Human Immunodeficiency virus lecture 1

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General HIV

  • It is a lentivirus, from the retrovirus family
  • It is a single stranded RNA virus
  • There are 2 distinct viruses, HIV 1 and HIV 2.
  • The HIV virus infects CD4 positive cells: e.g. T Lymphocytes, monocytes, macrophages, DC
  • There is a progressive qualitative and quantitative decline in CD4 Th1 lymphocyte subset

AIDS: Acquired immunodeficiency syndrome 

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Deaths from AIDS

The cumulative number of deaths due to HIV infections: 30 million. Around 5 million of these deaths are in children under the age of 15.

The estimated adult and child deaths from HIV/AIDS in 2014:

  • W.Europe and Northern America= 26,000. It is currently decreasing 
  • Caribbean=8,800 . It is currently decreasing 
  • Latin America=41,000. It is currently decreasing 
  • N.Africa and Middle East= 12,000. It is increasing 
  • Sub-Saharan Africa= 790,000. It is currently decreasing 
  • E.Europe and C.Asia= 62,000. It is currently increasing 
  • Asia and Pacific=240,000. It is currently increasing 
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New cases of HIV

Estimated number of adults and children newly infected with HIV in 2014

  • W.Europe and N.America= 85,000
  • Caribbean= 13,000 and is currenty decreasing 
  • Latin America=87,000 and is currently decreasing 
  • N.Africa and Middle East= 22,000 and is currently increasing 
  • Sub-saharan Africa= 1.4 million and is currently decreasing 
  • E.Europe and Central Asia= 140,000 and is currently increasing 
  • Asia and Pacific= 340,000 and is currently decreasing 
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Have we conquered HIV?

The number of new infections fallen by 35% since 2000, when there is a peak in epidemic. 

  • 15.8 million people are accessing antiretroviral therapy- This is an 84% increase since 2001.
  • AIDS related deaths fallen by 42% since 2004 peaks 
  • Challenging goals to end AIDS epidemic by 2030

The more people that are surviving, the more are able to infect other people. This makes it a victim of its own success.

AIDS challenges

UNAIDS stratergy (2016-2021),10 targets for 2020 includes:

  • 90% knowledge of HIV status
  • 90% treatment coverage
  • <500,000 new HIV infections 
  • <500,000 AIDS related deaths
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The first 10 years

1980: Physician in LA/NY observe cases of PCP and Kaposi's sarcoma in gay men
1981: 108 cases of new syndrome and 42 deaths, 1st reports from Europe
1982: 894 cases and 243 deaths in USA
1983: 3064 cases and 1263 eaths in USA, It was linked with the contamination of blood. 
Retrovirus isolated from T-cells
1984: HIV cultured, cloned and molecularly characterised 
1985: FDA approved HIV AB test, There were 15,948 cases and 8161 deaths in USA
1987: 40,051 cases and 23,163 deaths USA. 1st anti HIV drug approved (AZT)
1988: AIDS reported in 138 countries, 5-10 million cases worldwide
1989: 100,000 cases in USA, FDA approved sensitive HIV antigen assay- detects presence of antigen not the antibody. 

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The discovery of HIV

  • In the early 1900's, the retrovirus is 1st identified n chickens. 
  • in the late 70's/80's, there was a discovery of the 1st human oncogenic retrovirus (Human T cell lymphotrophic virus HTLV-1) 
  • It was the causative agent of aggresive T cell leukaemia in Japan 
  • HTLV-II was discovered in 1982
  • In May 1983 there were 2 reports in science
  • 1 by Luc Montagnier and Francois Barr-Sinoussi (Paris)
    Reverse tramscriptase activity from patients with lymphoadenopathy, could be transmitted to cultured lymphocytes of healthy donors. EM showed virus budding from plasma membrane. A patients serum reacted with this virus and HTLV-1 
    He called it lymphoadenopathy virus (LAV)
  • 2nd one was published by Robert Gallo in USA, 
    New virus was cultured from blood of a pateint with PCP, DNA from AIDS patient homology to HTLV-1. 
    Antibody studes showed cross reactivity with HTLV-1
    He called this HTLV-III
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Montagnier vs Gallo

  • Montagnier published 1st, but he didnt identify the virus. 
  • He provided a sample to Gallo which contaminated samples as NIH. 
  • They shook hands in 1987, however it wasnt until 2002 that they jointly published science article acknowledging each other contributions. 
  • However the nobel prize of physiology and medicine of 2008 went to Montagnier and Francois
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Sequencing of genome

  • The complex genomic sequences published 1985, it showed that it was not closely related to HTLV-1. Therefore it was renamed HIV
  • They also discovered HIV-2 in Western Africa and Simian immunodeficiency virus (SIV)
  • Macaque monkys at New England Primate research centre so it was named SIVmac. 
    SIVmac turned out to be virus from sooty mangabey monkeys (SIVsm) kept at the same centre. 
    SIVmac is not found in the wild, SIVsm closely related to HIV-2. 
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Where did HIV 1 come from

There are 4 distinct groups of HIV1 viruses

Group M

  • Worldwide pandemic-98% of HIV isolates
  • Widespread diversity-clades subtype A-K
  • Epicentre of diversty in Cameroon

Group O

  • Maximum of 100,000 people 
  • Confined to Cameroon/Gabon

Group N

  • 6 individuals in Cameroon

Group P

  • 2 Individuals in Cameroon
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Chimpanzee

In 1989, a related virus was isolated from chimpanzees- SIVcpz
Over the next 10 years, 1000 chimps were tested and only 1 SIVcpz isolated
SIVcpz is very rare, and it is believed humans and chimps were coinfected from another source

It was then shown to be definiely from chimps
There are 4 different Pan troglodytes species that are geographically isolated. Sampling of chimp poo showed that these difference sub species had different SIVcps viruses. 
They identified the chimpanzee virus and sequenced it, they found that only Pan troglodytes troglodytes virus SIVcpz ppt was related to HIV1.
Also then found that HIV-1 group M and N arose from different locations. Identified where transmission occured 

SIVcpz is a recombinant virus from chimp predating on Red capped manabey with SIVrcm and Greater spot-nosed monkey with SIVgsn. 

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Gorilla

Group P arose from SIVgor in Gorillas. 
Also hypothesised that group O did. 
Gorillas may have got it from eating chimpanzees. 

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Is HIV a zoonoses

A zoonosis is a disease of animals that may be transmittd to man under natural conditions.

  • A large number of exposure of SIV-infected monkeys, however only 12 cross species transmission events in 50 years. 
  • SIV infection in natural host assymptomatic, SIVcpz coevolved with host for over 100,000 years. There is a change in pathogenic potential required. 
  • Humans exposed to SIV for centuries. Why did HIV only emerge recently. May be due to deforestatin, urbanisation, travel and unsterile needles. There is a role of innate immune resonse. 
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Early instances of HIV

Plasma sample from an adult male living in Leopoldville, Belgian, Congo in 1959. 
A lymph node biopsy also from Kinsnasa, a long time before the epidemic. 

Sequence analysis 
Both M groups
12% divergence between these 2 samples 
Diversification of HIV occured long before pandemic
Estimate of ancestor between 1908-1921

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The spread of HIV through the human population

There was a rapid spread due to 3 causes: 
International travel e.g Patient O
Blood transfusion- haemophiliacs/factor VIII
Intravenous drug use 

Archival analysis of HIVsequences

  • NYC/ San Fransisco patients 1978/79 
  • Group M, subtype B, related to Caribbean isolates
  • Consistent with spread from Caribbean to US in 1971

Analysis of Patient O 

  • Not index case (not the case that spread)
  • One of thousands infected during 70's 

Africa --> Caribbean --> US

As the cost of disposabel needles declined, HIV incidence increased

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Transmission of HIV

Contact with blood or mucous membranes
The major route is via sexual contact
Estimated probability of transmission is 1/1000 sexual contact

The reason it is so inefficience?
Protective effect of the mucous layer
Physical barrier
Front line innate immune response, limited target cell availability 

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Risk factor for sexual transmission

  • High virus load (early and late in infection) 
  • Presence of cuts, abrasions, irritations and inflamation 
  • Other STD's such as herpes and Syphillis
  • Lack of, or failure of a condom

Other routes for transmission

  • Intravenous drug use, leads to an increased prevelance, especially in E.Europe/ Asia/ Pacific
  • Mother to child vertical transmission, This accounts for more than 90% of infant/child infections.
    Can be as high as 50% of births to HIV positive mother in Africa
    The highest risk is during delivery, but breastfeeding is also a significant route of infection
    Application of retroviral therapy and avoidance of breastfeeding reduces the rate of transmission to 2%
    Only a short course of antiretrovirals and some antiretrovirals toxic during pregnancy
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HIV diagnosis

  • A large number of rapid test format available 
  • They detect the antibodies to HIV
  • Can be used outside of diagnostic labs to provide results within 20 minutes
  • The accuracy however is only 99%, this means that there is a chance of getting it wrong.
  • Therefore need to follow up with confirmatory tests
    ELISA, Western blotting etc
    RT-PCR and sequencing to confirm isolate, and drug resistance
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