AIDS proposal
From Augix' Wiki
Abstract: Study HIV and its primate hosts from an evolutionary point of view
Origin of HIV
There is now clear evidence to prove that HIV causes AIDS. HIV is a lentivirus, and like all viruses of this type, it attacks the immune system. Lentiviruses have been found in a number of different animals, including cats, sheep, horses and cattle. However, it is now generally accepted that HIV is a descendant of the Simian Immunodeficiency Virus (SIV) in primates.
Lentivirus are in turn part of a larger group of viruses known as retroviruses which use reverse transcription to insert themselves into their host’s genome. Indeed, a significant portion (about 40%) of the human genome consists of endogenous retroviruses which probably representing footprints of ancient retroviral infections. Also it is hypothesized that the HIV/AIDS epidemic, which began nearly a century ago when SIV passed from wild chimpanzees into human host, is the latest episode in the longstanding coevolutionary struggle between retroviruses and their hosts.
Monkeys' help
HIV-1 causes AIDS in humans, and to a lesser extent, in chimpanzees. However, certain primate species were resistant to HIV-1 infection. In particular, monkeys from Africa and Asia, referred to as Old World monkeys could not be infected with HIV-1 and did not develop AIDS. A few years ago, researchers discovered that a gene called TRIM5 allows most primates to inhibit the HIV and other retroviruses. It turns out that TRIM5 exists in all primates, humans included, and that it’s involved in a rapid evolution: Each species has a unique TRIM5 gene that has evolved to deflect retroviruses, and each retrovirus has mutated in different ways to evade it in its particular host.
The discovery of TRIM5 not only answered a long-standing question in the HIV field (why monkeys are resistant to HIV), it also revealed a new pathway that protects human cells from retroviral infection. The human genome encodes more than 50 members of the TRIM family. These members were shown to be essential for antiviral activity and may block some retroviruses. Efforts aimed at enhancing these innate immune defenses may ultimately prove to be more effective at protecting humans from HIV than vaccine strategies. But these efforts probably can not be made without the discovery of these antiviral resistance factors and understanding of its evolution in primates.
Evolution of HIV
To fight against HIV, we must understand its evolution. One remarkable property of HIV-1 is its propensity to mutate rapidly during reverse transcription. This feature is amplified by the high replication rate of HIV-1, its high population density in infected tissues, and its persistence over many years in a single host. This results in genetic heterogeneity among viral isolates from a single individual, the potential for escape from antiviral immune responses, and the development of resistance to drugs we designed.
Therefore, it is very important to study the pattern of evolutionary change in HIV. The introduction of evolutionary biology concepts and methods have been proven helpful for this kind of study.
Evolutionary theory explains the drug cocktails treatment. Although HIV evolves so quickly that some mutant viruses gain a certain level of resistance to the drugs, basic evolutionary theory points out that the evolution of resistant virus can be delayed and the probability that the virus happens to be resistant to several different drugs at the same time is much lower than that in single-drug-treatment.
Population genetics helps us to understand why some people are resistant to HIV. The mutant CCR5 allele probably began to spread in northern Europe during the past 700 years and it's reported that this mutant confers resistance to HIV, so that its frequency increased in the human population.
Besides, many more studies of HIV evolution are carrying on and will contribute to the understanding of HIV:
Comparative genomics and phylogenetic methods have been used to classify HIV sequences into major groups and subtypes within these groups. With the sequencing data of many HIV samples, these methods can be used again to study the HIV's mutation pattern over time within individual and the pattern among individuals when transmission occurred. The latter could be extended to a sub-population level analysis which help us to understand how the HIV spread in the human population. At the species level, the result from comparative analysis already indicated that the origin of HIV could be due to the transmission of retrovirus from other primates. All these mutation pattern mentioned above could be modeled, simulated, and it finally will provide information about the molecular evolution of HIV.
The examination of molecular changes in HIV gives only one side of the HIV evolution, these changes should be further correlated with other factors. With the genetic information from different primate species, scientists have been illustrating the picture of the co-evolution between retrovirus and its hosts. With genotype data among humans, the impact of the host genotype on the evolution of HIV can be investigated, which would be helpful for the future personal medicine. By identifying the molecular changes in HIV and correlating it with treatments, we may able to understand how the HIV evolves the drug resistance. This knowledge will be useful for the development of an effective vaccine.
Understanding the evolution of regulatory machinery in HIV or even in retrovirus is crucial. HIV evolves very fast at its sequence level, but how exactly it evades the antiviral agents can not be solved without the study of its expression and regulatory machinery. The sequencing of the reverse transcriptase and protease HIV produced might give us some insight. Also the human regulatory elements and proteins that HIV used are important and can be studied in an evolutionary aspects.
Model for Life science
HIV is a very good model for the study of molecular evolution. For example, a longitudinal study of sequence diversity of HIV-1 in a single individual over a two-year period is the molecular evolutionist's equivalent of studying typical gene regions for two million years of evolution sampled every 100,000 years. Studying AIDS/HIV also gives us a model to study other epidemics.
Ultimately, understanding the evolutionary history of HIV and its pattern of evolutionary change may help us control and fight off this disease.
