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PA8.6 | HIV & AIDS — SDL Guide (Part 3)

AIDS-Defining Malignancies

Immune surveillance normally eliminates cells transformed by oncogenic viruses. Profound CD4 depletion allows these viruses to drive malignancy.

Kaposi Sarcoma (KS):
• Caused by HHV-8 (Human Herpesvirus-8 / Kaposi sarcoma-associated herpesvirus)
• Endothelial-derived vascular tumour; most common AIDS malignancy
• Presents as violaceous (purple-brown) patches/plaques/nodules on skin, mucous membranes, viscera
• Histology: spindle cells, slit-like vascular spaces, RBCs extravasated, PAS-positive hyaline globules

AIDS-related Non-Hodgkin Lymphoma (NHL):
• Usually high-grade B-cell lymphomas (diffuse large B-cell lymphoma, Burkitt lymphoma)
• Frequently EBV-associated; extranodal sites predominant (CNS, GI tract, liver)
• CNS primary lymphoma: solitary or multiple ring-enhancing lesions (must distinguish from toxoplasmosis — serology + biopsy)

Invasive Cervical Carcinoma:
• Associated with HPV (types 16, 18) — impaired CTL surveillance allows HPV persistence and malignant transformation
• An AIDS-defining illness in women; highlights importance of cervical screening in HIV+

A four-panel medical diagram showing how CD4 depletion in AIDS permits HHV-8, EBV, and HPV-associated malignancies: Kaposi sarcoma, AIDS-related lymphoma, and invasive cervical carcinoma. — **Panel A:** CD4+ T-cell depletion, reduced immune surveillance, HHV-8, EBV, HPV, Kaposi sarcoma, AIDS-related Non-Hodgkin lymphoma, invasive cervical carcinoma. **Panel B:** Kaposi sarcoma, HHV-8, violaceous purple-brown plaques/nodules, oral palate lesion, endothelial-derived vascular tumor, spindle cells, slit-like vascular channels, extravasated RBCs, PAS-positive hyaline globules. **Panel C:** AIDS-related high-grade B-cell Non-Hodgkin lymphoma, EBV association, diffuse large B-cell lymphoma, Burkitt lymphoma, CNS involvement, GI tract involvement, liver involvement, large lymphoid cells, vesicular nuclei, ring-enhancing brain lesions, toxoplasmosis differential. **Panel D:** Invasive cervical carcinoma, HPV types 16 and 18, impaired CTL surveillance, persistent HPV infection, cervical dysplasia, malignant transformation, cervical screening in HIV-positive women.

SELF-CHECK

A 31-year-old HIV-positive man presents with painless violaceous nodules on his palate and forearm, and a CD4 count of 45 cells/µL. Biopsy shows spindle cells with slit-like vascular channels. What is the causative oncogenic virus?

A. Epstein-Barr virus (EBV)

B. Human Papillomavirus (HPV) type 16

C. Human Herpesvirus-8 (HHV-8)

D. Cytomegalovirus (CMV)

Reveal Answer

Answer: C. Human Herpesvirus-8 (HHV-8)

The clinical picture (violaceous lesions in an AIDS patient) combined with the histology (spindle cells, slit-like vascular channels, extravasated RBCs) is classic Kaposi sarcoma. KS is driven by HHV-8 (Kaposi sarcoma-associated herpesvirus), which infects endothelial cells and prevents their apoptosis via viral FLICE-inhibitory protein (vFLIP). EBV is associated with B-cell lymphomas in AIDS; HPV with cervical cancer; CMV with retinitis, not KS.

HIV Encephalopathy, Wasting, and Other Systemic Manifestations

A four-panel educational diagram summarizing HIV encephalopathy, AIDS wasting syndrome, and sequential lymph node pathology in HIV infection. — **Panel A:** HIV-infected CNS macrophage, activated microglia, intact neuron lacking CD4, indirect neuronal injury, TNF-alpha, IL-1 beta, gp120, Tat, microglial nodule, multinucleated giant cell, vacuolar myelopathy inset.. **Panel B:** Clinical spectrum from mild cognitive impairment to HIV-associated dementia with memory loss, psychomotor slowing, and behavioural changes.. **Panel C:** AIDS wasting syndrome showing greater than 10% involuntary weight loss, chronic diarrhoea or weakness, fever for at least 30 days, anorexia, malabsorption, hypermetabolism, and hypogonadism.. **Panel D:** Sequential HIV lymph node pathology: follicular hyperplasia, follicular involution or mixed pattern, lymphocyte depletion with ghost follicles and opportunistic organisms..

HIV-associated neurocognitive disorder (HAND) / HIV encephalopathy:
• Direct infection of CNS macrophages and microglia (not neurons directly, which lack CD4)
• Macrophages release neurotoxic cytokines (TNF-α, IL-1β), viral proteins (gp120, Tat) that damage neurons indirectly
• Clinical spectrum: mild cognitive impairment → HIV-associated dementia (HAD) — memory loss, psychomotor slowing, behavioural changes
• Pathology: microglial nodules, multinucleated giant cells (fused HIV-infected macrophages), vacuolar myelopathy of the spinal cord

AIDS wasting syndrome:
• Involuntary weight loss > 10% body weight + chronic diarrhoea or weakness + fever for ≥ 30 days
• Mechanisms: anorexia (cytokines), malabsorption (enteropathy), hypermetabolism, hypogonadism
• An AIDS-defining diagnosis independent of CD4 count

Lymph node pathology in HIV (three sequential stages):
1. Follicular hyperplasia (early): reactive germinal centres, CD4 cells around follicles
2. Follicular involution/mixed pattern (intermediate): burnt-out follicles, plasma cells
3. Lymphocyte depletion (late/AIDS): ghost follicles, few lymphocytes, opportunistic organisms visible

Laboratory Diagnosis of HIV

Infographic showing HIV laboratory diagnosis using a timeline, screening-confirmation flowchart, Western blot interpretation, and monitoring markers. — **Panel A:** HIV infection timeline, Day 0 infection, HIV RNA/NAT detectable within days, p24 antigen, 4th-generation ELISA positivity around 2 weeks, antibody window period of 3-12 weeks, infectious window period.. **Panel B:** Patient sample, fourth-generation ELISA combined Ag/Ab screening, non-reactive pathway, reactive pathway, Western blot confirmation, HIV-1 RNA PCR confirmation for acute/window period infection and perinatal HIV.. **Panel C:** Western blot bands p24, gp41, gp120/160, positive rule of at least 2 bands, CD4+ count monitoring, CD4 less than 200 cells/microliter threshold for AIDS and PCP prophylaxis, HIV viral load for treatment response..

A systematic approach prevents missed diagnoses and false positives.

Screening — Fourth-generation ELISA (combined Ag/Ab test):
• Detects HIV-1/2 antibodies AND p24 antigen simultaneously
• Becomes positive ~2 weeks post-infection (earlier than 3rd-gen Ab-only ELISA)
• High sensitivity (~99.9%); used for initial screening
• Reactive result requires confirmation

Confirmatory tests:
• Western blot (gold standard): viral proteins separated by gel electrophoresis, probed with patient serum; positive if ≥ 2 of: p24, gp41, gp120/160 bands present
• HIV-1 RNA PCR (viral load): qualitative PCR used for confirmation in acute/window period infection when antibodies absent; also used to diagnose perinatal HIV in infants (maternal antibodies persist to 18 months)

The window period:
• Interval between infection and detectable antibody (~3–12 weeks, 4th-gen ELISA detects earlier at ~2 weeks)
• During window: patient is infectious but ELISA may be negative
• Nucleic acid tests (NAT) detect RNA within days — used for blood bank screening and suspected acute infection

Monitoring parameters:

Test	Purpose	Target / threshold
CD4+ count	Staging, prophylaxis timing	< 200 → AIDS; < 200 → start PCP prophylaxis
Viral load (HIV RNA PCR)	Assess replication, ART response	Goal: undetectable (< 20–50 copies/mL)
CD4:CD8 ratio	Immune recovery	Normal ≈ 2:1; inverts in HIV (< 1)

Principles of ART:
• Combination antiretroviral therapy (cART) uses ≥ 3 drugs from ≥ 2 classes to prevent resistance
• Drug classes: NRTIs (tenofovir, emtricitabine), NNRTIs (efavirenz), protease inhibitors (atazanavir), integrase inhibitors (dolutegravir, raltegravir), CCR5 antagonists (maraviroc)
• Goal: viral load undetectable → immune reconstitution → prevention of OIs
• 'U=U': Undetectable = Untransmittable (no sexual transmission when viral load < 200 copies/mL)

SELF-CHECK

A 26-year-old man was tested for HIV 3 weeks after a high-risk exposure. His 4th-generation combined Ag/Ab ELISA is non-reactive. Which statement is most accurate?

A. He is definitively HIV-negative and no further testing is required

B. He may be in the window period; HIV RNA PCR should be performed and repeat ELISA at 6 weeks

C. A non-reactive 4th-generation ELISA at 3 weeks fully excludes acute seroconversion illness

D. Western blot should be performed immediately as it has higher sensitivity than ELISA in early infection

Reveal Answer

Answer: B. He may be in the window period; HIV RNA PCR should be performed and repeat ELISA at 6 weeks

Although 4th-gen ELISA detects p24 antigen earlier than antibody-only tests (positive from ~2 weeks), the window period can extend to 6 weeks for this assay. A single negative test at 3 weeks does not exclude infection. HIV RNA PCR (qualitative NAT) would detect viraemia within days of infection and should be done if acute HIV is suspected clinically. A repeat ELISA at 6 weeks (and optionally 12 weeks) is recommended. Western blot is a confirmatory test for reactive screens, not a more sensitive primary test.

Putting It Together — Clinico-Pathological Correlations

A four-panel infographic links HIV pathological mechanisms such as CD4 binding, provirus integration, cytokine-driven inflammation, viral reactivation, and CNS microglial activation to clinical consequences including opportunistic infections, malignancy, wasting, and dementia. — **Panel A:** HIV virion, gp120, CD4 receptor, CCR5 co-receptor, CD4+ T lymphocyte, reverse transcription, provirus integration, host chromatin, viral replication, CD4 depletion, macrophage infection, dendritic cell infection, lymph node, gut mucosa, CNS reservoir. **Panel B:** Pyroptosis, bystander CD4 cell death, IL-1 beta, IL-18, chronic immune activation, gut mucosal breakdown, microbial translocation, systemic inflammation, wasting phenotype. **Panel C:** Falling CD4 count scale, CD4 <500, TB, oral candidiasis, zoster, CD4 <200, Pneumocystis pneumonia, CD4 <100, toxoplasmosis, cryptococcosis, CD4 <50, CMV retinitis, MAC, HHV-8 reactivation, Kaposi sarcoma, EBV reactivation, AIDS-related NHL, CNS lymphoma. **Panel D:** Infected macrophage, blood-brain barrier, microglial activation, neurotoxic mediators, neuronal injury, HIV encephalopathy, HIV-associated dementia.

The table below integrates the key pathological mechanisms with clinical presentations you will encounter on the wards:

Pathological event	Clinical consequence
gp120–CD4–CCR5 binding → CD4 depletion	Progressive immunosuppression, stage-specific OIs
Provirus integration into host chromatin	Lifelong infection; impossible to eradicate; ART suppresses, not cures
Macrophage/DC infection	Virus spreads to tissues; CNS reservoir established early
Pyroptosis-driven IL-1β/IL-18 release	Chronic immune activation, accelerated ageing phenotype
HHV-8 reactivation	Kaposi sarcoma
EBV reactivation	AIDS-NHL, CNS lymphoma
Microglial activation, neurotoxic mediators	HIV encephalopathy, dementia
Gut mucosal breakdown	Microbial translocation → chronic activation + wasting

Key numbers for MCQ/clinical use:
• CD4 < 500: TB, oral candida, zoster
• CD4 < 200: PCP prophylaxis (co-trimoxazole); AIDS diagnosis threshold
• CD4 < 100: Toxoplasma, Cryptococcus, candida oesophagitis
• CD4 < 50: CMV retinitis, MAC