24-25. retroviridae I & II

where did human immunodeficiency viruses come from?

zoonosis → multiple simian immunodeficiency viruses that jumped into human hosts

what type of genome do retroviruses have?

RNA

are retroviruses naked or enveloped?

enveloped

• envelope proteins often heavily glycosylated → masking from antibodies

what types of cells do retroviruses frequently target?

lymphocytes and/or macrophages → systemic spread, proliferation of infected cells

unique/notable properties of retroviruses

• reverse transcriptase: RNA → DNA

  • error-prone → high mutation rate; rapid evolution

• diploid particles (2 RNA copies) → facilitates within-host recombination

• integration of DNA provirus into host cell’s genome

  • enables long-lived, persistent, latent infections

  • cancer: insertional mutagenesis; disruption of normal gene expression

how can oncogenic retroviruses cause cancer?

• through recombination, retroviruses can acquire cellular oncogenes → these mutate through viral passage, becoming viral oncogenes (v-onc)

• viral oncogene-encoding viruses transduce the oncogene, rapidly causing cancer

  • require “helper viruses”; no longer able to recompilation on their own

• viruses can insert next to a cellular oncogene and upregulate its expression, causing cancer more slowly

• (complex retroviruses may have other oncogenic mechanisms)

feline lymphoma & FeLV infection

• lymphoma usually manifests as multicentric or thymic T cell tumors, frequently in cats < 3 y/o

  • multicentric, mediastinal: associated with FeLV; decreasing incidence

  • GI lymphomas: B cell tumors; more common currently; generally in older cats

• tumors develop slowly after FeLV infection → upregulation of cellular oncogene c-myc

FeLV variants

• only FeLV-A is replication-competent and transmissible among animals

• other forms arise in infected cats through mutation — recombination between FeLV & endogenous retroviruses or cellular proto-oncogenes

• non-A viruses occur only as co-infections, with FeLV-A as their helper virus

  • these variants are not replication-competent

• multiple variants have been described in association with specific disease complexes

FeLV progressive vs. regressive infection

• progressive infection (high-positive)

  • weaker immune response → higher levels of FeLV provirus & antigen

  • persistent high viremia & eventual disease

• regressive infection (low-positive)

  • stronger immune response → lower levels of FeLV provirus & antigen

  • (apparent) clearance of antigenemia; potential for longer survival

primary & secondary FeLV infection

• primary: initial infection; characterized by infection of lymphoid tissue

• secondary: infection of bone marrow sets up persistent viremia and progressive infection

abortive FeLV infection

no viral antigen or DNA detected, but antibodies present

FeLV clinical signs

• nonspecific symptoms

  • fever of unknown origin

  • lymphadenopathy

  • immunosuppression

  • wasting

  • abortion

  • anemia

• cattery history

FeLV diagnosis

• serology most common → ELISA and IFA tests for FeLV antigen

• level 1: ELISA tests detect cell-free virus

  • screening test; serum

• level 2: PCR for proviral DNA and RT-PCR for genomic RNA; or IFA (hardy test) to detect cell-associated virus

  • used to confirm positive ELISA

  • PCR commercially available

• whole blood may be best sample type

FeLV transmission

• secreted in saliva, blood, urine, feces

• primarily horizontal transmission → prolonged friendly contact

• dose required for oronasal transmission is likely high

• can also occur in utero or perinatally

FeLV control

• test and remove; isolate infected animals

  • test prior to vaccination, breeding, or co-housing; test all sick cats

  • do not decide to euthanize on the basis of (+) ELISA alone

• vaccinate

  • may prevent clinical disease but not infection

  • highly recommended for all kittens

    • 2 dose initial series, followed by booster and assessment for exposure risk

what neoplasm is associated with bovine leukosis virus? what organs does it typically affect?

• lymphosarcomas

• organs affected:

  • heart (right atrium)

  • uterus

  • nodules in central and peripheral lymph nodes

  • abomasum

  • other sites, causing additional tissue-specific signs

BLV & persistent lymphocytosis

• PL develops after a latent period lasting from months to several years

  • detectable in blood samples, but otherwise not clinically apparent

• distinct from leukemia → normal lymphocytes; could become leukemia

• increases animal’s risk of developing leukemia by 2x

BLV diagnosis

• routinely diagnosed by presence of antiviral antibody (after 6 months of age)

• PCR tests for provirus also available

BLV pathogenesis

• mechanism not completely defined, but involves viral Tax protein, a transcriptional transactivator

  • implicated in oncogenesis

  • inhibition of apoptosis?

  • may promote viral “sneakiness” by downregulating viral gene expression

BLV clinical signs

• tumors typically take several years to develop

• once animals develop symptomatic disease, frequently suffer weight loss and milk production is greatly reduced

• lymphosarcoma is rapidly progressive → wasting, death within 4 months of diagnosis

BLV transmission

• iatrogenic transmission most common (exposure to infected cells)

• BLV is strongly cell-associated, so not easily transmitted among animals

  • vertical transmission ineffecient

  • horizontal transmission among adult cattle

  • calves can become infected after birth (exposure to exudate & placenta from cows; calving instruments)

  • biting insects? evidence inconclusive

• proviral load is associated with transmission risk

BLV control

• no vaccine available in US

• test and slaughter, or test and segregate

• PCR tests make it possible to identify and remove “super-shedders”

• avoid procedures that can transmit infected lymphocytes (ex. do not reuse equipment; clean and disinfect between animals)

• manage biting insects

FIV serotypes

• at least 5 (A-E)

• A & B predominate in US

• animals can be superinfected with multiple subtypes

FIV transmission

• primarily secreted in saliva

• horizontal transmission → fighting and biting

  • prevalence higher among (intact) males than females

• can also be transmitted in utero or through milk, particularly by acutely infected queens

• (grooming, sexual contact NOT thought to be major modes of transmission)

FIV pathogenesis

• replication kinetics similar to HIV/SIV → high acute viremia followed by long asymptomatic stage

• decline in CD4+ T cells eventually leads to immunodeficiency

• tempo & severity of disease may be dependent on age of animal and route of infection

FIV clinical signs

• acute infection

  • nonspecific, “flu-like symptoms”: fever, malaise, lymphadenopathy

  • transient; not always apparent

• may have long latent stage

• chronic gingivitis, stomatitis

• chronic upper respiratory disease, enteritis

• opportunistic infections, including FeLV

FIV diagnosis

• tumors are a common reason for FIV-infected cats to be brought in

  • presenting signs may also be similar to FeLV

• IFA or ELISA → test for antibody against FIV

  • kittens may test false + for first ~12 wks due to maternal Ab

  • generally recommended to wait (or retest) at least 6 months after birth

FIV control

• best control is prevention → avoid contact with free-roaming cats

• vaccine no longer used in US

  • vaccinated animals seroconvert, confounding diagnostic tests

• FIV strain variability is a major obstacle to effective vaccine development

equine infectious anemia virus (swamp fever) transmission

• largely mechanical transmission by blood-sucking insects (tabanid & stable flies)

• other modes, including iatrogenic possible

EIAV pathology

• causes lifelong, persistent infection

• acute infection may be clinically inapparent, though some animals have rapidly progressive disease

• disease characterized by multiple interchanging syndromes; recurrent bouts of fever and illness

• death occurs after many years of progressive, debilitating illness

EIAV clinical signs

• 7-21d incubation

• acute onset of fever, mucosal hemorrhage, hemolytic anemia, fatigue, weakness, jaundice

  • high case fatality when acute signs apparent (up to 80%, particularly in foals?)

• subacute: recurrent fever, anemia

• recovered: no clinical signs, suitable for work

• chronic: failure to thrive, fatigue, cachexia

why does EIAV cause recurring bouts of illness?

within-host evolution → continually spawns novel antigenic variants that “escape” immune response

EIAV diagnosis

• Coggins test: agar gel immunodiffusion (AGID) detects anti-EIAV antibody

  • being replaced with ELISA tests: faster, can perform in field

• Western blot (confirmatory)

• PCR

** negative Coggins or ELISA required to transport animals across state lines

in what region(s) of the US is EIAV prevalent?

southeastern US, texas, (and mississippi valley?)

EIAV control

• spread controlled by euthanasia/isolation of infected animals & insect control

• due to antigenic diversity, vaccines are not effective