Pathogenic Viruses · Unit 26 of 28
Retroviruses — HIV and HTLV
01
The retroviruses ★★★
Retroviridae
Enveloped viruses possessing an RNA genome, which replicate via a DNA intermediate. The two enzymes that make this possible are reverse transcriptase and integrase.
⭐ Common characteristics — four
- Spherical enveloped virion, 80–120 nm
- Genome: TWO COPIES of linear +ssRNA, covalently linked, with gag, pol and env genes and also regulatory genes
- Contain REVERSE TRANSCRIPTASE
- Reverse transcribe the RNA genome into DNA and INTEGRATE it into the host genome as a PROVIRUS
| Group | Disease |
|---|---|
| HIV | AIDS |
| HTLV-1 / HTLV-2 | Adult T-cell leukaemia · hairy cell leukaemia |
Test yourself
- Define Retroviridae. → Enveloped viruses with an RNA genome that replicate via a DNA intermediate, using reverse transcriptase and integrase
- Give the four common characteristics. → Spherical enveloped virion 80–120 nm · two covalently linked copies of linear +ssRNA with gag, pol, env and regulatory genes · contain reverse transcriptase · reverse transcribe RNA to DNA and integrate as a provirus
- Name the two groups and their diseases. → HIV → AIDS; HTLV-1/2 → adult T-cell leukaemia and hairy cell leukaemia
02
HIV structure ★★★
The Nobel Prize in Physiology or Medicine 2008 went to Françoise Barré-Sinoussi and Luc Montagnier for their discovery of the human immunodeficiency virus.
| Layer | Content |
|---|---|
| Shape and size | Spherical, enveloped, 100 nm in diameter |
| Envelope | gp120 and gp41 |
| Capsid | p24 |
| Core | Two identical copies of +ssRNA (DIPLOID +ssRNA) · reverse transcriptase · integrase |
| Genome | Genes |
|---|---|
| 3 structural genes | env, pol, gag |
| 6 non-structural genes | tat, rev, nef, vif, vpr, vpu |
| Detail | |
|---|---|
| Cultivation | Cell culture in cells expressing CD4 only — T cells, macrophages. Animal model: primates |
| Resistance | WEAK. Inactivated by 70% ethanol and 0.3% hydrogen peroxide; inactivated at 56 °C for 30 minutes; survives 7 days at room temperature |
Test yourself
- Describe HIV structure. → Spherical, enveloped, 100 nm; envelope gp120 and gp41, capsid p24, core with two identical copies of +ssRNA plus reverse transcriptase and integrase
- Name the genes. → Three structural — env, pol, gag; six non-structural — tat, rev, nef, vif, vpr, vpu
- How is it cultured? → Only in CD4-expressing cells such as T cells and macrophages; primates as the animal model
- What is its resistance? → Weak — inactivated by 70% ethanol, 0.3% H₂O₂, and 56 °C for 30 min; survives 7 days at room temperature
03
The HIV life cycle ★★★
| Step | Detail |
|---|---|
| 1 · Binding | Infection begins with the interaction of gp120 with the CD4 MOLECULE on the surface of the target cell — of profound significance for therapy. Then a conformational change in the gp120/gp41 complex is induced by interaction of gp120 with the CHEMOKINE CO-RECEPTORS CCR5 or CXCR4 |
| 2 · Penetration | The virus FUSES with the cell and the viral core with its RNA is internalised |
| 3 · Uncoating | |
| 4 · Reverse transcription | From the RNA genome of HIV to DNA |
| 5 · Integration | The virus's own INTEGRASE inserts the viral DNA into the host cell's DNA. The integrated retroviral DNA is called a PROVIRUS |
| 6 · Transcription | The integrated proviral DNA is transcribed by HOST RNA POLYMERASE II into multiple copies of viral RNA, coding for viral proteins and enzymes and later packaged as new viruses |
| 7 · Translation | Nine genes: structural proteins (viral envelope, core protein, reverse transcriptase) and non-structural regulatory proteins. Viral RNA is translated into a LONG POLYPEPTIDE CHAIN, which VIRAL PROTEASE cuts into its individual enzyme components |
| 8 · Envelope processing | Newly synthesised gp160 localises to the Golgi apparatus, where it is cleaved into gp120 and gp41 by the host protease FURIN |
| 9 · Assembly | At the cell membrane |
| 10 · Extrusion | Budding |
The flow of information is RNA → DNA → RNA, by reverse transcriptase (viral) → integrase (viral) → host RNA polymerase II (host).
The life cycle is a list of drug targets — that is why it is examined
The deck's note on step 1 — of profound significance for therapy — applies to the whole cycle. Every step where the virus uses its own enzyme is a point where a drug can act without harming the patient. That is Unit 18 §6's argument about why antivirals are hard: HIV is the exception because it brings three enzymes of its own.
Reverse transcriptase (step 4) → AZT, ddI (nucleoside RT inhibitors) and nevirapine (non-nucleoside).
Viral protease (step 7) → saquinavir, indinavir, ritonavir.
Integrase (step 5) and fusion (steps 1–2) → the later drug classes.
HAART combines two nucleoside RT inhibitors with one protease inhibitor — attacking two different steps at once, so a virus resistant to one is still stopped by the other. That is the same principle as multi-drug tuberculosis therapy in Unit 13.
Notice also what is not targetable: step 5 makes the provirus a permanent part of the host chromosome. No drug removes it. That is why HAART “just controls the progress of AIDS”, in the deck's own words, and why treatment is lifelong.
Test yourself
- What does gp120 bind, and what is the co-receptor? → CD4; then the chemokine receptors CCR5 or CXCR4
- What is a provirus? → Retroviral DNA integrated into the host cell DNA by viral integrase
- Which enzymes are viral and which host? → Viral: reverse transcriptase, integrase, protease. Host: RNA polymerase II for transcription, and furin for cleaving gp160 into gp120 and gp41
- What does viral protease do? → Cuts the long translated polypeptide chain into individual enzyme components
- How does HIV leave the cell? → Assembly at the cell membrane, then budding
04
⭐ Transmission ★★★
Source: AIDS patients and asymptomatic HIV carriers.
| Route | Detail |
|---|---|
| 1 · Sexual contact — homosexual or heterosexual | Accounts for 80% of all infections |
| 2 · Blood | Exposure to infected blood or blood products · sharing contaminated needles (intravenous drug users) |
| 3 · Mother to baby | VERTICAL transmission |
Route 3 is Unit 20 §2's vertical transmission — HIV appears there in the group causing congenital infection without malformation.
Test yourself
- Name the source of HIV infection. → AIDS patients and asymptomatic HIV carriers
- Name the three routes with their weight. → Sexual contact (80% of all infections) · blood, including blood products and shared needles · mother-to-baby vertical transmission
05
Pathogenesis ★★★
The whole of AIDS is one sentence: immunodeficiency, from the destruction of CD4⁺ T cells. The deck lists five mechanisms of that destruction.
- Damage to the cell membrane — the virus destroys the cell as a result of BUDDING
- Formation of large MULTINUCLEATED cells
- Specific cytotoxic T cells kill infected cells; also NK cells
- Viral replication inhibits the biosynthesis of host cells
- APOPTOSIS of CD4⁺ T cells
Why HIV disables everything at once
Ask why destroying one cell type produces such total immune collapse, and the answer is which cell it is.
The CD4⁺ helper T cell is the conductor of the immune system. It licenses B cells to make antibody, activates macrophages to kill intracellular organisms, and helps cytotoxic T cells mature. Remove it and every other arm fails too.
That is why the AIDS-defining illnesses in §6 are precisely the ones controlled by cell-mediated immunity: tuberculosis (Unit 13 — the granuloma needs CD4 cells), candida, Pneumocystis, and the reactivation of latent herpesviruses from Unit 25 — CMV retinitis, and Kaposi's sarcoma from HHV-8.
It also closes a loop with Unit 20 §4: viruses destroy immune cells — e.g. HIV destroys CD4⁺ T cells was listed there as a mechanism of persistent infection. The virus survives by disabling the response that would clear it.
And note mechanism 3: your own cytotoxic T cells kill infected CD4 cells. Immunopathogenesis again — part of the CD4 loss is self-inflicted.
Test yourself
- What is the pathogenesis of AIDS in one line? → Immunodeficiency from destruction of CD4⁺ T cells
- Name the five mechanisms of CD4 cell injury. → Membrane damage from budding · multinucleated cell formation · killing by specific cytotoxic T cells and NK cells · inhibition of host biosynthesis by viral replication · apoptosis
- Why does losing CD4 cells disable all immunity? → The CD4 helper cell coordinates antibody production, macrophage activation and cytotoxic T-cell maturation
06
⭐ Clinical features ★★★
AIDS — the 2019 Section I term
Acquired immunodeficiency syndrome: the FINAL STAGE of HIV infection. People at this stage have badly damaged immune systems, which puts them at risk for opportunistic infections and tumours.
⭐ The four major categories
| Stage | Features |
|---|---|
| I · Acute infection (HIV seroconversion illness) | Extremely high HIV load — up to 10 million viruses per ml of blood. Mild symptoms: a flu-like illness with fever, large swollen lymph nodes, night sweats, skin rash and headache |
| II · Asymptomatic infection | Virus almost disappears from the blood, but persists in extravascular tissues — lymph node, dendritic cells — and continues to reproduce. Antibodies against both surface and internal proteins appear. No symptoms. The period may last 2–10 YEARS |
| III · Symptomatic infection — AIDS-related complex (ARC), with persistent generalised lymphadenopathy (PGL) | Massive loss of CD4⁺ cells. Severe symptoms: fever, night sweats, chronic diarrhoea, persistent generalised lymphadenopathy. HIV patients with high CD4⁺ counts do not develop AIDS |
| IV · Advanced disease — AIDS | CD4⁺ cells fall BELOW 200 per ml. Virus titre rises rapidly and the remaining immune response collapses. Opportunistic infections · cancer · death in about 2 years without intervention |
| Complication | Examples |
|---|---|
| Opportunistic infections | Tuberculosis (Mycobacterium) · candida glossitis |
| Cancer | Kaposi's sarcoma — human herpesvirus 8 |
| Neurological disease | AIDS dementia complex |
⭐ Two exam items answered from this section
“AIDS” — 4 marks, 2019 Section I
Acquired Immunodeficiency Syndrome — the final stage of infection with the human immunodeficiency virus (HIV), a retrovirus that destroys CD4⁺ T lymphocytes.
For the remaining marks:
• The defining number — CD4⁺ count falls below 200 per ml, the virus titre rises and the remaining immune response collapses.
• The consequences — opportunistic infections (tuberculosis, candidiasis), tumours (Kaposi's sarcoma, from HHV-8) and neurological disease (AIDS dementia complex).
• The outcome — death in about 2 years without intervention.
Do not stop at expanding the acronym — the four marks are for the mechanism, the CD4 threshold, and the opportunistic infections and tumours.
For the remaining marks:
• The defining number — CD4⁺ count falls below 200 per ml, the virus titre rises and the remaining immune response collapses.
• The consequences — opportunistic infections (tuberculosis, candidiasis), tumours (Kaposi's sarcoma, from HHV-8) and neurological disease (AIDS dementia complex).
• The outcome — death in about 2 years without intervention.
Do not stop at expanding the acronym — the four marks are for the mechanism, the CD4 threshold, and the opportunistic infections and tumours.
2019 Microbiology paper, Section I · TMU Microbiology — Retrovirus (55 slides)
“Please describe the transmission routes and clinical features of HIV.” (7 marks, 2020 Section III)
Transmission (3): sexual contact, homosexual or heterosexual — 80% of all infections; blood — exposure to infected blood or blood products and sharing contaminated needles among intravenous drug users; mother to baby — vertical transmission. The source is AIDS patients and asymptomatic carriers.
Clinical features — the four stages (4):
I · Acute infection — extremely high viral load (up to 10 million/ml), a mild flu-like illness with fever, lymphadenopathy, night sweats, rash and headache.
II · Asymptomatic infection — virus almost gone from blood but persisting and replicating in lymph nodes and dendritic cells; antibodies appear; lasts 2–10 years.
III · Symptomatic infection (ARC) — massive CD4⁺ loss, with fever, night sweats, chronic diarrhoea and persistent generalised lymphadenopathy.
IV · AIDS — CD4⁺ below 200/ml, opportunistic infections, cancer and neurological disease; death in about 2 years untreated.
Naming the 80%, the 2–10 years and the 200/ml is what lifts this from a list to a full-mark answer.
Clinical features — the four stages (4):
I · Acute infection — extremely high viral load (up to 10 million/ml), a mild flu-like illness with fever, lymphadenopathy, night sweats, rash and headache.
II · Asymptomatic infection — virus almost gone from blood but persisting and replicating in lymph nodes and dendritic cells; antibodies appear; lasts 2–10 years.
III · Symptomatic infection (ARC) — massive CD4⁺ loss, with fever, night sweats, chronic diarrhoea and persistent generalised lymphadenopathy.
IV · AIDS — CD4⁺ below 200/ml, opportunistic infections, cancer and neurological disease; death in about 2 years untreated.
Naming the 80%, the 2–10 years and the 200/ml is what lifts this from a list to a full-mark answer.
2020 Microbiology paper, Section III · TMU Microbiology — Retrovirus (55 slides)
Test yourself
- Define AIDS. → Acquired immunodeficiency syndrome — the final stage of HIV infection, with a badly damaged immune system putting the patient at risk of opportunistic infections and tumours
- Name the four clinical categories. → Acute infection · asymptomatic infection · symptomatic infection (ARC/PGL) · AIDS
- What happens in acute infection? → Extremely high viral load up to 10 million/ml with a mild flu-like illness
- How long is the asymptomatic stage, and what is happening? → 2–10 years; virus almost gone from blood but replicating in lymph nodes and dendritic cells, with antibodies present
- What defines AIDS numerically? → CD4⁺ cells below 200 per ml
- Name the complications of AIDS. → Opportunistic infections (tuberculosis, candida glossitis), cancer (Kaposi's sarcoma from HHV-8), and AIDS dementia complex
07
Diagnosis, prevention and treatment ★★★
- Detection of antibody or antigen — ELISA
- Detection of nucleic acid — RT-PCR
- Virus isolation
Significance of the diagnosis
- Diagnosis of infection in an individual with or without symptoms
- Monitoring disease progression with or without antiviral therapy
- Screening blood and organ donors, voluntary screening of at-risk individuals, and seroepidemiologic surveys
- Evaluation of new antivirals or vaccines
| Detail | |
|---|---|
| Prevention | Health education · strict examination of blood and blood products · strict selection of blood donors |
| ⚠️ Vaccine | NOT AVAILABLE — because of the high mutation rate, and because latent infection and the formation of multinucleated cells result in immune escape |
| HAART | Highly Active Anti-Retroviral Therapy: TWO nucleoside analogue RT inhibitors plus ONE protease inhibitor |
| Drug class | Examples |
|---|---|
| Nucleoside reverse transcriptase inhibitors | AZT (azidothymidine) · ddI (dideoxyinosine) |
| Non-nucleoside reverse transcriptase inhibitors | Nevirapine |
| Protease inhibitors | Saquinavir · indinavir · ritonavir |
The deck is blunt about the limits: these drugs just control the progress of AIDS. Its closing slide: education led to a levelling off in the rate of increase in AIDS, and HAART has greatly slowed the death rate.
Test yourself
- How is HIV diagnosed? → Antibody or antigen detection by ELISA, nucleic acid detection by RT-PCR, and virus isolation
- Why is there no HIV vaccine? → The high mutation rate, and immune escape through latent infection and multinucleated cell formation
- What is HAART? → Highly active antiretroviral therapy — two nucleoside RT inhibitors plus one protease inhibitor
- Name the three drug classes with examples. → Nucleoside RT inhibitors (AZT, ddI), non-nucleoside RT inhibitors (nevirapine), protease inhibitors (saquinavir, indinavir, ritonavir)
08
HTLV ★★
| Detail | |
|---|---|
| Characteristics | Oncovirinae · spherical, ~100 nm · enveloped, with gp21 and gp46 · capsid proteins p24 and p15 |
| Transmission | Blood transfusion · sexual contact (HTLV-2 may be poorly transmitted sexually) · mother to child — by breastfeeding, with 20% of children of seropositive mothers acquiring the virus |
| HTLV-1 | Associated with 2 fatal human diseases: adult acute T-cell lymphocytic leukaemia (ATLL), and HTLV-associated myelopathy (HAM), also called tropical spastic paraparesis (TSP) |
| HTLV-2 | Hairy cell leukaemia; myelopathy |
Test yourself
- Describe HTLV. → Oncovirinae, spherical ~100 nm, enveloped with gp21 and gp46, capsid p24 and p15
- How is it transmitted? → Blood transfusion, sexual contact, and mother to child by breastfeeding — 20% of children of seropositive mothers
- Which diseases? → HTLV-1: adult T-cell lymphocytic leukaemia and HTLV-associated myelopathy (tropical spastic paraparesis). HTLV-2: hairy cell leukaemia and myelopathy
09
Revision
⭐ The 2019 comprehensive question (Section IV, 10 marks)
Sexually transmitted pathogens — HIV as the worked example
“List at least SIX sexually transmitted pathogens and their diseases; select one and explain its pathogenesis.” (10 marks, 2019 Section IV)
The list (with their units): HIV → AIDS (this unit) · Treponema pallidum → syphilis (Unit 17) · Neisseria gonorrhoeae → gonorrhoea (Unit 9) · HSV-2 → genital herpes (Unit 25) · Chlamydia trachomatis D–K → nongonococcal urethritis, cervicitis, PID (Unit 16) · Ureaplasma urealyticum and Mycoplasma genitalium → NGU (Unit 14) · HBV → hepatitis B (Unit 24) · human papillomavirus → genital warts and cervical carcinoma.
Then go deep on ONE. HIV is the strongest choice because the pathogenesis is a complete story: gp120 binds CD4 with the CCR5 or CXCR4 co-receptor → fusion and entry → reverse transcription to DNA → integration by integrase as a provirus → destruction of CD4⁺ T cells by budding damage, syncytium formation, CTL and NK killing, inhibition of host biosynthesis and apoptosis → progressive immunodeficiency through the four clinical stages → CD4 below 200/ml, opportunistic infection, tumour and death.
Note the shape of the question: list ≥N pathogens, then go deep on one. Both 2019 and 2020 use it, so expect it again whatever the topic.
Then go deep on ONE. HIV is the strongest choice because the pathogenesis is a complete story: gp120 binds CD4 with the CCR5 or CXCR4 co-receptor → fusion and entry → reverse transcription to DNA → integration by integrase as a provirus → destruction of CD4⁺ T cells by budding damage, syncytium formation, CTL and NK killing, inhibition of host biosynthesis and apoptosis → progressive immunodeficiency through the four clinical stages → CD4 below 200/ml, opportunistic infection, tumour and death.
Note the shape of the question: list ≥N pathogens, then go deep on one. Both 2019 and 2020 use it, so expect it again whatever the topic.
2019 Microbiology paper, Section IV
The whole unit on one screen
| Question | Answer |
|---|---|
| Retrovirus? | Enveloped RNA virus replicating via a DNA intermediate |
| HIV structure? | 100 nm; gp120 and gp41 envelope; p24 capsid; diploid +ssRNA, RT and integrase |
| Genes? | env, pol, gag + 6 regulatory (tat, rev, nef, vif, vpr, vpu) |
| Receptor? | CD4, with co-receptor CCR5 or CXCR4 |
| Provirus? | Viral DNA integrated into host DNA by integrase |
| ⭐ Transmission? | Sexual (80%) · blood and needles · vertical |
| Pathogenesis? | Destruction of CD4⁺ T cells by 5 mechanisms |
| ⭐ Four stages? | Acute (viraemia 10⁷/ml) · asymptomatic (2–10 y) · ARC · AIDS (CD4 < 200/ml) |
| Complications? | TB, candida · Kaposi's sarcoma (HHV-8) · AIDS dementia |
| Vaccine? | None — high mutation rate and immune escape |
| HAART? | 2 nucleoside RT inhibitors + 1 protease inhibitor |
| HTLV-1? | Adult T-cell leukaemia and HTLV-associated myelopathy |
Test yourself — the whole unit
- Define AIDS for 4 marks. → The final stage of HIV infection, in which destruction of CD4⁺ T cells leaves the immune system badly damaged; CD4 falls below 200/ml, and the patient develops opportunistic infections, tumours such as Kaposi's sarcoma, and neurological disease, dying in about 2 years untreated
- Give the transmission routes and clinical features of HIV. → Sexual (80%), blood and needles, vertical; then acute infection with very high viral load, 2–10 years asymptomatic, ARC with massive CD4 loss, and AIDS below 200 CD4/ml
- Describe the HIV life cycle. → gp120 binds CD4 and CCR5/CXCR4 → fusion and internalisation → uncoating → reverse transcription to DNA → integration as provirus → transcription by host RNA polymerase II → translation and cleavage by viral protease → gp160 cleaved by furin → assembly at the membrane → budding
- Name the five mechanisms of CD4 cell injury. → Budding damage to the membrane · multinucleated cell formation · CTL and NK killing · inhibition of host biosynthesis · apoptosis
- Why is there no vaccine? → High mutation rate, and immune escape via latency and multinucleated cell formation