Chapter 1: Evolutionary Biology

The HIV epidemic

A deadly infectious disease that has killed millions across the globe. It has the largest effect on the sub-Saharan Africa

What does HIV stand for?

Human immunodeficiency virus

How is HIV transmitted?

Moves through bodily fluids can be transmitted by sex, needle sharing, blood transfusions, breastfeeding, and childbirth. Vast majority of new infections are in low and middle income communities.

What country has the largest number of people living with HIV?

Africa (highest in eastern and southern africa) followed by Asia and the pacific islands

What is the current trend of global HIV infections?

More people are living with HIV but there are less deaths

What is a virus?

An obligate intracellular parasite

What is HIV?

A virus that targets immune cells such as effector helper T cells and memory helper T cells along with macrophage cells (all carry CD4 and CCR5 receptors)

What is the life cycle of HIV?

1. Attaches via gp120 (CD4 receptor) and gp41 (CCR5 receptor)

2. Binding and virus entry

3. Reverse transcription

4. Integration

5. Transcription

6. Translation

7. Processing of proteins

8. Packaging of proteins and genome

9. Budding from host cell membrane

10. Release of progeny virus

How does HIV cause aids?

The body responds to infection by destroying virions in the bloodstream and killing its own immune cells such as T cells and macrophages, without treatment AIDS usually occurs 10 years after infection and death occurs within two years

Acute phase of HIV infection

First strike of infection immune system recognizes infection and begins to fight it

Chronic phase of HIV infection

Immune system continuously fights infection

Aids phase of HIV infection

Threshold for onset of aids immune system will collapse and can no longer fend off viruses, bacteria, or fungi

How is the HIV life cycle broken?

Therapies target enzymes specific to the virus and life cycle its targets are reverse transcriptase, integrase, and protease

What is AZT?

Azidothymidine which is a drug that interferes with reverse transcriptase to stop transcription of DNA it does this by inserting itself in thymidines place in the growing DNA strand

How does AZT work?

It fuses with host cells and the viral RNA is released into the cell cytoplasm where RT transcribes viral RNA into DNA using host nucleotides, it is biochemically very similar to thymidine once inserted it stops transcription

Why did AZT work then stop working?

It only worked because RT would make mistakes and not notice AZT over time the viruses with mistake prone RT started to die out, because RT is error prone mutations in transcribed viral DNA arise very frequently with enough mutations at least a few would carry changes in active site of RT with an altered binding site the strain would still reproduce even with AZT present over time only non error prone would be left and AZT wouldn't work for that person

Natural selection and AZT

Natural selection acted on HIV for low mistake RT conferring a newly evolved trait of AZT resistance this is viral microevolution that happened with each person on AZT therapy which caused it to fail as a long term treatment

Why was AZT failure predictable?

RT has a high error rate some part of the viral genome have error rates over 50% of DNA transcripts by RT have at least one mutation so adaptation by the virus was inevitable

What happens in the absense of AZT?

HIV populations return to being non selective due to the high inherent mutation rate this is because natural selection is reversible

Natural selection is...

not unidirectional or irreversible

What is the modern treatments for HIV?

Coreceptor inhibitors that block HIV from attaching to cells

Entry/fusion inhibitors that bar entry to host cells

RT inhibitors that inhibit RT by mimicking normal building blocks of DNA to interfere with binding site

Integrase inhibitors that block viral DNA incorporation into host DNA

Protease inhibitors that block the enzyme that cleaves the precursor proteins to allow maturation of virions

These are all used together which makes it much harder to evolve around all of these drugs

Louisiana v Richard J Schmidt

Doctor injected HIV into patient/nurse and she was diagnosed with HIV this was proved using a phylogenetic tree infected patient and nurse showed similar HIV on tree

How was an evolutionary tree helpful in the case study?

Can trace the history of diversification or how different the HIV is in different patients

Where did HIV come from?

HIV genome and life cycle is very similar to primate SIV virus

What are the two types of HIV?

HIV-1 the main variant which likely came from chimps

HIV-2 found primarily in west africa and is less prevalent which likely came from sooty mangabeys

How was HIV given to humans?

Two viruses independently jumped to humans likely from handling or eating these species of monkey

Chimps in east africa and Monkeys in west africa

Four introductions of HIV-1

Group M - major group that differentiated into 9 subtypes comes from chimps

Group N - Non-M less than 20 cases recorded from chimps in cameroon only

Group O - Outlier high diversity west and central africa possibly from chimps

Group P - Pending one case so far in cameroon could be from gorillas or humans to gorillas unsure

When did HIV evolve?

Using a plot of the rate of mutations biologists estimate it was around the 1930s or from 1915 to 1945

Why is HIV fatal in humans but not monkeys?

HIV needs a new host before its current host dies its high replication rate or viral load = more transmissions per year but also fewer years to spread, selection favors intermediate virulence

What is virulence?

the severity of harmfulness of a disease in this case caused by the reproductive rate of the virus

Transmission rate hypothesis

If transmission of sexually transmitted diseases is frequent, virulent viruses are naturally selected

If transmission is low, less virulent strains are selected for

Cost/benefit ratio for the virus

Aka it is better for the virus to replicate a lot and kill the host quickly if promiscuity is common with monogamy better to keep the host alive this is why AIDS appeared in the 1980s because of sexual practices in that time

Transmission in africa

Economic circumstances led to prostitution and virulence was selected for in the virus and HIV started to kill

Natural experiment HIV-2

HIV-2 has low virulence and recently introduced in southern asia may increase in virulence to lethal levels if promiscuity is high

HIV resistance

These people have a 32-nucleotide deletion of the CCR-5 receptors on macrophages this is a 32 bp deletion

Heterozygotes are also less likely to contract it

The Berlin Patient

Received bone marrow transplant (stem cell) for leukemia donor had delta 32 allele and his HIV went away and immune cells increased all new white blood cells were delta 32 and resistant