HIV produces a wide spectrum of CNS pathology: direct viral effects, opportunistic infections, neoplasms, and treatment-related complications. Despite the dramatic decline of severe HIV-related neurologic disease in the era of effective antiretroviral therapy (ART), HIV remains a major contributor to neurologic morbidity worldwide, and patients on long-term ART still develop more subtle cognitive disorders. This page covers the neuropathology of HIV infection and its complications.

HIV Encephalitis (HIVE)

Pathology

  • Multinucleated giant cells: characteristic; formed by HIV-infected macrophages/microglia, with cytoplasmic syncytia and HIV p24 antigen positivity on IHC.
  • Microglial nodules: clusters of microglia, often with neuronophagia.
  • Reactive astrogliosis.
  • Perivascular lymphocytic inflammation.
  • Demyelination: subcortical white matter.
  • Distribution: subcortical white matter, deep gray nuclei, brainstem; subependymal regions.

Clinical (HIV-Associated Dementia, HAD)

  • Subcortical pattern: executive dysfunction, slowed processing, depression, motor slowing.
  • Substantially less common in the ART era but persistent.
  • HIV-associated neurocognitive disorder (HAND) — current term — encompasses milder forms.

HIV Leukoencephalopathy

Diffuse white matter pallor with axonal damage, gliosis. Often coexists with HIVE. Distinguished from PML (focal, JC virus) by diffuse rather than focal distribution.

Opportunistic Infections in HIV/AIDS

Progressive Multifocal Leukoencephalopathy (PML)

JC virus reactivation in oligodendrocytes (separate page). Multifocal demyelination; once almost universally fatal, now treatable with immune reconstitution.

Toxoplasmosis

  • Reactivation of latent infection.
  • Ring-enhancing lesions, often multiple, basal ganglia predilection.
  • Tachyzoites and bradyzoite cysts on histology; toxoplasma IHC.
  • Empirical treatment with sulfadiazine + pyrimethamine often initiated based on imaging + serology + CD4 count.
  • Differential: PCNSL (toxo responds to treatment in 2 weeks; PCNSL does not).

Cryptococcal Meningitis

  • Cryptococcus neoformans: encapsulated yeast.
  • Predilection for basal cisterns + perivascular spaces.
  • “Soap bubble” appearance: cystic dilated perivascular spaces filled with cryptococci.
  • India ink, mucicarmine stain (red), GMS, and PAS stains identify the yeast.
  • Cryptococcal antigen in CSF.
  • Treatment: amphotericin B + flucytosine; severe ICP from CSF outflow obstruction.

CMV (CNS)

  • Ventriculitis (periventricular distribution).
  • Owl’s eye inclusions.
  • Treatment: ganciclovir.

Mycobacterium tuberculosis

Higher prevalence in HIV co-infection; basal meningitis, tuberculomas. (Separate fungal & TB page.)

Syphilis

Co-infection common; meningovascular and parenchymal forms.

HHV-6, HHV-8

HHV-6: occasional encephalitis. HHV-8: Kaposi sarcoma (rarely CNS).

HIV-Associated Neoplasms

Primary CNS Lymphoma (PCNSL)

  • EBV-positive in nearly all HIV-related cases.
  • Single or multiple periventricular masses, often homogeneously enhancing.
  • Differential: toxoplasmosis (PCNSL: SPECT thallium uptake positive; toxo negative; PCNSL: PCR for EBV in CSF positive).
  • Restricted diffusion centrally (highly cellular).
  • Often dramatic response to chemotherapy + radiation.

Kaposi Sarcoma, Systemic Lymphoma

CNS involvement is rare.

IRIS (Immune Reconstitution Inflammatory Syndrome)

Paradoxical worsening or unmasking of opportunistic infection or inflammation after ART initiation in patients with low CD4 counts (typically <100). Pathology: vigorous inflammation around persisting organisms (cryptococcosis, TB, PML).

Vacuolar Myelopathy

Spinal cord pathology in advanced HIV:

  • Vacuolar degeneration of dorsal columns and lateral corticospinal tracts.
  • Resembles subacute combined degeneration but without B12 deficiency.
  • Clinical: spastic paraparesis, sensory ataxia, bladder dysfunction.
  • Possibly related to HIV macrophage activation in cord.

HIV-Associated Peripheral Neuropathy

  • Distal sensory polyneuropathy: most common; “ART-related” + HIV-related.
  • Inflammatory demyelinating polyneuropathy (AIDP/CIDP).
  • Mononeuritis multiplex (vasculitic).
  • Progressive polyradiculopathy (CMV-related in advanced disease).
  • Treatment: optimize ART, antiretroviral substitutions, symptomatic neuropathic pain treatment.

HIV-Associated Myopathy

  • HIV-related myopathy: inflammatory.
  • Zidovudine (AZT) myopathy: mitochondrial toxicity; ragged-red fibers.

Diagnostic Approach in HIV with Neurologic Symptoms

  • CD4 count + viral load: predicts opportunistic infection risk.
  • CSF: cell count, glucose, protein; appropriate cultures and PCRs.
  • MRI brain.
  • HIV viral load in CSF.
  • Specific tests: cryptococcal antigen, EBV PCR, JC virus PCR, toxoplasma serology, treponemal tests.
  • Brain biopsy occasionally needed for diagnosis (PCNSL vs toxoplasmosis vs PML).

🔍 Did You Know?

The multinucleated giant cell (MGC) is the histologic signature of HIV encephalitis. These cells are formed by syncytial fusion of HIV-infected macrophages and microglia in the brain — the only true syncytial fusion of immune cells in any human encephalitis. They were identified soon after AIDS was characterized as a viral disease and provided some of the first direct histologic evidence of CNS infection. Today, the prevalence of severe HIV encephalitis with MGCs has dramatically declined due to effective antiretroviral therapy. But in patients with poor ART adherence, late diagnosis, or untreated advanced HIV, MGCs remain the defining histologic feature. The presence of MGCs in a brain biopsy of an unexplained encephalitis prompts immediate HIV testing. Conversely, on the autopsy of an HIV-positive patient, the presence or absence of MGCs is one of the first questions the neuropathologist answers — they distinguish HIV encephalitis from purely opportunistic infections and from purely ART-related pathology. The MGC has become a window into one of the most important pathologic shifts in modern neurology: from a disease of severe encephalitic damage to a disease of milder, treatment-modified neurocognitive impairment (HAND). Even as the dramatic histology fades from clinical practice, recognition of the multinucleated giant cell remains a fundamental piece of HIV neuropathology.

Pitfalls and Pearls

  • HIV encephalitis: multinucleated giant cells + microglial nodules + perivascular inflammation + subcortical predilection.
  • HAND: spectrum of HIV-associated neurocognitive disorder; common in ART era.
  • PML: oligodendrocyte JC virus infection; multifocal demyelination.
  • Toxoplasmosis: ring-enhancing basal ganglia lesions; treat empirically and reassess at 2 weeks.
  • PCNSL: EBV-positive in HIV; periventricular; CSF EBV PCR positive.
  • Cryptococcus: basal meningitis, soap-bubble cystic lesions, India ink, cryptococcal antigen.
  • IRIS: paradoxical worsening after ART initiation in low CD4.
  • Vacuolar myelopathy: HIV-related; mimics SCD without B12 deficiency.
  • HIV peripheral neuropathy: distal sensory + various inflammatory forms + CMV polyradiculopathy.
  • CD4 count predicts opportunistic infection risk: < 200 toxoplasmosis, PCNSL; < 50 CMV, MAC.
  • CSF HIV viral load: reflects CNS reservoir.
  • Restricted diffusion + ring enhancement: think PCNSL or abscess; toxo usually does not restrict.

References

  1. Love S, Budka H, Ironside JW, Perry A, eds. Greenfield’s Neuropathology. 9th ed. CRC Press; 2015.
  2. Antinori A, Arendt G, Becker JT, et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology. 2007;69(18):1789-1799.
  3. Saylor D, Dickens AM, Sacktor N, et al. HIV-associated neurocognitive disorder — pathogenesis and prospects for treatment. Nat Rev Neurol. 2016;12(4):234-248.
  4. Smith AB, Smirniotopoulos JG, Rushing EJ. From the archives of the AFIP: central nervous system infections associated with human immunodeficiency virus infection. Radiographics. 2008;28(7):2033-2058.
  5. Tan IL, McArthur JC, Clifford DB, Major EO, Nath A. Immune reconstitution inflammatory syndrome in natalizumab-associated PML. Neurology. 2011;77(11):1061-1067.