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Evolutionary Question: How has HIV evolved throughout time to remain such a virulent and dangerous virus to humans?

Gao, F., Bailes, E., Robertson, D. L., Chen, Y., Rodenburg, C. M., Michael, S. F., ... & Hahn, B. H. (1999). Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature, 397(6718), 436-441.

This article discusses the origin of the human immunodeficiency virus type 1, as it is believed to be very uncertain (in comparison to HIV-2). The researchers sequenced the genome of a new SIVcpz strain (Simian immunodeficiency virus), and were able to determine the subspecies identity of all known SIVcpz-infected chimpanzees. Using the identity of the SIVcpz-infected chimpanzees, the researchers are able to determine how the divergent lineages used in the HIV-1 strains that infect man are formed.

Sharp PM, Hahn BH (2010). The evolution of HIV-1 and the origin of AIDS. Philosophical Transactions of the Royal Society B: Biological Sciences,365(1552), 2487-2494.

The closest relatives of HIV-1 are SIVs which infect wild-living chimpanzees in Africa. Using phylogenetic analysis, the researchers were able to determine that the origin of HIV-1 has come from chimpanzees, in which four different lineages were developed through cross-species transmission to humans. Through the investigation of the genetic changes that occurred as viruses adapt to infect chimpanzees and then humans will help show how these viruses are so pathogenic.

Rambaut A, Posada D, Crandall KA, Holmes EC. 2004. The causes and consequences of HIV evolution. Nature Reviews Genetics 5, 52-61.

The researchers in this study studied frequent recombination in HIV-1 and HIV-2, to understand the transmission to humans. Through the use of our understanding of drug-resistance and immune-escape mutations, researchers were able to learn and determine how HIV evolution differs within and among hosts, and on the role played by positive selection.

Frost SD, Wrin T, Smith DM, Kosakovsky Pond SL, Liu Y, Paxinos E, Chappey C, Galovich J, Beauchaine J, Petropoulos CJ, Little SJ, Richman DD. 2005. Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection. PNAS 2005 102 (51) 18514-18519

HIV-1 is a successful virus, because it can escape from the body’s antibody responses very quickly. However, the genetics behind is not understood, so these researchers used the pattern of evolution from the HIV-1 env gene between individuals with recent HIV infection whose virus showed a low or a high rate of escape from neutralizing antibody responses, and the rate of infection has a correlation with the rate of amino acid substitutions.

Heeney JL, Dalgleish AG, Weiss RA. 2006. Origins of HIV and the evolution of resistance to AIDS. Science 313:462–466.

As lentiviruses (HIV and SIV) have gone from African primates to humans, many viral adapations have facilitated human-to-human transmission. HIV uses positive selection (by mutation) as well as recombination of segments from its genome to adapt. This can be supported by the fact that nonhuman primates who are naturally infected by HIV/SIV are resistant to AIDS-like symptoms, and hence understanding of this host resistance and the mechanisms, may help show how we can prevent AIDS.

3 questions in talk and one sentence addition to wiki page: wiki/HIV

Hi,

I believe that there needs to be a section regarding the evolution of HIV in the article -- much of the information could be rerouted into a new subsection regarding evolution of the virus. I propose the following three changes

1) Discuss genetic variability in new "Evolution' section 2) Discuss the transmission of HIV to humans with more details about the animal-to-human crossing 3) Usage of the divergent lineages used in HIV-1 strains to affect man to determine evolution.

One sentence addition (cannot add because page is locked): HIV uses positive selection (by mutation) as well as recombination of segments from its genome to adapt and create new variants of HIV. (Rambaut A, Posada D, Crandall KA, Holmes EC. 2004. The causes and consequences of HIV evolution. Nature Reviews Genetics 5, 52-61.)

Checked for updates on discussion; no one responded as of 10/12

FINAL DRAFT

HIV is an extremely new virus, having only been introduced in the 20th century. As such, humans have had very limited, if any immunity to the virus. In Africa, many species of indigenous nonhuman primates have related lentiviruses in their body, but do not suffer from the symptoms of HIV/AIDS (Heeney et al. 2006). As of 2002, an estimated 42 million people carry the virus currently, with a fatality rate close to 100%. 70% of these people live in sub-Saharan Africa (UNAIDS 2002). HIV is an epidemic that affects our global society, with disastrous effects on the social and economic well-being of individuals, unless an effective treatment (or cure) is found soon. To this, we must understand and figure out how HIV has evolved throughout time to remain such a virulent and dangerous virus to humans. The simian immunodeficiency virus became a part of the human genome much before it manifested itself into the current HIV virus. The initial infections of SIV would have taken place in rural areas, and died out due to a lack of susceptible hosts (Rambaut et al. 2004). But, it is said that chimpanzees affected hu¬¬¬mans through exposure to infected blood and body fluids whilst bushmeat was butchered (Hahn et al. 2000). This would take place most likely due to unclean cutting of the meat. In order to understand HIV, and create drugs that can fight it, it is important to learn the most we can about HIV pathogenesis. The reason HIV infection is so successful, and so difficult to fight in the human body, is its rapid rate of evolutionary change. The rapid rate of evolutionary change results in different types and forms of HIV being continuously created; hence the body finds it very difficult to build antibodies against HIV. The Red Queen hypothesis states that organisms must constantly adapt, evolve, and proliferate, in order to survive against ever-evolving opposing organisms (Bell 1982). Whilst HIV is not an organism, the same concept can apply here, in that HIV is able to survive in the body because it continuously adapts and changes. However, this rapid rate of evolutionary change also allows us to recreate the history of HIV with great specificity, and once we can realize the evolutionary process of HIV, we can create vaccines and antiviral agents to fight it (Heeney et al. 2006). There are two human AIDS viruses, HIV-1 and HIV-2. HIV-1 is the original virus, which is more virulent, but its exact origin is yet to be discovered. HIV-2 is from the Cercocebus atys. Through molecular phylogeny, it was determined that HIV-1 came from a strain of the simian immunodefiency virus, SIVcpz, which came from a subspecies of the common chimpanzee (Pan troglodytes troglodyes). There are three SIVcpz ancestors of HIV-1 that have crossed to humans, with only one causing AIDS. (Heeney et al. 2006). The vast majority of HIV is caused by this one strain of HIV-1, Group M. Within group M, there is a large amount of diversity, with the epicenter being in Africa. It has been determined through the study of SIVcpz that HIV-1 groups M and N came from chimpanzee populations that were extremely far apart in Cameroon. SIVcpz itself is a recombinant virus from the lentivuruses of the red capped mangabey and one or more of the greater spot-nosed monkey (SIVgsn) lineage or something closely related to it (Heeney et al. 2006). Initially, chimpanzees were not accepted as the source of HIV-1, as many chimpanzees would be tested, but only a single further example of SIVcpz would be found within the group. (Sharp and Hahn 2010). Researchers were able to isolate viruses related to HIV-1 from the common chimpanzee, in the search for the HIV-1 reservoir. Specifically, two chimpanzee subspecies in Africa, the P. t. troglodytes and the P. t. schweinfurthii harbor SIVcpz. Through this research, a new genome of a new SIVcpz strain was determined, in which the subspecies identity of all known SIVcpz-infected chimpanzees could be determined (Gao et al. 1999). HIV has a great amount of genetic variation within individual hosts, which makes HIV one of the fastest evolving viruses today. The virus has a high rate of mutation, with reverse transcriptase making approximately 0.2 errors per genome in each replication cycle. Additionally, HIV has a viral generation time of approximately 2.5 days, and can produce 1010-1012 virions every day (Rambaut et al. 2004). Through experimentation, it has been found that the rate of viral escape is strongly correlated with the rate of amino acid substitutions. A dramatic escape from antibodies responsible for neutralizing can take place when there are few changes in glycosylation, or in insertions and deletions in the envelope. However, changes in glycosylation and deletions occur even while neutralizing antibody responses do not exist. A possible mechanism for this involves a high rate of phenotypic escape being correlated with a high rate of amino acid substitutions in the viral envelope (Frost et al. 2005). However, correlation does not always lead to causation. This study becomes complicated due to the diversity between individuals in both the genetic sequence of the HIV virus, as well as what the neutralizing antibodies are made of, and how they metabolize in the body. As HIV evolves in the body though, the envelope protein can retain function whilst tolerating multiple and repeated changes in glycosylation sites (Richman et al. 2003). Evolution can take place within and among hosts, not just through the transmission from host to host. However, intra-host and inter-host evolution are very different processes, in which positive selection dominates intra-host evolution. It is not discernable whether HIV-1 group M, being the most populous, is due to a property of the virus (to make it more transmissible), or because the founding virus from Group M found itself in populations in which the epidemiology was ideal for transmission (Rambaut et al. 2004). HIV and SIV work with many host proteins, in order to spread throughout the organism’s body. When chimpanzees first got SIV, the virus had to adjust to replicate and spread in its new hosts. Whilst chimpanzees and humans are very similar genetically, there is evidence that the differences between chimpanzee and human proteins forced selection pressures on SIVcpz after it was transmitted from a chimpanzee to a human (Sharp and Hahn 2010). When a virus must adapt to a new host, Darwarian selection applies. In this sense, genetic differences determine the amount of resistance a person has to the disease, or how fast/slow HIV progresses (or rarely, not progressing). The most important antiviral innate and adaptive immune response is regulated by the major histocompatibility complex. In the absence of a vaccine or antiviral drugs, it is possible for the human population to adapt to HIV cooking, just as HIV evolves and adapts to selective pressures within its host (Heeney et al. 2006). Tetherin is a protein found in mammals, which has recently been found to have antiviral activity. Dimers made of tetherin form between virus envelopes and the cytoplasmic membrane of a cell, which prevents the virus from releasing its DNA/RNA changing material. The Vpu protein of HIV-1 is known to promote the release of progeny virions, and this takes place by removing the dimers made of tetherin. When SIVcpz was formed (through recombination), it received two genes with anti-tetherin activity. However, these two genes are very specific, and hence when SIVcpz first infected chimpanzees, neither had full anti-tetherin activity (Sharp and Hahn 2010). People with primary HIV infections very quickly generate significant neutralizing antibody responses to early autologous viruses, whilst responses to man-made strains tend to be lower and delayed. Hence, viruses continually and rapidly evolve to escape neutralizing, which means that antibodies place selective pressures on viruses (Richman et al. 2003). As the three HIV-1 groups (M, N. and O) came through separate transmissions of SIVs from apes, there would be selection pressure from three independent processes to negatively affect human tetherin. However, there have been three different outcomes; in HIV-1 group M, adaptation has been successful. In HIV-1 group O, human tetherin is unaffected, whilst in HIV-1 group N, human tetherin is negatively affected. For HIV-1 group N, one of the genes, Vpu, is active against tetherin, but cannot bind to CD4 to induce its degradation. This can explain why HIV-1 group M is the most common form of HIV found in humans (Sharp and Hahn 2010). Due to HIV’s great viral evolutionary capability, drug resistance is heavily reduced in HIV. There was a triple-drug combination antiviral theory, called HAART, which was thought to be able to affect different aspects of the viral life cycle and remove HIV from the body once and for all. But, the designers of HAART did not take into account the viral reservoirs, which replenish the main pool of the replicating virus, and viral evolution, in which the ability of the virus to escape immunity increases (Rambaut et al. 2004). Hence, the battle to fight HIV at its heart (the viral genome itself) continues. Many antiviral agents have made HIV more manageable in industrialized nations, but HIV continues to inflict a burden on our society. This partially comes from a lack of education, as well as ignorance regarding the issue. HIV/AIDS today continues to be a prevalent issue, due to a lack of patient testing, more than anything else. With the proper plans, the spread of HIV/AIDS could be stopped, especially in the United States.

Through the reconstruction of the origin of AIDS, it can be determined that the origin and main source is from HIV-1 group M. This can be traced back to a chimpanzee, the P. t. troglodytes, which is from the southeast corner of Cameroon (Sharp and Hahn 2010). To fight HIV, new antiviral drug combinations are being developed, with a strategy to reduce virus load and restore CD4+ T cell numbers. Additionally, antiviral chemotherapy becomes an interest of research, in order to make individuals become aviremic rather than viremic (Heeney et al. 2006). With a better analysis of the evolution of HIV, and how it has become more virulent, we are one step closer to creating successful treatments for HIV.

References Bell G. 1982. The Masterpiece Of Nature: The Evolution and Genetics of Sexuality. University of California Press, Berkeley, 378. Frost SD, Wrin T, Smith DM, Kosakovsky Pond SL, Liu Y, Paxinos E, Chappey C, Galovich J, Beauchaine J, Petropoulos CJ, Little SJ, & Richman DD. 2005. Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection. PNAS 2005 102 (51) 18514-18519

Gao, F., Bailes, E., Robertson, D. L., Chen, Y., Rodenburg, C. M., Michael, S. F., ... & Hahn, B. H. (1999). Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature, 397(6718), 436-441. Hahn, B. H., Shaw, G. M., De Cock, K. M. & Sharp, P. M. 2000 AIDS as a zoonosis: scientific and public health implications. Science 287, 607–614. Heeney JL, Dalgleish AG, Weiss RA. 2006. Origins of HIV and the evolution of resistance to AIDS. Science 313:462–466. Rambaut A, Posada D, Crandall KA, Holmes EC. 2004. The causes and consequences of HIV evolution. Nature Reviews Genetics 5, 52-61.

Richman DD, Wrin T, Little SJ, Petropoulos CJ. 2003. Rapid evolution of the neutralizing antibody response to HIV type 1 infection. PNAS 2003, 100 (7) 4144-4149.

Sharp PM, Hahn BH (2010). The evolution of HIV-1 and the origin of AIDS. Philosophical Transactions of the Royal Society B: Biological Sciences, 365(1552), 2487-2494. UNAIDS. AIDS Epidemic Update 2002,  (2002).

A small addition to HIV article
Hi,

I believe we can add the following to the HIV article, regarding its rate of evolutionary change, to provide readers with a more clear understanding of how the disease is spread. This is from my own research, and citations listed.

'''Genetic Variation '''

HIV has a great amount of genetic variation within individual hosts, which makes HIV one of the fastest evolving viruses today. The virus has a high rate of mutation, with reverse transcriptase making approximately 0.2 errors per genome in each replication cycle. Additionally, HIV has a viral generation time of approximately 2.5 days, and can produce 1010-1012 virions every day (Rambaut et al. 2004).

Through experimentation, it has been found that the rate of viral escape is strongly correlated with the rate of amino acid substitutions. A dramatic escape from antibodies responsible for neutralizing can take place when there are few changes in glycosylation, or in insertions and deletions in the envelope. However, changes in glycosylation and deletions occur even while neutralizing antibody responses do not exist. A possible mechanism for this involves a high rate of phenotypic escape being correlated with a high rate of amino acid substitutions in the viral envelope (Frost et al. 2005). However, correlation does not always lead to causation. This study becomes complicated due to the diversity between individuals in both the genetic sequence of the HIV virus, as well as what the neutralizing antibodies are made of, and how they metabolize in the body. As HIV evolves in the body though, the envelope protein can retain function whilst tolerating multiple and repeated changes in glycosylation sites (Richman et al. 2003).

'''Antiviral Activity with Tetherin ''' Tetherin is a protein found in mammals, which has recently been found to have antiviral activity. Dimers made of tetherin form between virus envelopes and the cytoplasmic membrane of a cell, which prevents the virus from releasing its DNA/RNA changing material. The Vpu protein of HIV-1 is known to promote the release of progeny virions, and this takes place by removing the dimers made of tetherin. When SIVcpz was formed (through recombination), it received two genes with anti-tetherin activity. However, these two genes are very specific, and hence when SIVcpz first infected chimpanzees, neither had full anti-tetherin activity (Sharp and Hahn 2010).

Frost SD, Wrin T, Smith DM, Kosakovsky Pond SL, Liu Y, Paxinos E, Chappey C, Galovich J, Beauchaine J, Petropoulos CJ, Little SJ, & Richman DD. 2005. Neutralizing antibody responses drive the evolution of human immunodeficiency virus type 1 envelope during recent HIV infection. PNAS 2005 102 (51) 18514-18519

Rambaut A, Posada D, Crandall KA, Holmes EC. 2004. The causes and consequences of HIV evolution. Nature Reviews Genetics 5, 52-61.

Richman DD, Wrin T, Little SJ, Petropoulos CJ. 2003. Rapid evolution of the neutralizing antibody response to HIV type 1 infection. PNAS 2003, 100 (7) 4144-4149.

Sharp PM, Hahn BH (2010). The evolution of HIV-1 and the origin of AIDS. Philosophical Transactions of the Royal Society B: Biological Sciences, 365(1552), 2487-2494.

Khawaja.6 (talk) 03:16, 17 November 2014 (UTC)

https://en.wikipedia.org/wiki/HIV