Lecture 9. The Origin and Evolution of HIV and AIDS

Question 1

What are Pneumocystis pneumonia and Kaposi’s sarcoma?

Answer 1

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

Question 2

What did the increase of Pneumocystis pneumonia and Kaposi’s sarcoma suggest?

Answer 2

The existence of an infectious disease (passed via bodily fluids) causing immune deficiency, AIDS

Question 3

What is the current definition of AIDS?

Answer 3

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

Question 4

When were human T-cell lymphotropic virus (HTLV-I) and the first human retrovirus (HTLV-II) discovered?

Answer 4

HTLV-I: Late 1970s
HTLV-II: 1982

Question 5

What do T-lymphotropic retroviruses infect?

Answer 5

T-lymphocytes

Question 6

In 1983, what was the isolate T-lymphotropic retrovirus able to do and what was it named?

Answer 6

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)

Question 7

When was LAV/HTLV-III found to be HIV and how?

Answer 7

In 1985, the complete genome sequence was published and found to not be closely related to HTLV-I

Question 8

How many species of HIV are there?

Answer 8

2: HIV-1 and HIV-2
HIV-2 was discovered in West Africa in 1986

Question 9

Where did HIV come from?

Answer 9

Zoonotic transmission from simian to human

Question 10

What virus does HIV-1 have genetic homology with?

Answer 10

Virus isolated from captive chimpanzees in 1989 - SIVcpz

Question 11

What virus does HIV-2 have genetic homology with?

Answer 11

Virus isolated from captive macaque monkeys in 1985 - SIVmac

Question 12

How did SIVmac come about?

Answer 12

Spillover of SIVsmm (from sooty mangabey monkeys) into macaques at the same captive centre

Question 13

Where is HIV-2 infection located and why?

Answer 13

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)

Question 14

Between 1989-1999, out of 1000 chimpanzees tested, how many were positive for SIVcpz and why?

Answer 14

1
Most chimps tested were Pan trolodytes verus (negative for SIVcpz). The two chimps positive for SIVcpz were P. t. troglodytes.

Question 15

What’s important to remember about the four distinct subspecies of chimpanzees?

Answer 15

Their habitats do not overlap

Question 16

How can the isolates of HIV-1 be divided?

Answer 16

HIV-1 isolates can be divided into four groups according to their sequence diversity

Question 17

What are the four groups of HIV-1 isolates?

Answer 17

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

Question 18

Where did the four isolate groups of HIV-1 come from?

Answer 18

HIV-1 groups M and N arose from different locations. No viruses with homology to group O or P found in chimpanzees

Question 19

Where did HIV-1 groups O and P originate from?

Answer 19

Western lowland gorilla (Gorilla gorilla gorilla)
SivcpzPtt → SIVgor → HIV-1 group O & P

Question 20

What is SIVcpz a recombinant virus of?

Answer 20

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

Question 21

How did SIVcpz arise?

Answer 21

One cell was infected with both SIVrcm and SIVgsn and recombination occurred during reverse transcription, becoming more efficient within chimpanzees

Question 22

How did SIVsmm evolve into HIV-2?

Answer 22

Evolved directly from sooty mangabey

Question 23

Is HIV truly a zoonotic virus?

Answer 23

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

Question 24

What may small differences in host cell proteins cause?

Answer 24

Prevent viral replication as viruses rely on the host cell proteins (such as cyclophillin A)

Question 25

What are restricting factors?

Answer 25

Antiviral defences in addition to the innate immune response found in mammalian cells
Host specific antiviral proteins

Question 26

In orer to infect and replicate in a new host, how must a virus evolve?

Answer 26

Must evolve to use the dependency factors in the new host, and to evade the restriction factors in the new host

Question 27

What allows rapid viral evolution of HIV?

Answer 27

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

Question 28

Why is SIV non-pathogenic in its natural host (African monkeys)?

Answer 28

Co-evolution for at least 100,000 years

Question 29

When did HIV-1 M crossover into humans?

Answer 29

1920s

Question 30

Why is it that HIV-infected humans progress to AIDS without treatment but SIV-infected monkeys are symptomatic?

Answer 30

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

Question 31

How does HIV stimulate the innate immune response and how could this result in AIDS?

Answer 31

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

Question 32

Why is it that SIV does not cause AIDS in monkeys? (SIV causes AIDS in chimpanzees but not the original African monkeys)

Answer 32

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

Question 33

What has probably happened to IRF-7 in monkeys?

Answer 33

Evolved in response to thousands of years coexistence with SIV - not beneficial to a virus to kill the host so less pathogenic