AIDS - Etiology, Routes of Transmission, Natural History, and Diagnosis

1. Etiology

The Causative Agent

• HIV-1: Most common type; associated with AIDS in the United States, Europe, and Central Africa
• HIV-2: Causes a similar disease, principally in West Africa and India

Structure of HIV

2. Routes of Transmission

A. Sexual Contact (most common globally)

• Men who have sex with men (MSM): account for >50% of reported cases in the United States (about 70% of new cases in 2016)
• Heterosexual transmission: ~20% of cases in the U.S.; globally, the most common mode of spread, especially in sub-Saharan Africa where >50% of infected individuals are female
• Risk is enhanced by co-existing STDs - especially those with genital ulceration (syphilis, chancroid, herpes); gonorrhea and chlamydia also serve as cofactors (genital inflammation provides more infectable cells)

B. Parenteral Inoculation

• Intravenous drug users: the largest parenteral group; transmission by sharing needles, syringes, and other paraphernalia contaminated with HIV-containing blood
• Hemophiliacs: historically received contaminated factor VIII/IX concentrates - now virtually eliminated due to recombinant clotting factors and blood screening
• Blood transfusion recipients: risk now extremely small (estimated at 1 in >2 million units transfused) due to anti-HIV antibody screening

C. Mother-to-Infant (Vertical) Transmission

1. In utero - transplacental spread
2. Intrapartum - during delivery through an infected birth canal (most common in the U.S.)
3. Postpartum - ingestion of breast milk

What Does NOT Transmit HIV

3. Natural History (Clinical Course)

Phase 1: Acute Retroviral Syndrome (Weeks 3-6 post-infection)

• HIV enters the body through mucosal tissues - DCs in epithelia capture the virus, migrate to lymph nodes, and pass HIV to CD4+ T cells via direct cell-to-cell contact
• Within days of first exposure: viral replication detected in lymph nodes, followed by viremia (high HIV particles in blood)
• Virus disseminates throughout the body, seeding helper T cells and macrophages in peripheral lymphoid tissues
• Host mounts antiviral humoral and cell-mediated responses - seroconversion occurs within 3 to 7 weeks of presumed exposure
• By ~12 weeks: CD8+ cytotoxic T cells develop; immune response partially controls viremia (drops to low but detectable levels - the "viral set point")

• Non-specific, self-limited flu-like illness lasting 2-4 weeks
• Sore throat, myalgias, fever, weight loss, fatigue, generalized lymphadenopathy, rash
• Often accompanied by a transient drop in CD4+ T-cell count followed by partial recovery

Phase 2: Chronic Infection / Clinical Latency (Years 1-10)

• Lymph nodes and spleen are sites of continuous HIV replication and cell destruction
• Few or no clinical manifestations (hence "clinical latency") - but viral destruction of CD4+ T cells continues silently
• HIV destroys up to 2 × 10⁹ CD4+ T cells every day; early on, T cells are replaced almost as quickly as destroyed
• CD4+ count steadily declines from ~1000 cells/µL at baseline, falling at ~50-80 cells/µL per year in untreated patients
• The viral set point at end of acute phase predicts rate of CD4+ decline: only 8% of patients with <4,350 viral RNA copies/µL progressed to AIDS in 5 years, vs. 62% with >36,270 copies

• Oral candidiasis (thrush)
• Vaginal candidiasis
• Herpes zoster
• Tuberculosis (especially common in sub-Saharan Africa)
• Autoimmune thrombocytopenia

Phase 3: AIDS (End Stage)

• Triggered when CD4+ count falls below 200 cells/µL (CDC definition)
• Characterized by breakdown of host defense, a dramatic increase in viral load, and severe life-threatening clinical disease
• Without treatment, most patients progress to AIDS after 7 to 10 years of chronic phase

• Long-lasting fever (>1 month), fatigue, weight loss, diarrhea, generalized lymphadenopathy

• Rapid progressors: Chronic phase telescoped to 2-3 years
• Long-term nonprogressors: ~1% remain asymptomatic for 10+ years with stable CD4+ counts and low viral loads without ART
• Elite controllers: Usually <50 viral RNA copies/mL; have vigorous anti-HIV immune responses and favorable HLA alleles

CDC Classification of HIV Infection

4. Diagnosis

A. Serologic Tests (Antibody-Based)

• ELISA for anti-HIV antibodies (also detects p24 antigen in 4th-generation combination assays): Standard screening test
  • Highly sensitive but less specific; positive results must be confirmed
• Western blot: Confirmatory test - identifies antibodies against specific viral proteins (gp120, gp41, p24)
• Seroconversion occurs within 3-7 weeks of exposure; the "window period" (antibody-negative but infected) is a source of false-negative screening

B. Virologic / Molecular Tests

• HIV-1 RNA PCR (viral load): Quantifies HIV RNA copies/mL plasma
  • Diagnostic in acute infection (before seroconversion)
  • Marker of disease progression and treatment response
  • Viral set point correlates with rate of CD4+ decline and risk of progression
• p24 antigen detection (ELISA): p24 is the most abundant viral antigen; detected in early infection when antibody tests may be negative

C. CD4+ T-Cell Count

• Primary clinical measurement for determining when to start ART and assessing immune status
• CD4+ <200 cells/µL = AIDS diagnosis, regardless of symptoms
• Most reliable short-term indicator of disease progression

D. Nucleic Acid Amplification Tests (NAATs)

• Used in early/acute infection and in neonates of HIV-positive mothers where maternal antibodies confound serologic testing
• HIV DNA PCR used in infants to detect integrated proviral DNA

E. Additional Testing

• HIV genotyping / resistance testing: before starting or changing ART
• CBC with differential: to detect lymphopenia and thrombocytopenia
• Opportunistic infection workup: chest X-ray, sputum for P. jirovecii, toxoplasma serology, CMV load, fungal cultures