Q3 LONG ANSWER 10M ★ High-yield

Describe the pathogenesis and natural history of HIV infection. Add a note on the opportunistic infections and tumours of AIDS.

Pathology · 2nd Professional — Para-Clinical

The Virus

Human immunodeficiency virus is a retrovirus of the lentivirus family, causing progressive destruction of CD4 T lymphocytes and hence profound cell-mediated immunodeficiency.

Single-stranded RNA with the enzymes reverse transcriptase, integrase and protease
Envelope glycoproteins gp120 and gp41; core protein p24
HIV-1 causes the world pandemic; HIV-2 is West African, less transmissible and slower

Transmission

Route	Share	Notes
Sexual	Over 85% worldwide	Heterosexual transmission predominates in India; risk raised by ulcerative sexually transmitted disease
Parenteral	—	Injecting drug use, contaminated blood products, needlestick injury (risk about 0.3%)
Vertical	—	In utero, during delivery, or by breastfeeding; 25–40% without treatment, under 2% with antiretroviral therapy

Pathogenesis

Gp120 binds the CD4 molecule — the primary receptor → A CO-receptor is also required: CCR5 (macrophage-tropic, early) or CXCR4 (T-cell-tropic, late) → gp41 mediates fusion; the virus enters → reverse transcriptase makes DNA from the viral RNA — error-prone, hence rapid mutation and drug resistance → integrase inserts the provirus into the host genome — the basis of latency and of the reservoir that cannot be eradicated → Activation of the cell triggers replication and CD4 cell death → Progressive CD4 depletion → failure of cell-mediated immunity

CD4 cells are lost by several mechanisms — direct cytopathic effect, apoptosis of infected and uninfected cells, killing by cytotoxic T cells, and syncytium formation
Macrophages and dendritic cells are relatively resistant and act as a reservoir, carrying the virus to lymphoid tissue and the brain
Homozygous CCR5-delta32 deletion confers near-complete resistance to sexually acquired infection — the observation that made CCR5 a drug target

Natural History

Stage	Duration	CD4 count	Features
Acute (seroconversion) illness	3–6 weeks after exposure	Falls transiently	Glandular fever-like illness — fever, sore throat, rash, lymphadenopathy; very high viral load and highly infectious
Clinical latency	Median 8–10 years	Falls slowly, about 50–100 cells a year	Asymptomatic, but the virus replicates continuously in lymphoid tissue — latency is clinical, not virological
Symptomatic	Variable	200–500	Weight loss, oral candidiasis, herpes zoster, tuberculosis
AIDS	—	Below 200/mm3, or an AIDS-defining illness	Opportunistic infection and malignancy

CLINICAL PEARL

"Latency" is a clinical description, not a biological one. Through the asymptomatic years the virus is replicating at enormous rates in lymphoid tissue and CD4 cells are being destroyed and replaced continuously. The count falls only when replacement can no longer keep pace — which is why treating early, before the lymphoid architecture is destroyed, gives much better outcomes.

Opportunistic Infections and Tumours

CD4 count	Typical infections
Any count	Tuberculosis — the commonest opportunistic infection in INDIA, and the leading cause of death; bacterial pneumonia; herpes zoster
Below 200	Pneumocystis jirovecii pneumonia, oesophageal candidiasis
Below 100	Toxoplasma encephalitis, cryptococcal meningitis, cryptosporidiosis
Below 50	Cytomegalovirus retinitis and colitis, Mycobacterium avium complex, primary CNS lymphoma

AIDS-defining tumours — KAPOSI sarcoma (caused by HHV-8), non-Hodgkin lymphoma (often EBV-driven), and invasive carcinoma of the cervix (HPV)
Kaposi sarcoma is uncommon in India compared with Africa, because HHV-8 seroprevalence is low — a genuine regional difference

Morphology in AIDS

Organ	Findings
Lymph nodes	Early — florid follicular hyperplasia with enlarged, irregular germinal centres. Late — follicular involution and complete "burnt-out" lymphoid depletion, so the node becomes small and fibrotic
Central nervous system	HIV encephalitis with microglial nodules and multinucleate giant cells; vacuolar myelopathy; progressive multifocal leucoencephalopathy (JC virus)
Lung	Pneumocystis pneumonia — foamy alveolar exudate with cysts shown by silver (GMS) staining
Gut	Cryptosporidial and CMV colitis; wasting and chronic diarrhoea
Skin and mucosa	Oral candidiasis and hairy leucoplakia (EBV); Kaposi sarcoma with spindle cells and slit-like vascular spaces

The lymph node changes summarise the whole disease — an initial vigorous response, then progressive exhaustion of the lymphoid system

Diagnosis and Applied Aspects

Fourth-generation ELISA detects both antibody and p24 antigen, shortening the window period to about two to three weeks; confirmed by a second test on a different platform
The window period is the interval before antibody is detectable, during which the patient is highly infectious and the test may be negative
CD4 count guides prophylaxis and staging; viral load monitors treatment — the two answer different questions
Antiretroviral therapy is now started at diagnosis regardless of CD4 count, and an undetectable viral load makes sexual transmission effectively impossible
Immune reconstitution inflammatory syndrome — paradoxical worsening as immunity recovers and mounts a response to a latent infection, most often tuberculosis; it is not treatment failure
Post-exposure prophylaxis within 72 hours after a needlestick injury, and pre-exposure prophylaxis for those at high risk
Prevention of parent-to-child transmission is one of the most effective public health interventions available in India, reducing transmission from 30% to under 2%
Co-trimoxazole prophylaxis is started when the CD4 count falls below 200, and prevents Pneumocystis and toxoplasmosis
Every patient with tuberculosis should be offered an HIV test, and every patient with HIV screened for tuberculosis — the two are inseparable in Indian practice
Antiretroviral drugs act at each step of the life cycle — entry inhibitors, reverse transcriptase inhibitors, integrase inhibitors and protease inhibitors; combination therapy is essential because the virus mutates so rapidly
The virus cannot be eradicated because the integrated provirus persists in resting memory CD4 cells, which is why treatment is lifelong
Universal precautions apply to every patient, not only to those known to be infected, since most transmission risk comes from undiagnosed infection
Stigma and disclosure remain major barriers to care in India, and confidentiality is both an ethical and a legal obligation
Tuberculosis in HIV is often atypical — sputum-negative, extrapulmonary, with normal or lower-zone chest radiographs and absent cavitation, because granulomas cannot form without CD4 cells
Antiretroviral therapy has converted HIV into a chronic manageable disease, with near-normal life expectancy if treatment is started early and taken consistently
Cardiovascular, renal and metabolic complications of long-term therapy and of chronic inflammation are now the dominant clinical problems
India's national programme provides free antiretroviral therapy, and adherence support is as important as the drugs themselves

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