Lecture 9. The Origin and Evolution of HIV and AIDS Flashcards
What are Pneumocystis pneumonia and Kaposi’s sarcoma?
Rare diseases linked with imunosuppresion that started appearing in healthy gay men in 1981
These diseases are clustered in sexually interactive groups and needle-sharing drug users
What did the increase of Pneumocystis pneumonia and Kaposi’s sarcoma suggest?
The existence of an infectious disease (passed via bodily fluids) causing immune deficiency, AIDS
What is the current definition of AIDS?
The presence of 1 of 25 conditions indicative of severe immunosupression or HIV interaction with a CD4+ T cell count of <200 cells/μl of blood
When were human T-cell lymphotropic virus (HTLV-I) and the first human retrovirus (HTLV-II) discovered?
HTLV-I: Late 1970s
HTLV-II: 1982
What do T-lymphotropic retroviruses infect?
T-lymphocytes
In 1983, what was the isolate T-lymphotropic retrovirus able to do and what was it named?
Reverse transcriptase activity in T cells from patient with lymphadenopathy
Virus could be transmitted to fresh T cells
Electron microscopy showed virus particles budding from plasma membrane
Lymphadenopathy-associated virus (LAV)
When was LAV/HTLV-III found to be HIV and how?
In 1985, the complete genome sequence was published and found to not be closely related to HTLV-I
How many species of HIV are there?
2: HIV-1 and HIV-2
HIV-2 was discovered in West Africa in 1986
Where did HIV come from?
Zoonotic transmission from simian to human
What virus does HIV-1 have genetic homology with?
Virus isolated from captive chimpanzees in 1989 - SIVcpz
What virus does HIV-2 have genetic homology with?
Virus isolated from captive macaque monkeys in 1985 - SIVmac
How did SIVmac come about?
Spillover of SIVsmm (from sooty mangabey monkeys) into macaques at the same captive centre
Where is HIV-2 infection located and why?
HIV-2 infection mostly limited to West Africa because that is where sooty mangabeys are located.
Low incidence worldwide, higher in countries with colonial ties to West Africa (France, Portugal)
Between 1989-1999, out of 1000 chimpanzees tested, how many were positive for SIVcpz and why?
1
Most chimps tested were Pan trolodytes verus (negative for SIVcpz). The two chimps positive for SIVcpz were P. t. troglodytes.
What’s important to remember about the four distinct subspecies of chimpanzees?
Their habitats do not overlap
How can the isolates of HIV-1 be divided?
HIV-1 isolates can be divided into four groups according to their sequence diversity
What are the four groups of HIV-1 isolates?
Group M (main) accounts for 98% of HIV-1 isolates; found worldwide (far more transmissible than O, started a pandemic)
Group O (outlier) 1-2% of HIV-1 isolates; limited to Cameroon and Gabon
Group N (new) 6 individuals in Cameroon
Group P (found in 2009) 2 individuals in Cameroon
Where did the four isolate groups of HIV-1 come from?
HIV-1 groups M and N arose from different locations. No viruses with homology to group O or P found in chimpanzees
Where did HIV-1 groups O and P originate from?
Western lowland gorilla (Gorilla gorilla gorilla)
SivcpzPtt → SIVgor → HIV-1 group O & P
What is SIVcpz a recombinant virus of?
SIVrcm (red capped mangabey) and SIVgsn (greater spot-nosed monkey)
Gag, Pol, Vif, Vpr and Nef from SIVrcm
Tat, Rev, Vpu and Env from SIVgsn
How did SIVcpz arise?
One cell was infected with both SIVrcm and SIVgsn and recombination occurred during reverse transcription, becoming more efficient within chimpanzees
How did SIVsmm evolve into HIV-2?
Evolved directly from sooty mangabey
Is HIV truly a zoonotic virus?
Humans have been exposed to SIV-infected monkeys for thousands of years; HIV has only emerged in the last 100 years, but only 12 cross-species transmission events (including between different species of monkey) in the last 50 years
Suggests genetic differences between host species are barriers to infection
Suggests viral mutations required to infect new hosts
What may small differences in host cell proteins cause?
Prevent viral replication as viruses rely on the host cell proteins (such as cyclophillin A)
What are restricting factors?
Antiviral defences in addition to the innate immune response found in mammalian cells
Host specific antiviral proteins
In orer to infect and replicate in a new host, how must a virus evolve?
Must evolve to use the dependency factors in the new host, and to evade the restriction factors in the new host
What allows rapid viral evolution of HIV?
The error-prone nature of the HIV reverse transcriptase
There is as much genetic diversity in one HIV patient, then an entire global population of flu
Why is SIV non-pathogenic in its natural host (African monkeys)?
Co-evolution for at least 100,000 years
When did HIV-1 M crossover into humans?
1920s
Why is it that HIV-infected humans progress to AIDS without treatment but SIV-infected monkeys are symptomatic?
Monkeys not susceptible to opportunistic infections
T cell depletion in HIV-infection; preserved T cell population in SIV-infection
High level of innate immune activation (inflammatory response) in HIV-infection; low level response in SIV-infection
How does HIV stimulate the innate immune response and how could this result in AIDS?
HIV stimulates innate immune response through TLR7 and TLR9 in plasmacytoid dendritic cells
TLR7+9 signal through IRF-7 to produce IFNα
Continual pDC activation and IFNα production are likely to lead to the accelerated destruction and impaired regeneration of T cells
Why is it that SIV does not cause AIDS in monkeys? (SIV causes AIDS in chimpanzees but not the original African monkeys)
Much lower amounts of IFNα are produced in response to TLR7+9 signalling
Monkey IRF-7 has several different amino acids in its activation domain compared to human IRF-7 = less active in stimulating transcription of IFNα
Less IFNα production = preservation of T cells
NB. Monkeys still produce other cytokines after TLR7+9 activation, so still mount an effective response to most other pathogens
What has probably happened to IRF-7 in monkeys?
Evolved in response to thousands of years coexistence with SIV - not beneficial to a virus to kill the host so less pathogenic
