HIV as a Case Study for Evolution by Natural Selection
Introduction to Evolution and Viruses
The lecture primarily introduces evolution by natural selection and the concept of evolutionary history, using the Human Immunodeficiency Virus (HIV) as a case study.
Understanding HIV's life cycle is secondary to appreciating its implications for evolutionary principles.
In the early 1980s, AIDS (Acquired Immunodeficiency Syndrome) emerged as a devastating disease, later linked to HIV. There is still no vaccine or cure, but education and treatment have reduced its spread and improved lives.
HIV as a Major Global Health Concern
Global Impact: HIV continues to kill more people per year than malaria or seasonal influenza.
Malaria: Roughly 500,000 deaths/year, predominantly children under 5 in the global South. Approximately 30 children die from malaria during a 45-minute lecture.
Influenza: Slightly under 500,000 deaths/year.
Current Trends:
The rate of new HIV infections (green line) is decreasing annually.
Deaths due to AIDS are also declining, partly due to reduced infections and improved treatments.
Geographic Distribution: Despite declining rates, HIV remains a significant concern, with a highly uneven global distribution.
North America: Well under 1\% of adults are HIV positive.
Sub-Saharan Africa: Experiences much higher prevalence (e.g., Lesotho saw an average human lifespan decrease by ~20 years since 1980, largely due to HIV/AIDS).
Zoonotic Origin of HIV
The high prevalence in Sub-Saharan Africa is because this region is where HIV first began infecting humans, due to species barrier jumping.
Zoonotic Disease Definition: A disease (e.g., virus) originally present in another animal species that jumps to humans (e.g., via bite, consuming infected meat).
Examples of Zoonotic Diseases: Lyme disease, COVID-19 (from bats), malaria (transmitted by mosquitoes, with a complex life cycle), rabies.
Spillover Events: More likely to occur between physiologically similar or closely related species (e.g., mammals like bats, dogs, monkeys to humans, rather than fish or insects).
The disease is often less harmful/pathogenic in the original reservoir host but becomes more lethal in the new host species.
Diseases can also jump from humans to non-human animals (e.g., requiring masks at zoos to protect primates).
Evolutionary Origin of HIV:
HIV originated from Simian Immunodeficiency Viruses (SIVs) found in non-human primates (simians), particularly chimpanzees and bonobos.
Phylogenetic Trees: Genetic analysis shows HIV (human strain) is extremely similar to chimpanzee SIVs, indicating its source.
Molecular Clocks: By analyzing the rate of genetic changes (mutations), scientists estimate that the initial spillover event from chimpanzees to humans likely occurred over 100 years ago, not in the 1980s.
There have been multiple spillover events from various primates (chimpanzees, sooty mangabeys) to humans, meaning it's likely to happen again.
Nature of Viruses
Are Viruses Alive? Viruses are generally not considered cellular life and thus do not fit on a standard phylogenetic tree of life, as they lack cellular structures and metabolic functions, relying instead on host cells for replication.
How viruses are similar to cellular life, how they are different, and why treating viral diseases is difficult
Similarities to cellular life
Viruses possess an evolutionary history and are capable of evolving and responding to natural selection.
They contain a nucleic acid genome, which can be in the form of double-stranded DNA (e.g., herpes virus) or RNA (e.g., COVID, HIV).
Differences from cellular life
Viruses are generally not considered cellular life; they do not fit on a standard phylogenetic tree of life.
They lack cellular structures and metabolic functions, making them obligate parasites that rely entirely on host cells for replication.
Retroviruses like HIV store their genetic information as RNA and "disobey the central dogma" by using reverse transcription to convert viral RNA into DNA, a process not found in typical cellular life.
HIV's reverse transcriptase enzyme lacks proofreading capacity, leading to a high mutation rate compared to the enzymes that replicate DNA in humans and most cellular life.
Why treating viral diseases is difficult
Antiviral drugs often have more severe side effects than antibiotics or antifungals because viruses extensively use the host cell's machinery and have few unique genetic targets.
It is challenging to target viral processes without also harming the host cell, as many essential viral functions are indistinguishable from the host's own cellular mechanisms.
The high mutation rate of viruses like HIV makes it extremely challenging to design drugs or vaccines that will continue to be effective long-term, as resistance can evolve very rapidly.
There is still no vaccine or cure for HIV, although education and treatments have improved patient outcomes and reduced spread.
Evolutionary origin of HIV
The high prevalence of HIV in Sub-Saharan Africa is because this region is where HIV first began infecting humans, due to species barrier jumping.
Zoonotic Disease Definition: A disease (e.g., virus) originally present in another animal species that jumps to humans (e.g., via bite, consuming infected meat).
Examples of Zoonotic Diseases: Lyme disease, COVID-19 (from bats), malaria (transmitted by mosquitoes), rabies.
Spillover Events: These are more likely to occur between physiologically similar or closely related species (e.g., mammals like bats, dogs, monkeys to humans, rather than fish or insects).
The disease is often less harmful/pathogenic in the original reservoir host but becomes more lethal in the new host species.
Diseases can also jump from humans to non-human animals (e.g., requiring masks at zoos to protect primates).
Evolutionary Origin of HIV:
HIV originated from Simian Immunodeficiency Viruses (SIVs) found in non-human primates (simians), particularly chimpanzees and bonobos.
Phylogenetic Trees: Genetic analysis shows HIV (human strain) is extremely similar to chimpanzee SIVs, indicating its source.
Molecular Clocks: By analyzing the rate of genetic changes (mutations), scientists estimate that the initial spillover event from chimpanzees to humans likely occurred over 100 years ago, not in the 1980s.
There have been multiple spillover events from various primates (chimpanzees, sooty mangabeys) to humans, meaning it's likely to happen again.
How HIV evolves resistance to drugs we use to treat it, and why anti-viral drugs often become less effective over time
The first antiretroviral drug, AZT, was designed to target HIV's reverse transcriptase enzyme, a process unique to retroviruses and thus a good drug target.
AZT functions by mimicking thymidine, one of the building blocks of DNA. When HIV's reverse transcriptase incorporates AZT instead of thymidine during DNA synthesis, the AZT molecule blocks the addition of subsequent nucleotides, halting the reverse transcription process.
Initially, AZT efficiently slowed HIV progression and maintained white blood cell counts. However, after a few months of treatment, patients required increasingly higher doses, and eventually, AZT became completely ineffective.
This loss of effectiveness is due to HIV evolving resistance to AZT, rather than changes in the human host's physiology.
Mechanism of Resistance Evolution (Natural Selection):
High mutation rate: HIV's reverse transcriptase is prone to errors, leading to a high mutation rate. Even starting with a population of AZT-susceptible virions, a tiny fraction (e.g., one in a million) will randomly acquire a mutation that alters the active site shape of the reverse transcriptase enzyme.
Heritable variation: Virions with this altered active site are AZT-resistant and can pass this trait to their offspring.
Selective pressure: When AZT is present in the host's system, it creates a selective environment. Susceptible virions struggle to replicate, while resistant virions can continue to reproduce effectively.
Increased frequency of resistant forms: Over time, the resistant virions out-compete the susceptible ones, becoming more and more frequent in the viral population. The viral population shifts from being predominantly susceptible to largely resistant.
To counter this rapid evolution of resistance, HIV treatment now often involves drug cocktails—a combination of multiple antiviral drugs that target different stages or enzymes in the viral life cycle (e.g., integrase enzyme). This significantly reduces the probability of a single virion acquiring simultaneous resistance to all drugs (e.g., from a one in a million chance for one drug to a one in ten trillion chance for several drugs).
Principles underlying evolution by natural selection: heritable variation, non-random reproduction or survival, change in genotype of a population
Evolution by natural selection occurs when certain conditions are met, leading to predictable changes in a population over time:
Heritable variation: Random mutations generate genetic and phenotypic variation within a population. Traits, like AZT resistance, are passed from parents to offspring.
Non-random reproduction or survival: Individuals vary in their reproductive success. In a specific environment (e.g., presence of AZT), some forms (e.g., AZT-resistant virions) have a significant advantage in survival and reproduction compared to others.
Change in genotype of a population: If these conditions are met, the population's genetic makeup will inevitably change over time, with advantageous traits becoming more prevalent.
How population size affects the likelihood that a specific mutation will occur
The likelihood of a specific mutation occurring is directly influenced by:
Generation time: Organisms with faster replication rates and shorter generation times (like viruses or bacteria, replicating in hours) have more opportunities for mutations than those with longer generation times (like oak trees).
Population size: A larger population offers more opportunities for random errors during replication. For example, a population of 500,000,000 individuals will have a higher chance of a specific mutation occurring than a population of 50. HIV benefits from this as billions of virions can replicate within a single human body.
Proofreading capacity: The fidelity of replication enzymes (their ability to proofread and correct errors) directly affects the mutation rate. Enzymes without proofreading capacity (like HIV's reverse transcriptase) lead to higher mutation rates.
Whether a mutation would be helpful or harmful does not influence the likelihood of it happening; mutations are random errors.
How HIV's mutation rate affects the likelihood of developing antiviral drugs or vaccines that will continue working in the long term
HIV's reverse transcriptase enzyme lacks proofreading capacity, leading to an extremely high mutation rate. This means it makes many mistakes during replication, constantly generating genetic variation.
This high mutation rate is a critical factor making it super challenging to design antiviral drugs that remain effective for extended periods. Resistance to single drugs can evolve very rapidly, often within months.
Similarly, the high mutation rate poses immense difficulties for vaccine development. HIV evolves significantly faster than common viruses like influenza or COVID-19, making it challenging to create a universal, long-lasting vaccine that can outpace the virus's ability to change its surface proteins and evade immune responses. It is possible that a universal HIV vaccine may never be developed due to this rapid evolution.