptive Immunity Activation<br/>Dendritic Cell Presentation]

    I --> J[Cellular Immunity<br/>CD8+ T-cells]
    I --> K[Humoral Immunity<br/>B-cells/Antibodies]

    J --> L[CTL Killing<br/>Apoptosis of Infected Cells]
    K --> M[Neutralization<br/>Opsonization, ADCC]

    L & M --> N[Viral Clearance]
    N --> O[Immunological Memory<br/>Memory T & B cells]

A. Interferon: Sistem Alarm Molekuler yang Canggih

Klasifikasi Interferon

Mekanisme Deteksi Virus (PAMPs Recognition)

Pattern Recognition Receptors (PRRs):

1. TLR3: dsRNA in endosomes (most viruses during replication)
2. TLR7/8: ssRNA (influenza, HIV)
3. TLR9: CpG DNA motifs (herpesviruses)
4. RIG-I: Short dsRNA with 5’PPP (influenza, measles)
5. MDA5: Long dsRNA (picornaviruses)
6. cGAS-STING: Cytosolic DNA (DNA viruses, retroviruses)

JAK-STAT Pathway: Transduksi Sinyal Interferon

Langkah-langkah:

1. Binding: IFN-α/β → IFNAR1/IFNAR2 dimerization
2. Phosphorylation: JAK1 and TYK2 activation
3. STAT Activation: Phosphorylation of STAT1 and STAT2
4. Dimerization: STAT1-STAT2 heterodimer + IRF9 = ISGF3 complex
5. Nuclear Translocation: ISGF3 → nucleus
6. Gene Activation: Binding to ISRE (Interferon-Stimulated Response Element)

Interferon-Stimulated Genes (ISGs): Senjata Antiviral

Protein-Protein Kunci:

1. PKR (Protein Kinase R):

• Activated by dsRNA
• Phosphorylates eIF2α → global translation shutdown
• Blocks viral protein synthesis

1. 2′-5′ Oligoadenylate Synthetase (OAS):

• Produces 2′-5′ oligoadenylates
• Activates RNase L → degrades viral and cellular RNA
• Creates “suicidal” state in infected cell

1. Mx Proteins:

• GTPases that trap viral components
• MxA: inhibits influenza, measles, bunyaviruses
• MxB: inhibits HIV-1

1. ISG15:

• Ubiquitin-like protein
• ISGylation of viral and host proteins
• Inhibits viral replication and modulates immune response

1. Viperin (RSAD2):

• Inhibits viral budding by disrupting lipid rafts
• Effective against influenza, HIV, HCV

Regulasi dan Downregulation

Sistem Umpan Balik Negatif:

1. SOCS (Suppressors of Cytokine Signaling): Inhibit JAK-STAT
2. USP18: De-ISGylating enzyme, negative feedback
3. Optimal Timing: IFN response must be transient to avoid immunopathology

B. Respons Seluler: CD8⁺ T-Cells Sitotoksik

Pembentukan dan Aktivasi CTLs

Lokasi dan Proses:

1. Thymic Education: Positive/negative selection → TCR repertoire
2. Naïve CD8⁺ T-cells: Circulate through secondary lymphoid organs
3. Cross-Presentation: DCs present viral antigens via MHC I to CD8⁺ T-cells
4. Signal 1 (TCR-MHC): TCR recognizes viral peptide (8-10 aa)
5. Signal 2 (Co-stimulation): CD28-B7 interaction
6. Signal 3 (Cytokines): IL-12, IFN-γ, IL-2
7. Clonal Expansion: Up to 10,000-fold increase in 5-7 days

Mekanisme Killing yang Presisi

1. Granule-Exocytosis Pathway:

CTL Recognition
    ↓
Immunological Synapse Formation
    ↓
Polarization of Cytotoxic Granules
    ↓
Fusion with Plasma Membrane
    ↓
Release of Cytotoxic Proteins:
    • Perforin: Forms pores (16 nm)
    • Granzymes: Serine proteases
    • Granulysin: Antimicrobial peptide

Granzyme Subtypes:

• Granzyme A: Caspase-independent apoptosis via SET complex
• Granzyme B: Caspase-dependent apoptosis (cleaves caspase-3, Bid)
• Granzyme M: Caspase-independent, cleaves ICAD

2. Fas-FasL Pathway:

• FasL on CTL binds Fas on target cell
• FADD recruitment → caspase-8 activation
• Extrinsic apoptosis pathway

3. Cytokine-Mediated Killing:

• TNF-α secretion → TNFR1 activation
• TRADD/FADD → caspase-8 activation

Kontrol Kualitas dan Regulasi

Biomarker CTL Aktivasi:

1. Early Activation: CD69⁺ (within hours)
2. Proliferation: Ki-67⁺
3. Effector Differentiation: CD44hi, CD62Llo
4. Cytotoxic Machinery: Perform⁺, Granzyme B⁺
5. Exhaustion Markers: PD-1⁺, TIM-3⁺, LAG-3⁺

Kontrol Autoregulasi:

1. Activation-Induced Cell Death (AICD): Fas-FasL on CTLs themselves
2. IL-2 Withdrawal Apoptosis: After viral clearance
3. Regulatory T-cells (Tregs): Suppress excessive CTL response

C. Sinergi Antar Sistem Imun

Cross-talk antara Innate dan Adaptive Immunity

DC sebagai Jembatan:

1. Virus Sensing: DCs detect virus via PRRs
2. Maturation: Upregulate MHC, costimulatory molecules
3. Migration: To lymph nodes via CCR7
4. Priming: Activate naïve T-cells

NK Cells dan CTLs:

• Early: NK cells control viral spread before CTL expansion
• Feedback: IFN-γ from NK cells promotes CTL differentiation
• Regulation: NK cells can kill overactivated CTLs

Antibody-Dependent Cellular Cytotoxicity (ADCC)

Mekanisme:

1. Antibody Binding: IgG binds viral antigens on infected cells
2. Fc Receptor Recognition: FcγRIII (CD16) on NK cells binds antibody
3. NK Activation: Syk/ZAP70 phosphorylation → perforin/granzyme release
4. Target Killing: Selective elimination of antibody-coated cells

Efektor Seluler ADCC:

• NK cells: Main effectors
• Monocytes/Macrophages: Lower efficiency
• Neutrophils: Under specific conditions

D. Viral Immune Evasion Strategies

Strategi Evasi terhadap Interferon

Contoh Spesifik:

1. Influenza A:

• NS1 protein blocks RIG-I activation
• Inhibits PKR and OAS/RNase L
• Degrades cellular mRNA to limit IFN production

1. HIV-1:

• Vif degrades APOBEC3G (cellular cytidine deaminase)
• Vpu inhibits tetherin (blocks viral release)
• Nef downregulates CD4 and MHC I

1. Herpesviruses:

• HSV ICP34.5 dephosphorylates eIF2α
• HCMV US11 re-translocates MHC I from ER to cytosol
• KSHV vIRFs inhibit IRF3/7

Strategi Evasi terhadap CTLs

1. MHC I Downregulation:

• HIV Nef: Redirects MHC I to lysosomes
• HCMV US2/US11: Retrotranslocates MHC I to cytosol for degradation
• Adenovirus E3-19K: Retains MHC I in ER

1. Inhibition of Antigen Processing:

• EBV EBNA1: Gly-Ala repeats prevent proteasomal degradation
• HPV E7: Inhibits TAP transporter function

1. Resistance to Apoptosis:

• Adenovirus E1B-19K: Bcl-2 homolog
• Poxvirus CrmA: Serpin inhibitor of caspase-8

E. Implikasi Klinis dan Terapeutik

Diagnostik Imunovirologi

Biomarker Infeksi Viral:

1. Viral Load: PCR quantification (copies/mL)
2. IFN Signature: ISG expression profiling
3. CTL Response: Tetramer staining, ELISpot
4. Antibody Response: Neutralization assays, avidity testing

Imunoterapi Antiviral

Terapi Berbasis Interferon:

1. Pegylated IFN-α: Chronic hepatitis B/C (now largely replaced)
2. IFN-β: Multiple sclerosis (immunomodulatory effects)
3. IFN-λ: Emerging for respiratory viruses (less systemic side effects)

Imunoterapi Adoptif:

1. CAR-T Cells: Engineered TCRs for viral antigens
2. Virus-Specific T-cells (VST): For transplant patients (CMV, EBV)
3. TCR Gene Therapy: Redirect T-cell specificity

Vaksinologi Modern

Strategi Imunogenisitas:

1. Neutralizing Antibodies: Target viral entry proteins
2. CTL Epitopes: Conserved internal proteins
3. Adjuvants: TLR agonists to enhance IFN response
4. mRNA Vaccines: Induce strong type I IFN response

Contoh Sukses:

• mRNA COVID Vaccines: Spike protein + lipid nanoparticles → robust IFN-I + CTL response
• HPV Vaccine: Virus-like particles → neutralizing antibodies
• Shingrix: Varicella-zoster glycoprotein E + AS01B adjuvant → strong CD4⁺ response

F. Patologi Imun: When Defense Turns Dangerous

Cytokine Release Syndrome (CRS)

• Mekanisme: Excessive IFN-γ, IL-6, TNF-α release
• Contoh: Severe COVID-19, CAR-T therapy
• Treatment: Tocilizumab (anti-IL-6R), corticosteroids

Immunopathology Virus-Spesifik

1. Hepatitis B: CTL-mediated liver damage (not viral cytopathic effect)
2. Dengue: Antibody-dependent enhancement (ADE)
3. COVID-19: Hyperinflammation → ARDS, coagulopathy
4. HIV: Chronic immune activation → exhaustion

Kesimpulan: Evolusi Bersamaan dalam Perlombaan Senjata

Prinsip-Prinsip Kunci:

1. Layered Defense: Redundant systems ensure robustness
2. Speed vs Specificity: Innate (fast, broad) ↔ Adaptive (slow, specific)
3. Homeostatic Balance: Enough response to clear virus, not too much to cause damage
4. Immunological Memory: Basis of vaccination

Frontier Research:

1. Trained Immunity: Innate immune memory via epigenetic reprogramming
2. Inflammasome Activation: Pyroptosis in viral infections
3. Microbiome-Immune Axis: Commensal bacteria regulate antiviral responses
4. Single-Cell Immunology: Heterogeneity in immune responses

Perang melawan virus adalah tarian molekuler yang telah berevolusi selama miliaran tahun. Memahami respons imun terhadap virus bukan hanya untuk mengobati penyakit, tetapi untuk memanipulasi, memodulasi, dan meniru sistem yang luar biasa ini untuk mencegah penyakit di masa depan. Dari interferon pertama hingga memori imunologis jangka panjang, setiap lapisan pertahanan mengajarkan kita tentang kecerdasan biologis yang tertanam dalam setiap sel tubuh kita.