• Acute viral infections
– Rabies, Enteroviridae, Mumps, Arenaviridae,
Arboviruses
• Herpes viral infections
– HSV, VZV, CMV
• Chronic viral infections
– JC-virus (PML), Measles (SSPE)

• Forms of acute neurological disease
– Meningitis, Panencephalitis, Leukoencephalitis and Poliomyelitis
– Uncommon complications of common systemic infections
• Clinical Features: Depend on which cells are infected
– Meningitis
• headache, fever, stiff neck, CSF pleocytosis
• Most common cause of viral meningitis: enteroviruses,
HSV2, mumps, HIV LCMV

• Encephalitis
– Increased intracranial pressure common
– Altered consciousness, focal neurological signs, accentuated tendon reflexes, seizures, tremors,
– Involvement of hypothalamus can lead to hypothermia diabetes insipidus, SIADH
– Spinal cord involvement - flaccid paralysis, bowel and bladder symptoms.
– With the exception of HSV, the topography of lesions is of little help in diagnosis

• Panencephalitis (involving both gray and white matter)
– Necrotizing
• HSV-1 or -2, VZV, Arbo
– Non-necrotizing
• HIV, CMV, HTLV-1, measles
• Polioencephalitis (predominantly involving gray matter)
– Polys followed by lymphs, neuronophagia and microglial nodules
– Enteroviruses, rabies, arboviruses
• Leukoencephalitis (predominantly involving white matter)
– PML, HIV, Post-infectious

• One of the rhabdoviruses, a group of negative-single-strand RNA viruses with a distinct bullet shape
• Receptor: NCAM (CD56), Acetylcholine receptor
• Can grow in a wide variety of cell cultures
• generally noncytopathic, in curious contrast to the fatal outcome of infection in vivo in virtually all warm blooded animals.
• Susceptibility is variable as are periods of latency and infectivity and salivary excretion

• Virus is sustained in wild carnivores and insectivorous bats
– Sylvatic reservoirs: foxes, skunks raccoons and bats
– Skunk now the commonest reservoir of wildlife rabies in US.
– Airborne transmission in bat caves
– Transmission from man to man has not been documented (except for corneal transplants)

• 50% of dogs with proven rabies do not have virus in saliva.
– Overall transmission through bite is 15%.
– Dog excretes virus up to 5 to 7 days prior to clinical symptoms
• other carnivores viral secretion not known, therefore quarantine and observation of no use except for dogs
(e.g. bats frequently without clinical symptoms).

• Incubation period in man 15 days to 1 year
(?)
• Half of patients in US with no history of bite.
• Half develop hydrophobia.
• Ascending paralysis with pleocytosis in 25% and elevation of protein

• Bland pathologic findings -
• Grossly normal
– diagnosis in dogs used to be made by examining stomachs
• Microscopic
– Perivascular inflammation
– Without tissue necrosis
– Neuronophagia uncommon
– Pathognomonic feature is Negri body
• 1 to 7 micron inclusions mostly in neurons
• Found in ammon's horn and Purkinje cells of cerebellum

From: Neuropathology Illustrated 1.0
Negri Body

• H&E stained section of cerebellum showing purkinje cell with eosinophilic cytoplasmic inclusion (Negri body)
• Electron micrograph of myelinated axon showing viral inclusions (between arrows) with axoplasm
From C.A. Wiley
From C.A. Wiley

• Saliva inoculation through bite
– Local infection of individual muscle cells
• Incubation period determined by persistent infection of muscle fibers prior to ascension of nerves
• Replicates in parikaryon and dendritic processes of neuron
– Localized to limbic system with relative sparing of the cortex
• Later transmitted centrifugally to many organs including hair follicles

• Nonenveloped positive single-stranded
RNA viruses
– 70 human enteroviruses are known
– Replication is species-specific
• Cell receptor for polio on chromosome
#19
– Approximately 3000 copies of receptor on
HeLa cells

• Cause 30 to 50% of viral meningitis and most cases of paralytic polio
• Transmission by fecal to oral contamination
– "man's fecal veneer"
• High infectivity 76% of household contacts for coxsackie,
– Epidemic Poliomyelitis
• 1916 9,000 cases in NYC,
• 80% in children under 5
• But primary infection of adults and adolescents 10 times more likely to progress to paralysis.

• Coexistence of rash and meningitis may be helpful but confusion with meningococcemia
• Meningitis lasts days to weeks
• CSF may contain a few polys initially but progresses to lymphocytes by 24 hours.

• Gray matter hemorrhage
– Neuronophagia
• Viral binding within CNS is greater than restricted distribution of receptor.
– Neuron phagocytosed by surrounding microglia
Dieing neuron
From: Neuropathology Illustrated 1.0

Mumps: Clinical / Epidemiology
• Respiratory route during winter
• Single most common cause of aseptic meningitis and mild encephalitis
– 15% of all cases of aseptic meningitis
• Half of all infections associated with CNS symptoms
• 50% of cases with CNS involvement without parotitis.
– Most resolve without neurological complications
• CSF pleocytosis may extend for 1 year

• Excretion and viremia for 6 days prior to clinical symptoms
• Cleared with appearance of IgA and IgM respectively.
• Infection of CNS is secondary to choroid plexus infection
– CSF isolation within first 4-5 days(20-50%)
• Compression of facial nerve with parotitis, hearing loss due to cochlea infection.
• Occasionally associated with lower motor neuron disease

• Fecal to oral in families, respiratory in epidemics.
– Can be transmitted by fomites
– 50% of infections cause clinical disease.
• Respiratory infections, conjunctivitis, hemorrhagic cystitis and gastroenteritis.
• Encephalitis rather than aseptic meningitis occurs but rare
– Very rare neurological complications
• almost exclusively in children

• Zoonotic infection in which man acquires virus from the mouse or hamster
• Biphasic course- pneumonitis followed by meningitis
(and encephalitis in half of these)suggests that second phase may be immunologically mediated
– Multisystem disease in which primary viral attack of lymphoid and bone marrow cells leads to damage of cells, release of vascular permeability mediators, shock.
– Clinical CNS disease remains unexplained

• Lassa fever more virulent - 10 reported autopsies
– No consistent findings- no CNS lesions seen in 4 patients.
– Lassa fever (Nigeria 1969) human to human spread hospital outbreaks with 30 to 60% mortality among infected personnel
– Pathologist who preformed the first autopsy died of Lassa.

• Include majority of Togaviruses,Flaviviruses,
Bunyaviruses, Reoviruses and Bunyaviruses.
• Obligatory cycle of multiplication in arthropod
– In ticks and mosquitoes infection can be transovarian.
– Incubation in mosquitoes for 4 days to 2 weeks
– Geographic and seasonal limitations

– 4 syndromes associated with arboviruses
• Encephalitis
• Yellow fever
• Hemorrhagic fever
• Undifferentiated tropical fevers.
– Pathology
• nonspecific inflammation

Neuron Neuron
From: Charleen Chu MD/PhD
Viral Capsids
From: Charleen Chu MD/PhD
Viral Capsids

• Usual transmission between marsh birds and mosquitoes
– Changes in marsh condition etc. lead to spill over into mosquito hosts that feed on mammals.
• Horse being important sentinel animal but dead-end host for virus.
– Ratio of inapparent infections to apparent infections is low (20:1)
• Pathology
– meningeal and perivascular inflammation, neuronophagia.

• Mosquito and birds in cycle but mosquito does feed on large vertebrates
– Ratio of unapparent to apparent infections is very high
• 1000:1 sequelae rare but fatal

• Commonest cause of human arbovirus encephalitis
• Paradoxically urban epidemics occur in drought years
– Poor drainage, rural outbreaks with high rainfall
• Man can become active intermediate host

• Venezuelan Equine Encephalitis
• California Encephalitis
• Japanese Encephalitis
• Colorado Tick Fever virus
• Tick-borne Encephalitis
• Undefined virus
– Recapitulate epidemiological patterns of virus dissemination

• Infections masquerading as viral CNS infections
– TB, brucellosis, fungi, Syphilis, Lyme disease, Rickettsial Diseases,
Leptospirosis, Mycoplasma
– Noninfectious disease
– carcinomatosis meningitis, gliomatosis cerebri, glaucomatous angitis, sarcoidosis, SLE, rheumatoid meningitis, ruptured cysts in subarachnoid

Diffuse inflammatory infiltrate
Perivascular inflammatory cuff
From: Neuropathology Illustrated 1.0
From: Neuropathology Illustrated 1.0

• Most herpesviruses are restricted to their natural host, only herpes simiae of macaque causes significant disease in man.
• Host never clears infection
• To have endemic acute disease virus you need:
– a population of 200,000
– or zoonotic infection
– or LATENCY

• Property of all herpes viruses
• Term used in two ways:
– Continuous shedding of small amounts
– or more usually implies persistent without production of recoverable virus

• virus particles and antigen not present during quiescent periods
– may involve integration of viral DNA into chromosomal,
• but since integration usually occurs during cellular DNA synthesis for latency in neurons must postulate that integration occurs during DNA repair or that episomal form of virus is sequestered.
• Latency in either neural cells or hematopoetic cells
– Transport up sensory nerve fiber during primary infection leading to establishment of latency

• Alpha- (HSV1 & 2, VZV)
– variable host range
– short reproductive cycle
– latency usually in ganglia
– have viral encoded thymidine kinase
• Beta- (CMV, HHV6 & 7)
– resticted host range
– long reproductive cycle
– latent in secretory glands & lymphoreticular tissue
• Gamma - (EBV, HHV8)
– limited host range
– frequently arrested replication pre-viral production

• Very similar to adenovirus with some splicing
• Cascade - Immediate early, early, late
– Immediate early proteins peak at 2-4 hours
• required to synthesize early proteins
– Early proteins peak 5-7 hours
• TK and other DNA synthesis related proteins
– Late proteins require DNA synthesis
• capsid proteins

• 90% of adults have antibody, despite rare involvement of the CNS it is the commonest cause of nonepidemic fatal encephalitis in US
– 1000 to 2000 cases per year with death in over half of untreated
• Spread by salivary or respiratory contact, primary infection is asymptomatic or gingivostomatitis
– herpes gladiatorum from inoculation with saliva
• Most patients who develop CNS complications in good health with cold sore of similar incidence to rest of population

• Initial infection (e.g. gingivostomatitis)
– Half of the cases first infection does not produce clinically apparent disease
– In immunosuppressed spreads rapidly and is lethal
– Otherwise primary infection terminated with appearance of immune response
• Significant neurological disease
– Insidious or fulminant onset, fever and headache,
– Local lesion in one or both fronto-temporal lobes giving personality changes
– Seizures and coma late

• T-2 weighted MRI showing increased signal in frontal lobe
(orbital gyrus on right) and bilaterally in temporal lobe
From C.A. Wiley

Swollen
Hemorrhagic
Temporal lobe
From Neuropathology Illustrated 1.0

• Adults: HSV I localization to orbital-frontotemporal lobes - often unilateral
• Children: diffuse encephalitis caused by type 1 or 2
• Immunofluorescence shows virus in ipsilateral olfactory nerve, but not in all patients.
• Not usually found in CNS with primary infection except in immunosuppressed, rather reactivation of trigeminal latency

Microscopic hemorrhages
Perivascular and parenchymal inflammation
From Neuropathology Illustrated 1.0
From Neuropathology Illustrated 1.0

Low power of needle biopsy immunostained
(red) for HSV antigens
From C.A. Wiley

From Neuropathology Illustrated 1.0
Cowdry A Inclusions
Intranuclear Viral capsids
From Neuropathology Illustrated 1.0

• Earliest change EEG slowing sometimes focal, similar to SSPE.
• MRI abnormalities early
• CT abnormalities are late
• CSF shows increased pressure early few cells or polys, but late usually mononuclear cells.
– Protein up and glucose normal.
– CSF PCR usually positive during encephalitis

• Prophylactic Acyclovir to bonemarrow transplant patients
• Age and level of consciousness at time of initiation of treatment is critical in prognosis
• Half of patients suspected of HSV encephalitis turn out not to have it
– 20% of these have a different, treatable disease
– Therefore diagnosis is critical part of care
• Acyclovir - acyclic nucleotide that is selective substrate for herpesvirus thymidine kinase.
– Cellular thymidine kinase in uninfected cells does not use acyclovir.
• Therefore drug is phosphorylated only in infected cells.

• Primary infection can occur in utero or during parturition.
– Majority of infections between 14 and 35 years of age (when
20 to 30% develop antibody).
• 250,000 genital infections / year in US
– Shedding can occur without disease
• 80% recovery from second or fourth sacral ganglia of routine autopsies.

• Infected at birth develop disseminated herpetic infections.
• Adults primary infection is complicated by acute benign meningitis
– With exacerbations of genital lesions, meningitis or radiculitis may recur in contrast to the lack of correlation of mucocutaneous lesions with HSV I.
• Immundeficiency disease can lead to fatal dissemination
• Recurrences more often in type 2 (74/123) than type 1 (2/14).
• Pathology
– Infants hepatitis and adrenal necrosis and diffuse encephalitis.

• Varicella= diminutive form of variolasmallpox
– Cell associated- inoculation with infected cells necessary even though virus is stabled in cell-free form in vesicular fluid.
– ganglionic latency

• Two distinct clinical diseases
(chickenpox and shingles)
• Shingles (herpes zoster= Greek to girdle) less common endemic disease of older or immunocomrpomised individuals
– First suggestion that both diseases were manifestations of the same infection in
1888.

Highly contagious generalized exanthematous disease with marked seasonality (winter and spring)
Occurs at a rate of 5 per 1000 population per year
Spread by respiratory route
Majority of infections are clinically obvious less than 4% escape detection.
Rare pulmonary infection and acute neurological complications
Including encephalomyelitis, localized myelitis, acute ataxia, GBS or Reye's syndrome.
CNS involvement in 1:1000 acute cerebellar ataxia - transient
Neonatal varicella in utero infection with cicatricial scarring during first trimester

• Half of people by age of 85 suffer at least one attack of shingles.
– Proposed decline in immunity with age
– Activation with or without rash
• Dysesthesia usually precede rash for 4 to 5 days
• Persistent pain for months to years
• Ophthalmic division of trigeminal account for 10-15% of all cases of
Zoster
• Immune suppression does lead to reactivation
– Life-threatening encephalitis in immunosuppressed, acute transverse myelitis and fatal ascending myelitis
– Multifocal demyelinating lesions of brain
• Resembles PML

– Primary skin infection presumably originates from blood
• Transported along sensory nerves to ganglia where it becomes latent
– Acute ganglionitis with intense inflammation and cell necrosis and occasional hemorrhage.
• Virus can not be recovered from ganglia at autopsy - only found within ganglia during acute disease
• Motor paralysis in 5% in same region as dermatomal rash
– Mild lymphocytic meningitis frequently occurs
• Unilateral poliomyelitis can occur
• Necrotizing encephalitis and transverse myelitis can occur

Confluent regions of demyelination
Nuclear Viral capsids
From:Francoise Gray MD
From:Francoise Gray MD

Ganglion cells
Ganglion cell surrounded by inflammatory cells
From Neuropathology Illustrated 1.0
From Neuropathology Illustrated 1.0

From C.A. Wiley From C.A. Wiley

• Ancient virus - (salivary gland virus)
– Genome 50% larger than HSV
– Replication- similar to HSV
• 1 to 2% of all newborns have evidence of intrauterine infection
– 30,000 infections per year in U.S.
– 12% of autopsied infants
• Another 50% infected in first 5 months
– breast milk is major source
• 50-90% of adults with steady rate of antibody acquistion throughout life.

• Primary infection usually subclinical (even in utero )
• Congential Infection
– 1% of all live births
– 5% with CID, 5% with atypical infection, 90% with subclinical
• 10% of these go on to deafness
– CMV transmitted in utero with primary and secondary infections of mother, but CID seen only in primary infections

• Numerous scattered glial nodules in gray matter
• Infrequent cytomegalic cells
• Extensive necrosis and calcifications seen in the fetal infections are not encountered in adult

Periventircular erosions
From Neuropathology Illustrated 1.0

High Power H&E of microglial nodule with central cytomegalic cell (arrow)
Electron micrograph of nucleus containing numerous round to hexagonal nucleocapsids
From C.A. Wiley
From C.A. Wiley

H&E of lateral ventricle (V) showing mostly denuded ependyma with occasional cytomegalic cell (arrow)
V
Immunostain for CMV antigens (red) shows numerous infected ependymal and underlying glial cells
From C.A. Wiley
V
From C.A. Wiley

• Often asymptomatic involvement of
CNS in immuno-suppressed patients
– Cardiac transplant patients retrospectively had confusion, tremor spastic quad
• Numerous scattered glial nodules in gray matter with infrequent cytomegalic cells

Periventricular mineralization
From Neuropathology Illustrated 1.0
Centrifugal inflammation
From Neuropathology Illustrated 1.0

• Neurological complications - pleocytosis and protein elevation probably less than 1% of patients
• Reported complications aseptic, meningitis, encephalitis,
GBS, Bell's Palsy and transverse myelitis, acute cerebellar syndrome
• Virus is difficult to recover and has never been recovered from CSF or brain seizures and coma late tissue(?)
• Occasionally with CNS symptoms of cranial nerve involvement
Lymphomas that arise in EBV positive immune compromised individuals

• Differentiate between chronic infection and chronic disease
– e.g. paralysis of polio
• Some symptoms develop late in life suggesting a progressive disease, but independent of chronic infection.
– e.g. delayed onset of paralysis after childhood infection with polio.
• Frequently fetal and neonatal acute self-limited infections suggest a progressive deterioration as the animal matures.
– Chronic diseases as sequel of acute fetal infection.

• Definitions of chronic infections
– Lingers on and has an irregular unpredictable course
– Continually demonstrable virus
• Definitions of slow infections
– Long period of latency
• Latent implies potential to be reactivated
– Regular course after clinical signs

• Long incubation periods, insidious onset, afebrile, progressive neurological disease leads to death.
• 1957 Sigurdsson described "visna"(Icelandic for wasting) inflammatory demyelinating disease of sheep
• CNS appears to be favored site of persistence

• Tolerance
– Ineffective antibody response (poor affinity, high antigen concentration).
• Immunosuppression
– measles general immune suppression
– invasion of lymphoid tissue with elimination of responsive clones.
• No antigen produced
• Antigenic variation
– e.g. Rhinoviruses Equine infectious anemia virus
• Inaccessible to immune system
– Absence of complement in CNS
• Decreased interferon induction or responsiveness

• CNS unique lack of vascular permeability and tightly packed parenchyma deters infection and clearance.
• Devoid of lymphatics or immuno-competent cells.
• Low levels of immunoglobulin and complement leading to failure to neutralize or lyse virus.
• Static nature of CNS cells encourages persistence
– e.g. rubella chronic noncytopathic infection leads to slowed cell growth rapidly overgrown by normal replacement populations in most organs.

• Virus
– Identified in 1907 as capable of transmitting diseases from human to human by inoculation of cell-free wart extract
– Papovavirus family
• Papilloma (wart), polyoma and vacuolating virus (SV-40)

– Initial site in GI or respiratory tract then disseminate to internal organs
• Tissue culture - BKV grows in epithelial cells and fibroblasts, while JC virus grows only in primary human fetal glial cells (can be adapted to grow in other cells)
• may undergo nonpermissive infection and transform cells in tissue culture
• cytocidal for oligos in culture and “transforms” astrocytes
– ?site of persistence Kidney versus bone marrow

– Ubiquitous virus
– Mostly species specific
• Human viruses not recovered from animals, but SV40 has been found in monkeys with PML
– Majority of persons develop antibody by 14 years of age
• 50% of children + by age of 10, 75% by adult
– Role of viruria
• Virus shed from urine and throat.

• First chronic demyelinating disease for which viral cause firmly established
– Develops in background of lymphoproliferative disease malignancy or immunosuppression
• Therefore disease is due to a reactivation
– Afebrile death in 3 to 6 months.
– CSF normal,
• antibodies against virus are ubiquitous
• antibody not found in CSF
– CT shows multiple radiolucent lesions in white matter

Multifocal white matter discoloration
White matter necrosis

• Sparing of axons, loss of myelin and oligos around lesion with large intranuclear inclusions.
• Astrocytes are enlarged with bizarre mitotic figures
• Little inflammatory response except for macrophages
• Viral DNA in lymph node, spleen, liver, lung kidney, brain

Gliosis and bizarre astrocytes
Nuclear inclusions
Sea of Macrophages
CD68
In Situ Hybridization for JC virus

• Not recoverable from normal brain.
– 10 10 particles per gram of PML brain.
– With immunosupression virus appears in CNS and renal tubules.
• ? reinfection versus reactivation versus spread to CNS
• Usually explainable on the basis of virus-induced cytopathology and destruction of the infected cell
– In vivo primarily leads to lysis but some surviving astrocytes proliferate rapidly and contain T antigen.
– Why it evolves slowly is not known given its rapid in vitro cycle.

• Serology worthless
– Ig does not increase with disease
• Lymphocytes of PML patients do not respond to JCV antigens
• Restoration of immunocompetence, if possible otherwise relentless progression
• Because papovaviruses utilize host-cell polymerase to replicate DNA cytosine arabinoside does not work.

• Rash on forehead spreads within 24 to 48 hours
• Catarrhal (inflammation of mucous membranes) 2
- 4 days before Koplik's spots on buccal mucosa
• Acute appendicitis prior to rash in some cases secondary to lymphoid inflammatory changes
• Enteropathic changes are a particular problem in developing countries

• Involvement of CNS is common
– 5 - 7 days post rash presumed autoimmune etiology
• 10% with pleocytosis
• 50% of children with EEG changes
– 1:1,000 cases with symptomatic encephalitis
• Virus usually not recoverable

• SSPE in 1/300,000
– normal humoral and cellular immune response?
– viral clearance?
– 60% of people with detectable nucleic acids in CNS?
• ATYPICAL measles
– Acute measles in patients vaccinated with inactivated vaccine
• Inactivation destroy immunogenecity of F protein and therefore does not confer long term immunity.
• Sets up Arthus reaction

• Requires population of 2-300,000 to support endemic disease
– disease first appeared in 2500BC possibly associated with domestic animals
– noninmmunized populations have epidemics every 2 to 5 years each lasting 3 - 4 months
– usually in late winter and early spring.
– Subclinical infection is rare

• First signs of disease 9-11 days PI
– shortened to 7 days if given parenterally
• Local viral replication in epithelial membranes followed by lymphatic spread and then viremia
• Dissemination includes mucosal membranes, small blood vessels, lymphatic system and CNS
– difficult to isolate virus from patients usually from lymphocytes
– Intranuclear and intracytoplasmic inclusions
• Certain CNS cells permit only non-lytic infection

• virus isolation difficult
• IF of skin biopsies
• SSPE patients have 10 to 100 times antibody with oligoclonal CSF bands

• Defined by Dawson in 1930 postulated viral cause but took 35 years to relate measles
• Rubeola, same as wild measles strains
• Epidemiology
• 1:10 6 children per year (immune intact)
• Age range 2 to 32 with average 7 to 8.
• Males three times more common.
• 1 to 10 years after recovery from uncomplicated measles

• Insidious onset, early dementia, disturbed motor function, myoclonic jerks, seizures, focal retinitis with optic atrophy, cerebellar ataxia leading to stuporous rigid state progresses to death in 1 to 3 years
• No fever or headache
– EEG high amplitude slow waves followed by flat wave pattern
• No CSF pleocytosis, and normal protein and sugar
– Relative increase in IgG
– CSF IgG titers to measles high
• Intrathecal synthesis of IgG
• Oligoclonal bands

Cowdry A Inclusions
Perivascular Inflammation
From: Neuropathology Illustrated 1.0
From: Neuropathology Illustrated 1.0
EM

• Mild meningitis
• Gray and white matter involved
– Mostly posterior hemispheres
– Microglial reaction
– Eosinophilic inclusions most commonly in oligos
– EM: tubular structures

• Abnormal Host response
– Immune responses not involved - virus remains cell associated in vitro
– More frequent in children with history of measles prior to 2 years of age
– M-protein defect
• Normally RNA is replicated in cytoplasm while still encapsulated in nucleocapsid protein
– Major glycoproteins; hemagglutin and fusion protein inserted into cytoplasmic membrane
– EM of SSPE show no virions

• seen in children and adults following immunosuppression, neurological disease follows systemic measles by 1 to 6 months
– Course of days to weeks ending in death
– Elevations of antibodies not found, inclusions seen in neurons and glia and antigen and virus recovered from one patient
• Subacute encephalitis in immuncompromised adult is clearly different from acute postinfectious encephalomyelitis and SSPE seen in normal children

• Both DNA and retroviruses capable of establishing static latency by sequestration of viral or proviral DNA
– Mechanism of persistence of other RNA viruses more complex
– No DNA intermediates seen in these
• Picornavirus
– Difficult to explain latency, since it is not enveloped defects of maturation are not known
• Infection may be limited to a small population of cells-smoldering lytic infection
• Temperature sensitive mutants
• Defective interfering particles
• May promote persistence - host deficit leads to failure to clear virus

• ~1/4 of terminally ill AIDS patients
• Macrophage tropic virus
• ?Mechanism of neurodegeneration
• Reversibility with immune reconstitution?