Phase 7 — Tissue-to-Virus Mapping
Program: PROJECT STRANDSHIFT
Classification: Tissue-Origin Viral Attribution Framework
Primary Objective:
To systematically compare diseased tissue molecular signatures against viral reference databases, endogenous retroviral elements, retrotransposons, and host genomic injury signals in order to distinguish:
- Active viral infection
- Latent viral reactivation
- Endogenous retroviral activation
- Retrotransposon activation
- Viral mimicry
- DNA injury responses
- Apoptotic nucleic acid release
1. EXECUTIVE SUMMARY
The Tissue–Virus Evidence Table (TVET) is the primary evidence-integration framework used to determine whether viral-like signals identified in diseased tissues originate from:
- Exogenous viruses
- Endogenous retroelements
- Viral mimicry pathways
- DNA injury responses
- Cellular degeneration
The framework assigns evidence scores and classification confidence to each detected signal.
The purpose is to prevent misclassification of:
- damaged DNA
- retrotransposons
- HERVs
- apoptotic nucleic acids
as infectious viral agents.
2. TISSUE PRIORITIZATION HIERARCHY
Tier I — Primary Disease Tissues
Tissue | Rationale |
Caudate Nucleus | Highest HD vulnerability |
Putamen | Major degeneration site |
Frontal Cortex | Cognitive decline region |
Medium Spiny Neurons | Primary target cell |
Tier II — Secondary Neural Tissues
Tissue | Rationale |
Motor Cortex | Motor dysfunction |
Hippocampus | Cognitive contribution |
Cerebellum | Comparative control region |
Tier III — Peripheral Tissues
Tissue | Rationale |
PBMCs | Immune surveillance |
Monocytes | Innate immune profiling |
Plasma | Cell-free nucleic acid analysis |
CSF | Neurodegeneration biomarkers |
3. VIRAL REFERENCE CLASSES
Class A — Exogenous Viruses
DNA Viruses
Virus
HSV-1
HSV-2
EBV
CMV
HHV-6
VZV
JC Virus
BK Virus
RNA Viruses
Virus
Influenza
SARS-CoV-2
Enteroviruses
West Nile Virus
HCV
Class B — Endogenous Retroviruses
Element
HERV-K
HERV-W
HERV-H
HERV-Fc
Class C — Retrotransposons
Element
LINE-1
Alu
SVA
4. EVIDENCE MATRIX STRUCTURE
Required Evidence Domains
Domain | Evidence Type |
Genomic | Viral DNA/RNA |
Transcriptomic | Viral transcripts |
Proteomic | Viral proteins |
Integration | Host–viral junctions |
Immune | Antiviral signatures |
Cellular | DNA injury markers |
Histopathologic | Tissue localization |
5. EXOGENOUS VIRUS EVIDENCE TABLE
Evidence Layer | Positive Criteria | Confidence |
Viral genome detected | Sequencing-confirmed viral reads | High |
Replication transcripts | Active viral RNA | High |
Viral proteins | Protein detection | High |
Integration site | Host–viral junction | Moderate–High |
Replicate confirmation | Multiple assays | High |
Classification
TVET-A
Confirmed Exogenous Virus
Requirements:
- Viral genome
- Replication evidence
- Independent validation
6. LATENT VIRAL REACTIVATION TABLE
Evidence Layer | Positive Criteria |
Viral genome present | Yes |
Viral RNA detected | Limited |
Viral proteins | Episodic |
Host immune activation | Present |
Classification
TVET-B
Latent Viral Reactivation
Examples:
- EBV
- HSV
- CMV
7. HERV ACTIVATION TABLE
Evidence Layer | Positive Criteria |
HERV transcripts | Present |
HERV proteins | Present/possible |
Viral genome | Human genomic origin |
Hypomethylation | Present |
Classification
TVET-C
Endogenous Retroviral Activation
Interpretation
Human-genome derived signal.
Not infectious virus.
8. RETROTRANSPOSON ACTIVATION TABLE
Evidence Layer | Positive Criteria |
LINE-1 transcripts | Present |
ORF1p | Present |
ORF2p | Present |
New insertions | Possible |
Classification
TVET-D
Retrotransposon Activation
Interpretation
Genome instability marker.
Not viral infection.
9. VIRAL MIMICRY TABLE
Evidence Layer | Positive Criteria |
Interferon signature | Present |
OAS1 | Elevated |
MX1 | Elevated |
ISG15 | Elevated |
Viral genome | Absent |
Classification
TVET-E
Viral Mimicry State
Interpretation
Antiviral-like biology without infection.
10. DNA-INJURY RESPONSE TABLE
Evidence Layer | Positive Criteria |
γH2AX | Elevated |
53BP1 | Elevated |
Micronuclei | Present |
cGAS-STING | Activated |
Viral genome | Absent |
Classification
TVET-F
DNA Injury–Associated Antiviral State
Interpretation
Genome-stress response.
11. APOPTOTIC NUCLEIC ACID TABLE
Evidence Layer | Positive Criteria |
Caspase-3 | Elevated |
Caspase-7 | Elevated |
TUNEL | Positive |
Cell-free DNA | Elevated |
Viral genome | Absent |
Classification
TVET-G
Apoptotic Nucleic Acid Release
Interpretation
Cell death debris.
12. ARTIFACT DETECTION TABLE
Evidence Layer | Positive Criteria |
Single-run detection | Yes |
No replication evidence | Yes |
No orthogonal confirmation | Yes |
Batch-specific appearance | Yes |
Classification
TVET-H
Experimental Artifact
13. MASTER TISSUE–VIRUS EVIDENCE TABLE
Tissue Signal | Viral Genome | Viral RNA | Viral Protein | HERV | LINE-1 | IFN Signature | DNA Injury | Classification |
Signal Type 1 | + | + | + | - | - | + | ± | TVET-A |
Signal Type 2 | + | ± | ± | - | - | + | ± | TVET-B |
Signal Type 3 | - | - | - | + | - | + | + | TVET-C |
Signal Type 4 | - | - | - | - | + | + | + | TVET-D |
Signal Type 5 | - | - | - | ± | ± | + | + | TVET-E |
Signal Type 6 | - | - | - | - | - | + | + | TVET-F |
Signal Type 7 | - | - | - | - | - | - | + | TVET-G |
14. STRANDSHIFT TISSUE EVIDENCE FLOW
Tissue Sample
↓
DNA/RNA Sequencing
↓
Virome Screening
↓
HERV Screening
↓
Retrotransposon Screening
↓
DNA Injury Assessment
↓
Innate Immune Assessment
↓
Evidence Classification
↓
TVET Assignment
↓
Confidence Scoring
15. CONFIDENCE SCORING FRAMEWORK
Level 1
Weak Evidence
Single evidence stream
Level 2
Moderate Evidence
Two independent evidence streams
Level 3
Strong Evidence
Three evidence streams
Level 4
Very Strong Evidence
Multi-omic confirmation
Level 5
Definitive Evidence
Independent replication and orthogonal validation
16. INTEGRATED TISSUE–VIRUS SCORES
Exogenous Viral Evidence Score (EVES)
Measures:
- Viral genome burden
- Replication markers
- Protein evidence
HERV Activation Score (HAS)
Measures:
- HERV transcription
- HERV protein expression
- Derepression burden
Retrotransposon Activity Score (RAS)
Measures:
- LINE-1 activity
- Insertion burden
- ORF expression
Viral Mimicry Score (VMS)
Measures:
- IFN activation
- ISG burden
- dsRNA sensing
DNA Injury Antiviral Score (DIAS)
Measures:
- DNA breaks
- Micronuclei
- cGAS-STING activation
Apoptotic Debris Score (ADS)
Measures:
- Caspase activity
- Cell-free DNA
- TUNEL burden
17. HTT-SPECIFIC APPLICATION
For Huntington disease tissues, the Tissue–Virus Evidence Table is primarily intended to test whether observed viral-like signatures originate from:
- active infection
- latent viral reactivation
- endogenous retroelements
- somatic expansion–associated DNA injury
- cGAS-STING activation
- interferon signaling
- apoptosis
rather than assuming a viral origin.
18. CONCLUSION
The Tissue–Virus Evidence Table provides the definitive classification framework for evaluating viral-related signals within PROJECT STRANDSHIFT. By integrating genomic, transcriptomic, proteomic, immunologic, and tissue-pathology evidence, the framework distinguishes true viral infection from endogenous retroviral activation, retrotransposon activity, viral mimicry, DNA injury responses, and apoptotic nucleic-acid release.
The framework serves as the final evidence-integration layer linking disease tissue biology to viral reference systems while maintaining strict separation between infectious viral processes and host-derived genome-stress phenomena.