Retroviruses, oncoviruses and prions

Dr Faseeha Noordeen Department of Microbiology Faculty of Medicine University of Peradeniya May 2013

Learning outcomes
Transmission and the pathogenesis of HIV / AIDS The outcome of HIV / AIDS Principles of diagnosis, management & prevention of HIV / AIDS

Aim: make students aware pathogenesis

& clinical significance of retro, oncogenic viruses and prions Objectives:
1. to conceptualise the pathogenesis of retro virus infections to diagnose these (History + Symptoms + Lab) 2. to prevent/control in retro virus infections and prion disease

Retroviruses
Classification: Disease, tissue tropism and genomic identity
1. Oncovirus - HTLV 1, HTLV 2 and HTLV 5 2. Lentivirus - HIV 1 and HIV 2 3. Human foamy virus - Clinical importance?

General features of retroviruses

First

identified tumour virus Medium sized and enveloped Envelope GP - Fusion protein - gp 41 - Attachment protein - gp 120 Virion - 2 copies of RNA genome - Reverse transcriptase and integrase

HIV schematic diagram

Genome - gag, pol and env genes capsid enzymes envelope

Oncogenic

retroviruses

- Growth stimulating genes - Captured cellular genes - Resemble cellular genes

HIV - Modes of transmission

Retrovirus pathogenesis
1. Attachment 2. Entry 3. Integration

HIV attachment + fusion Molecular mechanisms

Copyright 2002 Pearson Education, Inc., publishing as Benjamin Cummings

Attachment
Virus attaches to cell specific receptors HIV gp 120 to CD26 of T lymphocytes

Integration
cDNA integrated into host DNA (Integrase) HIV RT causes mutations (error prone) Integrated cDNA is transcribed as a cellular gene by host RNA polymerase Accessory proteins of HIV regulate replication and pathogenesis Virus buds - envelope Virus form syncytia - lysis

Entry
Envelope fuses with cell membrane RT synthesizes complementary DNA strand (cDNA)

Pathogenesis cont .

Tropism - CD4 T cells & macrophages, neurons HIV - lytic infections - T cells - latent ,, - T cells & macrophages - persistent ,, - T cells & macrophages Continuous killing of (mature + stem ) T cells Reduced T cells + Immunodeficiency

Pathogenesis cont .
Persistently

infected M - reservoir + distribution vehicle

HIV

infection in neurones + brain M

Neurologic abnormalities

Human Immunodeficiency Virus (HIV) (Depicted in green, budding off infected white blood cell)

Pathogenesis cont.
HIV

infection
Months to years

AIDS
ARC Full blown Wasting AIDS dementia AIDS <500/mL

Laboratory diagnosis of HIV infection

1. Serology - ELISA and latex agglutination Confirmation - Western blot 2. Ag detection - HIV p 24 antigen - early marker and indicator for active virus replication 3. Demonstration of viral NA - PCR and may be useful because of its extremely high sensitivity 4. Prognostic test/CD4/CD8 ratio - A decrease in the ratio correlates with progression to AIDS

Treatment
Resolution

is prevented by the ability of the HIV to

Inactivate immune system Replicate in privileged sites Alter its antigenicity Drugs target RT and proteases Epidemiology and prevention

HTLV I and HTLV II

Acquisition - Venereal, blood transfusion and breast feeding Infection CD4 T cells, remain latent and replicate slowly for years

Transactivation - Viral tax proteins trigger cellular genes & promote growth Leukaemia - Chromosomal aberrations & rearrangements leukaemia

Disease
Incubation period is > 30 years Asymptomatic infections Neoplasia of CD 4 T cells , elevated WCC Can progress to adult acute T cell lymphocytic leukaemia (ATLL) Acute disease is fatal Also causes tropical spastic paraparesis

Other Human oncogenes/viruses

Prions
Infective

particles, no genome and

structure Aggregates of protease resistant GP Do not elicit immune response Resistant to inactivation Infected brains have PrPsc infectious PrPsc is similar to PrPc

Pathogenesis
No

CPE in vitro studies Long incubation period Cause vacuolation + gliosis (spongiform
changes) No

inflammation and immune changes Human disease - CJD and kuru Animal disease - BSE - transmissible to lab animals and man

Which of the following about HIV are true

1. HIV establishes lytic, persistent and latent infections of CD4 T cells & also infects macrophges & neurons 2. HIV Infection in CD4 T cells does not induce cytolytic syncytia 3. Mutation of HIV within an individual promotes escape from immune control 4. HIV p24 is an indicator of virus replication 5. Major anti HIV drug target is pol gene product

I . Name three infections that can be transmitted during this process II . State how would you prevent these

1. Write short notes on

1.1. Prions and associated diseases (50 marks) 1.2. Oncogenic viruses (50 marks)