Natural History of HIV/AIDS

Acquired immune deficiency syndrome (AIDS) caused by Human Immunodeficiency Virus (HIV).

Disease first described in 1981.

Immune system attacked. Victim dies of secondary infections.

Scale of problemThe WHO estimated that in 2009 about 33.4 million people (including about 2.1 million children) were infected with HIV.In 2008 an estimated two million people died of HIV infection (about 76% in sub-Saharan Africa) and an estimated 2.7 million new infections occurred.Globally, infection rates are highest in sub-Saharan Africa, but also are high in southeast Asia.

HIV TransmissionHIV transmitted in bodily fluids –semen, blood, vaginal fluid, breast milk. Enters via mucous membranes or into blood stream.

About 5-10% of new infections result from male-male sexual intercourse and about two thirds of all infections from male female intercourse.

Transmission by needle sharing accounts for about 10% of infections and about 5-10% of infections occur in health care settings (needle sticks, contaminated blood products)

About 11% of infections are of babies who acquire the virus during childbirth or from breastfeeding.

Prevalence of infection among

adults age 15-45.

Controlling HIV transmission

Some success has been achieved in reducing transmission of the virus.

Education is the single most effective weapon in fighting infection.

Increased latex condom use reduces transmission.

The Human Immunodeficiency Virus

HIV, like all viruses, is an intracellular parasite

Parasitizes macrophages and T-cells of immune system

Uses cells enzymatic machinery to copy itself. Kills host cell in process.

HIV binds to two protein receptors on cell’s surface : CD4 and a co-receptor, usually CCR5.

Host cell membrane and viral coat fuse and virus contents enter cell.

What the virus inserts

RNA genome: codes for several proteins.

Reverse transcriptase: transcribes viral RNA into DNA

Integrase: this enzyme splices DNA into host DNA

Protease: this enzyme involved in production of viral proteins

Viral DNA inserted in host DNA produces HIV mRNA and all components of virus

Viral particles self assemble and bud from host cell.

HIV budding from

human immune cell

HIV hard to treat

Because HIV hijacks the host’s own enzymatic machinery: ribosomes, transfer RNAs, polymerases, etc. it is hard to treat.

Drugs that targeted these would target every cell in the host’s body

How HIV causes AIDS

Human body responds to infection with HIV by mobilizing the immune system.

The immune system destroys virus particles floating in bloodstream and also destroys cells infected with virus.

Unfortunately, the cells that HIV infects are critical to immune system function.

How HIV causes AIDS

HIV invades immune system cells especially helper T cells.These helper T cells have a vital role in the immune system.When a helper T cell is activated (by having an antigen [a piece of foreign protein] presented to it, it begins to divide into memory T cells and effector T cells.

Memory T cells

Memory T cells do not engage in current fight against the virus.

Instead they are long-lived and can generate an immune response quickly if the same foreign protein is encountered again.

Effector T cellsEffector T cells attack the virus. They produce signaling molecules called chemokines that stimulate B cells to produce antibodies to the virus.

Effector T cells also stimulate macrophages to ingest cells infected with the virus.

In addition effector T cells stimulate killer T cells to destroy infected cells displaying viral proteins.

Why is HIV hard to treat?Viral disguise

Killer T cells deplete helper T cells (those that produce memory cells that can remember and recognize HIV).

Loss of helper T cells is costly, but the immune system now primed to recognize and attack the viral protein.

What’s the problem?

Why is HIV hard to treat?Viral disguise

Virus mutates and the proteins on its outer surface (gp120 and gp41) change.These new surface proteins are not recognized by the immune system’s memory cells.Mutant virus particles bearing new surface proteins survive immune system attack and begin new round of infection

Why is HIV hard to treat?Viral disguise

Each round of infection reduces numbers of helper T cells because they are infected by virus and destroyed.

Furthermore, because each lineage of T cells has a limited capacity for replication, after a finite number of rounds of replication the body’s supply of helper T cells becomes exhausted. The immune system eventually is overwhelmed and collapses.

Why is HIV hard to treat?Drug resistance.

AZT (azidothymidine) was the first HIV wonder drug

It works by interfering with HIV’s reverse transcriptase, which is the enzyme the virus uses to convert its RNA into DNA so it can be inserted in the host’s genome.

Why is HIV hard to treat?Drug resistance.

AZT is similar to thymidine (one of 4 bases of DNA nucleotides) but it has an azide group (N3) in place of hydroxyl group (OH).

An AZT molecule added to DNA strand prevents the strand from growing. The azide blocks the attachment of next nucleotide in the DNA chain.

Why is HIV hard to treat?Drug resistance.

AZT was successful in tests although with serious side effects.

But patients quickly stopped responding to treatment.

Evolution of AZT-resistant HIV in patients usually took only about 6 months.

How does resistant virus differ?

The reverse transcriptase gene in resistant strains differ genetically from non-resistant strains. Mutations are located in active site of reverse transcriptase.These changes selectively block the binding of AZT to DNA but allow other nucleotides to be added.

How did resistance develop?

HIV reverse transcriptase very error prone.

About half of all DNA transcripts produced contain an error (mutation).

HIV highest mutation rate known.

There is thus enormous VARIATION in the HIV population in a patient.

High mutation rate makes occurrence of AZT-resistant mutations almost certain.NATURAL SELECTION now starts to act in the presence of AZT.

Natural selection means that certain variants are better able to survive and reproduce than others. These variants produce more offspring and contribute more copies of their genes to the next generation.

Selection in action

The presence of AZT suppresses replication of non-resistant strains.Resistant strains are BETTER ADAPTED to the environment.Resistant strains reproduce more rapidly. There is thus DIFFERENTIAL REPRODUCTIVE SUCCESS of HIV strains.

Selection in action

Resistant strains replicate and pass on their resistant genes to the next generation.

Thus resistance is HERITABLE.

Selection in action

AZT-resistant strains replace non-resistant strains. The HIV gene pool changes from one generation to the next.

EVOLUTION has occurred: EVOLUTION is change in the gene pool from one generation to the next.

Evolution of HIV population in an individual patient

Process of natural selectionVariation in population – some members of a population possess alleles [recall alleles are different versions of a gene] that make them better adapted to the environment than others.

Variation is heritable – these beneficial alleles can be passed on to offspring.

Variation affects reproductive success – Individuals differ in how many offspring they produce. Those individuals who are better adapted to the current environment [those with the best alleles for the current environment] leave behind more offspring and so pass more copies of their alleles on to the next generation.

Process of natural selection

Differential reproductive success results in some alleles becoming more common in the gene pool and other alleles less common and eventually extinct.

As a result of the process of natural selection, the gene pool changes from one generation to the next. This change in the frequency of alleles from one generation to the next is Evolution.

Using selection bases thinking to devise better treatment regimens.

Several different types of drugs have been developed to treat HIV.

Reverse transcriptase inhibitors (e.g. AZT).Protease inhibitors (prevent HIV from producing final viral proteins from precursor proteins).Fusion inhibitors prevent HIV entering cells.Integrase inhibitors prevent HIV from inserting HIV DNA into host’s genome.

Using selection to devise better treatment regimens.

Because HIV mutates so rapidly treatment with a single drug will not be successful for long.

Is there a better way?

Using selection to devise better treatment regimens.

Most successful approach has been to use multi-drug cocktails (referred to as HAART [Highly Active Anti-Retroviral Treatments]

HAART cocktails usually use three different drugs in combination (e.g. two reverse transcriptase inhibitors and a protease inhibitor).

Using selection to devise better treatment regimens.

Using multi-drug cocktails sets the evolutionary bar higher for HIV.

To be resistant, a virus particle must possess mutations against all three drugs. The chances of this occurring is a single virus particle are very low.

Using selection to devise better treatment regimens.

If the same drugs were provided in sequence to an HIV population each time it faced a new drug it would need only a single mutation to gain resistance, which would then spread through the population.

Using selection to devise better treatment regimens.

Offering drugs one at a time is analagous to providing a stairway that HIV must climb.

Offering multiple drugs at once requires HIV to leap from the bottom to the top in a single bound, which is much more difficult

Using selection to devise better treatment regimens.

Multi-drug treatments have proven very successful in reducing viral load and reducing mortality of patients.

Using selection to devise better treatment regimens.

However, HIV infection is not cured. Reservoir of HIV hides in resting white blood cells. Patients who go off HAART therapy experience increased HIV loads.

Using selection to devise better treatment regimens.

For patients on HAART whether HIV replication is stopped completely or not is crucial. In some HIV appears dormant and no replication means no evolution.

In other patients replication occurs, although slowly. However, this allows HIV to mutate and resistance to develop. So far, few HAART regimens are effective for more than 3 years.

Using selection to devise better treatment regimens.

Other downside of HAART therapy is that many patients experience severe side effects.

These patients have difficulties maintaining their treatment regimen.

Using selection to devise better treatment regimens.

Because of severe side effects of HAART therapy some doctors have advocated “drug holidays” for their patients (i.e., to have patients stop taking drugs for a while). From an evolutionary perspective does this seem like a good idea or not?What is likely to happen to the HIV population in the patient?

Natural resistance to HIV

Some people appear resistant to the virus not becoming infected even though exposed to HIV multiple times.

HIV enters T cells using co-receptor molecules on cell’s surface. Some resistant individuals possess a mutant CCR5 co-receptor protein whose gene is missing 32 base pairs. This allele is referred to as the CCR5 Δ32 allele.

Natural resistance to HIV

Frequency of the CCR5-Δ32 allele is highest in European populations (9%), but scarce or absent elsewhere.

Frequency of CCR5- Δ32 allele in the Old World

Natural resistance to HIV

Suggested that the allele either became widespread by chance (genetic drift) or provided a selective advantage against another disease (e.g. plague or smallpox).

Natural resistance to HIV

Other mutant alleles have also been identified that confer resistance.

Study of how these mutant alleles hinder HIV is useful in developing new drugs (e.g., one drug called Schering C binds to the CCR5 receptor and prevents HIV using it to enter cells.)

Origins of HIV

Where did HIV come from?

HIV similar to virus found in monkeys and apes called SIV (simian immunodeficiency virus).

To identify ancestry of HIV scientists have sequenced various HIV strains and compared them to various SIV strains.

Origins of HIV

HIV-1 is most similar to an SIV found in chimps and HIV-2 is most similar to an SIV found in a monkey called the sooty mangabey.

Origins of HIV

HIV-1 occurs in three different subgroups (called M,N and O) and each appears closely related to a different chimpanzee SIV strain.

Origins of HIV

Thus, it appears that HIV-1 jumped to humans from chimps on at least 3 occasions.

Most likely the virus was acquired through killing and butchering chimps and monkeys in the “bushmeat” trade.

When did HIV move to humans?

Sequence data from several group M strains has been used estimate when HIV moved from chimps to humans.

Korber et al. (2000) analyzed nucleotide sequence data for 159 samples of HIV-1 strain M. Constructed a phylogenetic tree showing relatedness to a common ancestor of the 159 samples.

When did HIV move to humans?

Extrapolating based on rates of change of different strains suggests that subgroup M probably infected humans in the early 1930’s.