Retroviruses infect a wide range of animal species
and cause a variety of diseases including:
tumours, wasting and auto-immune diseases, immunodeficiency syndromes and aplastic and haemolytic anaemias.

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Human retroviruses
Four human reteroviruses have been identified. All infectCD4 bearing cells. These were only identified in the 1980's when it became possible to culture T-cells in vitro.

• HTLV1 - T-cell leukaemias/lymphomas
  Tropical spastic paraparesis
• HTLV2 - No known pathology
  
• HIV 1 & 2 - AIDS

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They are enveloped viruses, with an RNA genome. The name is derived from the fact that the virus particle contains an RNA-dependent DNA Polymerase (Reverse transcriptase). This enzyme converts the RNA genome into DNA, which then integrates into the host chromosomal DNA. The reverse transcriptase is highly error prone and rapid genetic variation is a feature of this group.

The genus is divided intothree sub families:

Oncovirinae - oncogenic - cause sarcomas and leukaemias in animals;
eg Rous Sarcoma Virus

Lentivirinae - slow progressive degenerative disorders
eg visnavirus of sheep, human immunodeficiency virus (HIV)

Spumavirinae - no pathology known

Defective virus
Virus which haslost a gene that is essential for replication and can, therefore, only undergo productive infection if the cell that is harbouring the virus is superinfected with a helper virus that can supply the function of the lost gene.
Many oncogenic retroviruses are defective.

Endogenous reteroviral sequences
Defective retroviruses which integrate into the host genome and are passed down from generation to generation. Two percent of the human genome is made up of endogenous retroviral sequences.

Genome organization The virus has adiploid genome (2 copies of RNA genome per virus particle). The genome codes for at least three genes: gag, pol andenv.

• gag - codes for the core proteins, structural virion components
• pol - reverse transcriptase
• env - envelope glycoprotein

LTR -Long terminal repeat - is a regulatory sequence at each end of the genome.

Their presence allowsintegration into the host chromosome and controls gene expression

onc - (see oncogenes)

Life cycle of lentiviruses

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Viruses of theOncovirinae subfamily contain an extra gene termed, 'onc'. These genes are called oncogenes because their expression in the virus infected cell is associated with tumour production. These genes were originally acquired from the host cell itself. The cellular gene was picked up during integration of the virus genome into the host DNA, way back in evolution. Most oncogenes code for proteins with growth promoting properties and their expression can lead to uncontrolled proliferation of the infected cell and tumour development.

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HTLV1

Clinical features
1. T-cell leukaemia/lymphoma. Aggressive tumour of CD4 cells which infiltrates skin and brain. Tumours are only produced after a prolonged latent period. The virus does not contain an oncogene and it is believed that the malignant change is the result of interruption and disregulation of host DNA, by viral genome insertion. Less than 1% of HTLV 1 infected individuals develop this malignancy.

2. Tropical spastic paraparesis. Aggressive non-demyelinating spastic paraparesis.

Epidemiology
Seroprevalence is high in South West Japan, the Caribbean and parts of West Africa. In high incidence areas up to 10% of adults may be infected. The seroprevalence increases with age and family clustering of infection is common. Spread occurs through blood transfusion and sexual intercourse. Mother to child transmission through breast feeding has also been shown.

Laboratory Diagnosis
HTLV 1 specific antibody, ELISA.

HTLV 2

The virus shares extensive nucleic acid homology with HTLV 1. It was first isolated from a patient with hairy cell leukaemia, but no specific pathology has been attributed to it.

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Background:-
In the spring of 1981, previously healthy homosexual men in New York and Los Angeles were found to be suffering from severe immunodeficiency states associated with severe opportunistic infections and rare malignancies.

At this time an infectious aetiology was suspected especially when it was perceived the disease could be transmitted by blood transfusions and blood products. (Haemophiliacs)

In 1983, a new retrovirus termed LAV (now calledHIV 1) was isolated from the T-cells of a patient with persistent generalised lymphadenopathy.

In 1986, a second closely related virus, termedHIV 2 was isolated from a patient from West Africa with acquired immunodeficiency syndrome, AIDS.

Currently, about 14 million people are believed to be infected, world-wide; nine million of these are in Africa (see figure 2). HIV1 is the major cause of the AIDS pandemic; HIV2 is of lower virulence and infection has largely remained confined to West Africa.

Origin
AIDS appears to be a new disease. The origin of the virus is obscure but it is probable that infection arose in Africa. Retrospective screening of stored sera has shown that the earliest known infection occurred in Kinshasa, Zaire, in 1959.
HIV is believed to have evolved from related viruses that infect African monkeys, namely the simian immunodeficiency viruses (SIV) (which cause a similar disease to AIDS in monkeys). HIV 2 is more closely related to SIV than HIV 1. It is not known how the original transfer of virus from monkey to man took place. These viruses mutate readily which explains the rapid subsequent divergence.(figure 4)

Spread(figure 3)

Epidemiology - South Africa
HIV was introduced into South Africa from two sources:
a) Into the homo-sexual community - from North America and Europe,and
b) into the hetero-sexual community - from north of our borders by truck drivers, returning exiles, migrant labourers.

A survey, conducted in October/November 1993, of women attending ante natal clinics in different parts of the country has shown that the prevalence of HIV infection varies from 1.33% in the Cape to 9.62% in KwaZulu/Natal.

Transmission
Infection is transmitted in a manner identical to that of hepatitis B.
1.) Blood products

• Blood transfusions
• Intra-venous drug abusers - sharing of needles
• Health care workers:
  needlestick injuries - risk approximately 0.36% (depends on extent of the injury)
  muco-cutaneous exposure - no sero-conversion incidents have been reported

2.)Organ transplants
3.) Sexual intercourse
Both homosexual and hetero-sexual exposure
Increased risk of transmission if partners have other sexually transmitted diseases

4.) Vertical Transmission
10-40% of babies born of HIV-infected mothers will be infected.

Infection may occur

in utero

during birth

post-natally, through breast feeding

NB! THERE IS NO EVIDENCE TO SUGGEST THAT HIV CAN BE TRANSMITTED BY:

Insects

Casual contact saliva, kissing

sharing of eating and drinking utensils

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Clinical features

Primary infection
About 90% of patients develop a flu-like illness which co-incides with seroconversion, between 2 and 4 weeks post exposure. Symptoms include, fever, night sweats, sore throat, lymphadenopathy, diarrhoea. The illness is self limiting.

Asymptomatic phase
Of variable duration, from 2 to 10 years. Patients are clinically well, but infectious.

Prodromal phase
This period is heralded by the insidious onset of a variety of prodromal disorders, including: weight loss, fever, persistant lymphadenopathy, oral candidiasis and diarrhoea. These symptoms precede the progression to AIDS.

Acquired Immunodeficiency Syndrome (AIDS)

Syndrome with the following features:

1) Constitutional disease: fever, diarrhoea, weight loss, skin rashes

 

2) Neurological disease: dementia, myelopathy, peripheral neuropathy

3) Immunodeficiency: Increased susceptibility to opportunistic infections: (see table 1)

4) Rare malignancies: Kaposi sarcoma, oral hairy leukoplakia, lymphomas.

Kaposi sarcoma - is a tumour of endothelial cells. Prior to the AIDS epidemic, this tumuor was rare and only found in middle aged African and Mediterranean Jewish men, in whom it was an indolent condition. AIDS patients develop a disseminated highly aggressive form of the disease.

Paediatric Infection
Following infection in the perinatal period, babies may develop a progressive illness in the first few months of life (No latent period). Clinical features include: Failure to thrive, diarrhoea, lymphadenopathy, susceptibility to opportunistic infections hepato-splenomegaly, lymphoid interstitial pneumonia and parotitis.

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IMMUNO-DEFICIENCY

Cell tropism: CD4+ T cells, Macrophages

Destruction of CD4 cells occurs through the following mechanisms:

direct lysis of infected cells

syncytium formation

Infection of precursor cells and destruction of microenvironment

Impairment of CD4 cell function

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LABORATORY DIAGNOSIS

Serology
IgG develops 4-6 weeks post exposure and remains detectable for life. Its presence in serum therefore indicates infection.
Exception: Uninfected infants of HIV positive mothers

Direct detection of virus
p24 antigen ELISA
culture from PBMC's
PCR

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VACCINE PROSPECTS

There is no effective vaccine available for HIV. Attempts have been made to develop a vaccine, using:

• purified viral envelope glycoproteins, gp120 or 160
• whole inactivated virus
• live attenuated HIV strains (lacking certain genes)
• live recombinant virus vectors, expressing HIV proteins.

A major difficulty is the fact that neutralizing antibody in the serum does not protect the host from infection with HIV: Possible reasons for this include:

• Antibody enhancement of infection
  
• Rapid virus mutation may result in variation of envelope antigens (escape mutants)
  
• HIV can infect cells in sites that are sequestered from antibody
  
• Host may be infected by whole virus-infected cells