HIV (Human Immunodeficiency Virus) - Comprehensive Overview

Scanning electron micrograph: HIV (yellow) budding from an infected H9 T cell (blue/green)

1. Virology and Structure

• HIV-1: Responsible for the vast majority of infections worldwide. Has four groups - M (Main), N, O, and P. Group M is further divided into 11 subtypes (clades A-K), with clade B predominating in Western nations.
• HIV-2: Found primarily in West Africa; similar pathogenesis but slower disease progression and naturally lacks the Vpu gene (has Vpx instead).

Viral Genome and Proteins

2. Epidemiology

• Global burden: Approximately 39 million people living with HIV worldwide (UNAIDS 2023 data).
• Transmission routes: Unprotected sexual intercourse (most common globally), intravenous drug use (needle sharing), mother-to-child (vertical transmission - perinatal/breastfeeding), blood transfusion/organ transplantation (rare in developed countries), occupational needlestick exposure.
• Risk quantification (Harrison's):
  • Needlestick from HIV+ source: ~0.23% per exposure (untreated)
  • Mucous membrane exposure: ~0.09%
  • Male-to-male sexual contact: accounts for ~two-thirds of incident cases in men in the USA
  • Heterosexual contact: ~90% of new infections in women in the USA
• HIV disproportionately affects minority populations; ~60% of prevalent US cases affect Black women. - Goldman-Cecil Medicine International Edition
• CCR5-Δ32 mutation: ~1% of northern Europeans are homozygous and resistant to HIV infection; ~10-15% are heterozygous.

3. Pathogenesis

3a. Entry Mechanism

• CCR5 (C-C chemokine receptor type 5): Used by R5 (M-tropic) viruses - predominate in early infection; infect monocytes/macrophages
• CXCR4 (C-X-C chemokine receptor type 4): Used by X4 (T-tropic) viruses - emerge in later disease; associate with rapid CD4 decline
• Dual-tropic R5X4 viruses: Use both co-receptors

1. gp120 binds CD4 → conformational change in gp120
2. gp120 engages CCR5 or CXCR4 co-receptor (via V3 loop)
3. gp41 undergoes conformational change → membrane fusion
4. Viral RNA enters cytoplasm

3b. Replication Cycle

1. Attachment and fusion (gp120/gp41 - CD4/co-receptor interaction)
2. Reverse transcription: Viral RNA → dsDNA via reverse transcriptase
3. Nuclear import: Pre-integration complex enters nucleus
4. Integration: Integrase incorporates proviral DNA into host genome
5. Transcription: Host RNA polymerase II transcribes viral genes; Tat amplifies transcription; Rev exports unspliced mRNA
6. Translation and processing: Viral protease cleaves polyproteins
7. Assembly and budding: New virions bud from cell membrane

3c. CD4+ T Cell Depletion - Mechanisms

• Loss of plasma membrane integrity during viral budding
• Accumulation of unintegrated viral DNA
• Intracellular gp120-CD4 autofusion events
• Syncytia formation (especially X4 viruses)

• Pyroptosis: Abortive HIV infection of resting CD4+ T cells activates the inflammasome (caspase-1), releasing inflammatory cytokines and recruiting more cells - a major mechanism of CD4 depletion
• Activation-induced cell death: Chronic immune activation of uninfected cells causes apoptosis
• Autoimmunity and innocent bystander killing
• Inhibition of lymphopoiesis: Loss of CD4+ precursors in thymus
• Elimination of HIV-infected cells by CD8+ cytotoxic T cells

3d. Infection of Non-T Cells

• Macrophages: Infected via CCR5; serve as a reservoir; do not die but carry virus to tissues including the brain
• Dendritic cells (DCs): Carry HIV to lymph nodes, presenting it to CD4+ T cells; Langerhans cells beneath mucosal surfaces are early targets during sexual transmission
• Microglial cells of the brain: Infected via CCR5; underlie HIV-associated neurocognitive disorder (HAND)
• Gut-associated lymphoid tissue (GALT): Massive early depletion of intestinal CD4+ T cells occurs within days to weeks of primary infection - a key early event

3e. Immune Dysfunction

4. Clinical Course

Stage 1 - Acute (Primary) HIV Infection

• Occurs 2-4 weeks after transmission
• ~50-70% of individuals develop a mononucleosis-like acute HIV syndrome:
  • Fever, malaise, lymphadenopathy, pharyngitis, rash (erythematous maculopapular), myalgia/arthralgia
  • Less commonly: headache, oral ulcers, diarrhea, nausea/vomiting
  • Rarely: aseptic meningitis, peripheral neuropathy
• Very high viral load (up to 10^7 copies/mL) - peak viremia → wide dissemination
• CD4+ count drops sharply then partially recovers
• Lasts 1-2 weeks; resolves as immune response develops
• HIV establishes itself in lymphoid organs (seeding phase)

Stage 2 - Chronic Asymptomatic (Clinical Latency)

• Lasts average 8-10 years untreated
• Patient is clinically well but virologically active (viral set point: typically 10^3-10^5 copies/mL)
• CD4+ count declines slowly (~50-100 cells/μL/year)
• May have persistent generalized lymphadenopathy (PGL)
• Viral replication is ongoing in lymphoid tissues
• "Virologic set point": Higher set point = faster progression to AIDS

Stage 3 - Symptomatic / AIDS

• Defined by CDC as:
  • CD4+ count <200 cells/μL (in persons >6 years), OR
  • Presence of an AIDS-defining opportunistic illness (Stage C conditions)
• Constitutional symptoms precede OIs: fever, night sweats, weight loss, diarrhea

5. AIDS-Defining Opportunistic Illnesses

6. Diagnosis

HIV Testing

• 4th generation combination assays (preferred): Detect both p24 antigen AND HIV-1/HIV-2 antibodies; can detect infection as early as 18-45 days after exposure (window period shortened)
• 3rd generation antibody-only ELISA: Window period ~3-6 weeks
• Western blot / Immunofluorescence assay: Confirmatory (now being replaced by supplemental antibody differentiation assays)
• HIV RNA (viral load) PCR: Detects acute infection before seroconversion; quantifies viral burden; guides treatment
• CD4+ T cell count: Absolute count and percentage; determines stage and guides prophylaxis decisions
• HIV genotyping/resistance testing: Done at baseline and at treatment failure
• Rapid tests: Point-of-care antibody tests; results in 20-60 minutes

Monitoring Parameters

• HIV RNA (viral load): Goal is <50 copies/mL on ART (undetectable)
• CD4+ count: Every 3-6 months; determines need for OI prophylaxis
• Drug resistance testing (genotype): Before starting ART and at virologic failure
• HLA-B*5701 testing: Before abacavir use (risk of hypersensitivity reaction)
• CCR5 tropism assay: Before maraviroc use

7. Treatment - Antiretroviral Therapy (ART)

When to Start

• Cryptococcal meningitis: Delay ART 4-6 weeks (immune reconstitution inflammatory syndrome risk)
• Active TB: Delay ART 2-8 weeks depending on CD4+ count
• For patients with an OI and CD4 ≥50: Consider 2-4 week delay
• For CD4 <50: Start ART as soon as possible

Drug Classes

Preferred Initial Regimens (DHHS Guidelines)

• Two NRTIs (usually tenofovir-based [TDF or TAF] + FTC/3TC)
• PLUS one of: NNRTI, INSTI, or boosted PI

• Biktarvy: Bictegravir/TAF/FTC (once daily - preferred first-line)
• Triumeq: Abacavir/Dolutegravir/Lamivudine
• Atripla: Efavirenz/FTC/TDF
• Cabotegravir + Rilpivirine (Cabenuva): Monthly or every-2-month injectable regimen

Treatment Goals

• Achieve and maintain undetectable viral load (<50 copies/mL)
• Preserve and restore CD4+ count
• Prevent opportunistic infections
• Reduce HIV transmission risk ("U=U": Undetectable = Untransmittable)
• Minimize drug toxicity

Drug Resistance

• Resistance arises from mutations in viral genes encoding drug targets
• High-level replication in the absence of ART generates quasi-species with resistant mutations
• Resistance testing (genotype) guides regimen selection at baseline and at virologic failure
• Drugs with high genetic barrier to resistance (e.g., dolutegravir, bictegravir) are preferred because multiple mutations are needed to overcome them

8. Opportunistic Infection Prophylaxis

9. Prevention

Pre-Exposure Prophylaxis (PrEP)

• Oral PrEP: Tenofovir/emtricitabine (Truvada) once daily - reduces transmission risk by >99% with adherence
• Injectable PrEP: Cabotegravir LA (every 2 months) - shown to be even more effective than oral TDF/FTC
• Recommended for high-risk individuals (MSM, serodiscordant couples, IDU)

Post-Exposure Prophylaxis (PEP)

• Must be initiated within 72 hours of exposure
• nPEP regimen: Tenofovir-emtricitabine 300/200 mg daily + Raltegravir 400 mg q12h OR Dolutegravir 50 mg once daily for 28 days
• Follow-up HIV testing at 6 weeks
• Risk of transmission: ~0.23% per needlestick (untreated); PEP dramatically reduces this. - Washington Manual of Medical Therapeutics

Other Prevention Strategies

• Consistent condom use
• Harm reduction for PWID (needle exchange programs, opioid agonist therapy)
• Treatment as prevention (TasP): ART in HIV+ individuals reduces transmission to near zero when viral load is undetectable
• Male circumcision: Reduces female-to-male transmission by ~60%
• Prevention of mother-to-child transmission (PMTCT): ART during pregnancy, safe delivery practices, formula feeding (where safe and feasible)
• Universal precautions in healthcare settings

10. HIV-Associated Complications

Neurological (HAND - HIV-Associated Neurocognitive Disorder)

• HIV enters CNS early via infected monocytes/macrophages (Trojan horse model)
• Microglial cell infection disrupts neuronal function
• Spectrum: Asymptomatic neurocognitive impairment → HIV-associated mild neurocognitive disorder → HIV-associated dementia

Malignancies

• Kaposi's sarcoma (AIDS-defining): Caused by HHV-8; cutaneous/visceral vascular tumors
• Primary CNS lymphoma: EBV-driven; occurs at CD4 <50
• Non-Hodgkin lymphoma (Burkitt's, immunoblastic)
• Invasive cervical cancer: HPV-related; annual Pap smear recommended for all HIV+ women
• Increased risk of anal, lung, hepatic, and other cancers

Immune Reconstitution Inflammatory Syndrome (IRIS)

• Occurs 2-8 weeks after ART initiation
• Paradoxical worsening of a pre-existing opportunistic infection as immunity recovers
• Risk factors: Low baseline CD4+ count, high antigen burden, rapid CD4+ increase
• Management: Continue ART; NSAIDs or corticosteroids for severe cases

Metabolic and Cardiovascular

• Dyslipidemia (especially with PIs)
• Insulin resistance / lipodystrophy
• Increased risk of cardiovascular disease (partly due to chronic immune activation)
• Some "non-AIDS-defining" serious adverse events (heart attack, stroke) are linked to ongoing HIV replication - reason why treatment interruptions are harmful

11. Genetic Host Factors Influencing Disease Progression

• HLA-B57 and HLA-B27 alleles: Protective - associated with slower progression, lower viral set point, stronger CD8+ T cell responses. Enriched among "elite controllers" (spontaneously control HIV without ART)
• HLA-B35 allele: Detrimental - faster progression to AIDS, higher viral load
• HLA-A1/B8/DR3 (AH 8.1 haplotype): Common in Europeans; associated with rapid CD4 decline and faster progression
• CCR5-Δ32 homozygotes: Near-complete resistance to HIV-1 infection
• CCR5-Δ32 heterozygotes: Slower disease progression
• "Berlin patient" and subsequent cases: Allogeneic stem cell transplant from CCR5-Δ32 homozygous donors led to functional cure in a small number of HIV+ cancer patients - the only documented cases approaching eradication - Harrison's 22E

12. Special Populations

Pregnancy

• ART should be given to ALL pregnant women regardless of CD4+ count
• Same principles apply; regimen chosen for safety in pregnancy
• Undetectable viral load at delivery reduces vertical transmission to <1%

Children

• Unique pharmacologic, virologic, and immunologic considerations
• Earlier and more aggressive ART initiation recommended

Recent Evidence (2024-2025)

• Harrison's Principles of Internal Medicine 22E (2025, McGraw Hill Medical)
• Robbins & Kumar Basic Pathology; Robbins, Cotran & Kumar Pathologic Basis of Disease
• Sherris & Ryan's Medical Microbiology, 8th Edition
• Goldman-Cecil Medicine International Edition
• The Washington Manual of Medical Therapeutics
• Medical Microbiology 9e (Murray)