AIDS (Acquired Immunodeficiency Syndrome)

Definition

• Cellular and Molecular Immunology, p. 1426
• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 237

Etiology and Virology

• Caused by HIV-1 (globally predominant) and HIV-2 (West Africa)
• HIV is a retrovirus (RNA virus) belonging to the lentivirus family
• The HIV genome encodes structural genes: gag (core proteins), pol (reverse transcriptase, integrase, protease), and env (envelope glycoproteins gp120 and gp41)
• The virus carries reverse transcriptase, allowing it to convert its RNA genome into DNA (the provirus), which integrates permanently into the host cell genome

Epidemiology

• Approximately 39 million people worldwide were living with HIV in 2022
• About 630,000 deaths attributable to HIV/AIDS in 2022
• ~67% of all people living with HIV reside in Sub-Saharan Africa
• By 2022, 76% of people living with HIV globally were on antiretroviral therapy (ART)
• UNAIDS "95-95-95" targets for 2030: 95% of people with HIV know their status, 95% of those on treatment, 95% achieving viral suppression
• Harrison's Principles of Internal Medicine 22E, p. 1013

Transmission

1. Sexual contact - the most common route globally; heterosexual sex predominates in Africa and Asia; MSM (men who have sex with men) predominant route in high-income countries
2. Mother-to-child (vertical) - in utero, during delivery, or via breast milk; accounts for the majority of pediatric cases
3. Inoculation with infected blood - shared IV drug needles (most common), rarely blood transfusion (now screened). HIV can remain infectious in a used needle for up to 6 weeks

• Cellular and Molecular Immunology, p. 1426

Pathogenesis

Life Cycle of HIV

1. Attachment: HIV surface glycoprotein gp120 binds to CD4 receptor on T-helper lymphocytes (also macrophages and dendritic cells). This is the basis of selective tropism for CD4+ T cells.
2. Coreceptor binding: gp120 must also bind a coreceptor - primarily CCR5 (M-tropic / R5 strains, dominant early) or CXCR4 (T-tropic / X4 strains, accumulate later and cause greater T-cell depletion).
3. Fusion: Coreceptor binding induces conformational change in gp41, exposing its fusion peptide, which inserts into the target cell membrane and allows viral core entry.
4. Reverse transcription: Viral RNA is converted to double-stranded DNA by reverse transcriptase.
5. Integration: Viral DNA integrates into the host genome as a provirus (can remain latent).
6. Replication and budding: When activated (by antigens, cytokines such as TNF), viral genes are expressed. New virions bud from the cell, destroying it.

Strains and tropism

• R5 (M-tropic) strains: use CCR5, dominant in early infection, infect macrophages/monocytes and T cells
• X4 (T-tropic) strains: use CXCR4, accumulate over time, more virulent, cause greater T-cell depletion

Mechanisms of Immune Deficiency

• Direct T-cell killing: cell death during viral replication and budding
• Apoptosis: chronic T-cell stimulation triggers programmed cell death
• Decreased thymic output: progressive thymic damage
• Functional defects in surviving CD4+ T cells, macrophages, and dendritic cells
• B-cell dysregulation: early follicular hyperplasia, then "burnt-out" lymph node involution with lymphocyte depletion
• Robbins, Cotran & Kumar, p. 237-242

Clinical Course - Three Phases

Phase 1: Acute HIV Syndrome (Acute Retroviral Syndrome)

• Occurs 3-6 weeks after infection in 40-90% of newly infected individuals
• Marked by high viremia (viral load spike) and modest fall in CD4+ T cells
• Symptoms are non-specific (flu-like): fever, sore throat, myalgias, fatigue, weight loss, rash, cervical adenopathy, diarrhea, vomiting
• Resolves spontaneously in 2-4 weeks; immune response leads to seroconversion within 3-7 weeks of exposure

Phase 2: Chronic Latency Phase

• Can last many years (average ~10 years without treatment)
• Virus is contained in lymphoid tissues; ongoing slow CD4+ T-cell destruction
• Patient is asymptomatic or has minor infections
• The viral set point (stable plasma viral load level) and CD4+ count are key predictors of progression
• CD4+ count of <500 cells/µL indicates immunosuppression; <200 cells/µL = AIDS

Phase 3: AIDS

• CD4+ T-cell count drops below 200 cells/mm³
• Viremia climbs as viral replication accelerates unchecked
• Characterized by:
  • Opportunistic infections (see below)
  • AIDS-associated neoplasms
  • HIV wasting syndrome (cachexia)
  • HIV nephropathy (kidney failure)
  • HIV-associated neurocognitive disorder (HAND) - formerly called AIDS encephalopathy
• Cellular and Molecular Immunology, p. 1427-1428

CDC Classification of HIV Infection

• A: Asymptomatic, acute HIV infection, or persistent generalized lymphadenopathy
• B: Symptomatic conditions not included in category C (e.g., oral candidiasis, cervical dysplasia)
• C: AIDS-defining conditions (e.g., PCP, cryptococcal meningitis, Kaposi's sarcoma, CMV retinitis)
• Robbins, Cotran & Kumar, p. 242

Opportunistic Infections and Neoplasms in AIDS

Diagnosis

• HIV antibody test (ELISA + confirmatory Western blot): standard screening
• HIV RNA PCR (viral load): for acute infection (before antibody development), monitoring treatment response
• CD4+ T-cell count: staging, timing of treatment initiation, risk stratification
• Window period: antibodies develop within 3-7 weeks of exposure (can take up to 3 months)

Treatment - Antiretroviral Therapy (ART)

• ART is indicated for all HIV-infected individuals regardless of CD4 count
• Treatment goal: undetectable viral load (U=U: Undetectable = Untransmittable)
• First-line ART in low- and middle-income countries now available for <$45/patient/year (vs. >$10,000/year in 2000)
• Standard regimen: typically 2 NRTIs + 1 INSTI (preferred backbone)
• Harrison's Principles of Internal Medicine 22E, p. 1015-1021

Prevention

• Safe sexual practices (condoms), PrEP (pre-exposure prophylaxis with tenofovir/emtricitabine)
• Harm reduction for IV drug users (clean needles)
• Prevention of mother-to-child transmission (PMTCT): ART during pregnancy
• Elective cesarean section + avoiding breastfeeding reduces vertical transmission
• No vaccine is currently available (key challenge: high viral genetic variability and complex correlates of immune protection)

Morphology (Pathology)

• Lymph nodes - early: follicular hyperplasia with enlarged germinal centers; late: lymphoid depletion, hyalinized germinal centers, "burnt-out" nodes laden with opportunistic organisms
• Spleen and thymus: progressively converted to "wastelands" devoid of lymphocytes in late AIDS
• Brain: microglial nodules, multinucleated giant cells, white matter vacuolation in HAND

LEPROSY (Hansen Disease)

Definition

• Goldman-Cecil Medicine International Edition, p. 3269
• Harrison's Principles of Internal Medicine 22E, p. 685

The Pathogen - Mycobacterium leprae

• Gram-positive, acid-fast (Fite stain preferred), rod-shaped bacterium
• Length 1-8 microns, diameter 0.3 microns
• Non-motile, non-spore forming, microaerophilic, slow-growing
• Average generation time: 14 days (extremely slow - longest of any pathogen)
• Cannot be cultivated in vitro on any artificial medium
• Research model: mouse footpad inoculation; nine-banded armadillos (natural reservoir in Americas)
• Requires optimum temperature of ~30°C - hence favors cooler parts of the body (ears, nose, superficial nerves, skin)
• Mycolic acid-rich cell wall; has ~2000 fewer genes than M. tuberculosis - obligate intracellular organism

Epidemiology

• Neglected tropical disease with >200,000 new cases/year globally
• ~75% of cases from India, Brazil, and Indonesia
• Globally eliminated (<10 cases/10,000 population) as a public health problem in 2000; India achieved this in 2005
• During COVID-19 pandemic: case detection dropped, ~130,000 on treatment in 2020; rebounded to 140,594 new cases in 2021 (18/million population)
• In the U.S.: extremely rare, <250 cases/year, mostly in immigrants
• Transmission: respiratory droplets (primary route), or via breached skin
• Not highly transmissible: requires prolonged, close contact with untreated cases
• Incubation period: typically 2-5 years, can be up to 20 years
• Nine-banded armadillos in Americas are an animal reservoir

Pathogenesis and Immunogenetics

• Only 0.1-1% of exposed individuals develop clinical disease - susceptibility is primarily determined by host immune factors
• Susceptibility genes: HLA-DR2, HLA-DR3 (class II MHC), NRAMP1, TLR2, TNF-alpha, and IL-10 gene SNPs
• Chromosomal region 10p13 linked to tuberculoid leprosy susceptibility

Classification (Ridley-Jopling Spectrum)

1. Indeterminate leprosy (IL) - earliest form; subtle hypopigmented macule, sparse perineurovascular lymphoid infiltrate; may resolve spontaneously or progress
2. Tuberculoid (TT) - single or few large, well-defined, hypopigmented/erythematous, anesthetic plaques; well-formed granulomas with no bacilli on Fite stain; thickened nerve palpable
3. Borderline Tuberculoid (BT) - similar to TT but more lesions, less well-defined
4. Mid-Borderline (BB) - "punched out" annular lesions with well-defined inner edge and ill-defined outer edge; unstable immunologically
5. Borderline Lepromatous (BL) - multiple small hypopigmented to coppery-colored macules, symmetrically distributed
6. Lepromatous (LL) - most severe; diffuse skin infiltration, nodules, papules; leonine facies (loss of eyebrows/eyelashes, thickened facial skin), nasal septal perforation, anosmia, symmetric sensorimotor polyneuropathy in glove-and-stocking distribution

• Paucibacillary (PB): 1-5 skin lesions
• Multibacillary (MB): >5 skin lesions

Clinical Features

Skin Lesions

• Hypopigmented, hypoesthetic/anesthetic, non-pruritic patches (cardinal feature)
• May progress to papules, plaques, nodules, diffuse infiltration depending on type
• Lesions have reduced or absent sweating and hair growth

Nerve Involvement

• Superficial cutaneous nerves of ears, distal limbs commonly affected
• Commonly thickened and palpable peripheral nerves: ulnar nerve (at elbow), common peroneal (at knee), great auricular nerve, radial cutaneous, posterior tibial
• Results in: mononeuropathy, multiple mononeuropathies, or symmetric sensorimotor polyneuropathy
• Sensory loss → painless injuries (burns, ulcers), secondary infections
• Motor loss → clawhand, foot drop, lagophthalmos (inability to close eyes)

Systemic Features (Advanced Lepromatous)

• Anosmia, nasal crusting, nasal septal perforation (in up to 40%)
• Gynecomastia, orchitis, infertility (testicular involvement)
• Eye involvement: corneal anesthesia, uveitis, blindness
• Loss of lateral eyebrows (madarosis)

Leprosy Reactions (Lepra Reactions)

Type 1 Reaction (Reversal Reaction)

• Delayed hypersensitivity reaction; Th1 immune shift
• Occurs in borderline (BT, BB, BL) disease
• Existing lesions become erythematous, swollen, tender; new lesions may appear
• Nerve involvement is severe: acute painful neuritis, nerve abscesses
• Can occur anytime during treatment as immune response is "upregulated"
• Treatment: high-dose glucocorticoids (prednisolone)

Type 2 Reaction (Erythema Nodosum Leprosum, ENL)

• Immune complex-mediated (type III hypersensitivity); leukocytoclastic vasculitis
• Occurs in BL and LL disease (areas of high bacterial burden)
• Tender erythematous nodules + systemic features (fever, malaise, lymphadenopathy, iridocyclitis)
• Treatment: thalidomide (first-line if available) or glucocorticoids

Lucio Phenomenon

• Rare, seen in diffuse lepromatous leprosy
• Thrombosis of large and small vessels with vasculitis
• Presents as retiform purpura and stellate ulcers

Diagnosis

1. Definite loss of sensation in a pale (hypopigmented) or reddish skin patch
2. Thickened or enlarged peripheral nerve with loss of sensation and/or muscle weakness
3. Acid-fast bacilli on slit-skin smear

• Slit-skin smear: simplest, confirms diagnosis and quantifies bacterial load
  • Bacteriologic Index (BI): graded 0-6+ (count of AFB per field)
  • Morphologic Index (MI): % of solid (viable) vs. granular (dead) bacilli
• Skin biopsy: from active, infiltrated edge of most active lesion; Fite stain for AFB
• PCR: specificity 100%; sensitivity 34-80% (PB) to >90% (MB); detects M. leprae DNA
• Nerve biopsy: for pure neuritic leprosy (no skin lesions); thickened radial cutaneous or sural nerve preferred
• Lepromin test: measures cell-mediated immunity (positive in tuberculoid, negative in lepromatous - not diagnostic, indicates immune response type)

Treatment - Multidrug Therapy (MDT)

Paucibacillary (1-5 lesions): 6 months

Multibacillary (>5 lesions): 12 months

• Rifampicin: red/orange discoloration of body fluids, hepatitis, flu-like syndrome, drug interactions (induces CYP450)
• Dapsone: hemolytic anemia, methemoglobinemia; severe dapsone hypersensitivity syndrome (fever, rash, hepatitis) in 4-6 weeks
• Clofazimine: orange-brown skin discoloration (reversible), crystal enteropathy at high doses, abdominal pain

Drug Resistance

• Rifampicin resistance: treat with at least 2 of - clarithromycin 500 mg/day, minocycline 100 mg/day, or a quinolone (ofloxacin 400 mg, levofloxacin 500 mg, or moxifloxacin 400 mg) + clofazimine 50 mg/day for 6 months, then clofazimine + one second-line drug for additional 18 months

Treatment of Reactions

• Type 1 reaction: Prednisolone starting at 40 mg/day, tapered over months; MDT is continued
• ENL (Type 2): Thalidomide (first-line, 100-400 mg/day) or prednisolone; NSAIDs for mild cases
• Prophylaxis: BCG vaccination provides partial protection; single-dose rifampicin post-exposure prophylaxis shown effective in close contacts

Complications and Disability

• Peripheral neuropathy → painless trauma → burns, ulcers, secondary infection → amputation risk
• Claw hand (ulnar nerve damage), foot drop (peroneal nerve), wrist drop (radial nerve)
• Lagophthalmos → corneal exposure → corneal ulcer → blindness
• Preventable with early diagnosis, MDT, and rehabilitation

Key Differences - AIDS vs Leprosy