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 The final Draft

Introduction HIV/AIDS is a well known topic by a majority of people whether young or old. This is because the disease is not biased in its infections, and the fatalities are almost 100% (Rambaut et al. 2004). HIV is a retrovirus that causes AIDS (Auto Immune Deficiency Syndrome) and it belongs to the lentivirus family (Gerretti, 2006). The research question is the role of evolution in the spread and persistence of HIV/AIDS infections. The virus continues to be a challenge in the research and biomedical fields due to its evolutionary mechanism making the engineering of vaccines and curative drugs nearly impossible. Understanding the evolution of the disease is important in coming up with curative drugs and understanding the spread and introduction of new variants of the virus. HIV/AIDS also have an economical, social, and psychological impact on the society (Little et al. 2014). The government and affected victims spend a lot of finances into finding a cure for the disease to no success. Risk factors for acquiring the infectious variant include risky sex behaviors, sharing of injecting materials, and perinatal infection (Cohen et al. 2008).

Variants of the HIV virus The persistence of HIV infections, its spread and lack of vaccines and cure are attributed to the evolution of the virus. The retrovirus undergoes mechanisms of evolution such as genome mutation and recombination to give rise to the different variants and subtypes associated with human infections. According to (Cohen et al. 2008), there are two main variants associated with human infections; HIV-1 and HIV-2 with the former being more prevalent than the latter. An interesting fact in the spread and persistence of HIV is the unequal distribution among the world population. Insight into the difference in human susceptibility to especially HIV-1 is attributed to genetic factors, innate resistance, and even acquired resistance (Overbaugh & Morris, 2012). In the latter, HIV-1-specific CD8+ T cell immune response in some individuals have been associated with the resistance to infection (King & Larsson-sciard, 2001). HIV-1 is thought to arise from a cross-species transmission from a chimpanzee to a human and HIV-2 a cross-species transmission of a Sooty Mangabey virus (Pingen et al. 2011). HIV-1 has been categorized into three phylogenetic groups namely M, N and O with group M having a global distribution while the other two groups are restricted to West Africa (Rambaut et al. 2004). A review into the evolutionary processes of the HIV virus provides insight into the persistence of the infections among hosts. Evolutionary processes of the HIV virus The spread and persistence of HIV infections are attributed to the evolution of the virus. This results in drug-resistant strains in treated individuals and the introduction of new variants through recombinant strains. (Pingen et al. 2011) conducted a study that showed 10% of new HIV-1 infections are due to spread of infections from drug-resistant strains. Another observation is the genetic variation of the virus within individuals indicating within-host evolution. This rapid evolution within hosts is associated to the high rate of mutation of the virus. Each replication cycle of the genome involves an approximate 0.2 errors (Pingen et al. 2011). Mutations of the genome also arise during the reverse transcription resulting in a new variant of the virus and hence propagating the evolution of the virus. Another factor that explains the evolution of the virus is the duration of the replication cycle and the rate of replication. Approximately 1010- 1012 virions are replicated daily, and the majority of them have mutations arising from replication errors (Pingen et al. 2011). Another factor that contributed to within-host evolution of the virus is the numerous recombination and natural selection of the virus leading to its adaptability hence evolution and increased persistence of infections and resistance to drugs. The development of the HIV virus infection to AIDS is associated with the broadening of co-receptor usage (Cotton et al. 2014). Earlier studies show that the mode of infection was through attacks to the CD4 cells (immune system). Recent studies show that the virus also utilizes CCR5 and CXCR4 receptors (Pingen et al. 2011). This broadening of co-receptor usage results in the introduction of new strains. For example, viral strains that utilize the CCR5 receptors give rise to NSI strains and those affecting macrophages utilizing CXCR4 receptors result in X4 strains (Pingen et al. 2011). The evolution of drug Resistance Drug resistance by the HIV is a consequence arising from its evolution (Overbaugh & Morris, 2012). This resistance is central to the disease as it impacts on the health status of individuals, their emotional well-being and also on their finances. This is in that a disease with resistance to pharmacological interventions translates to management of the condition rather than curing the diseases that have negative impacts. Highly active antiretroviral therapy (HAART) targets various stages of the viral life cycle is being applied as a managerial intervention (Van de Vijver, Wensing, & Boucher, 2012). The pooling of the virus in cells such as T lymphocytes, follicular dendritic cells, and macrophages has contributed to the failure of the therapy (Pingen et al. 2011). The rapid evolution of drug-resistant strains is due to exchange of resistant mutations in a nonlinear fashion due to high rates of recombinants taking place in the above cell reservoirs. An example of a hypothetical scenario is where a mutation in one strain results in resistance to drug Y and another strain mutates and is resistance to drug Z. The two mutated strains bearing drug resistance can then recombine during replication to give rise to a strain showing double resistance. Hence, evolution leading to drug resistance will have taken place. Inter-host evolution where partners can acquire different strains (sexual transmission) has been used to explain the evolution of drug-resistance and also the existence of various strains within an individual (Cotton et al. 2014). Various studies have been conducted to explore various ways to explain the evolution of drug-resistant HIV virus in an attempt to curb the HIV/AIDS plague. Evolutionary pathways of transmitted drug resistance A study carried out by (Pingen et al. 2011) show that drug resistance mutations occurring in RT and PR lowers the replication capacity of the virus. If the resistance mutations do not serve a beneficial role after transmission to a new host, a reversion to wild type may occur. In the process of reversion to the wild type, incomplete process results in the formation of intermediates (Van de Vijver et al. 2012). These intermediates have been shown to have a higher replication capacity that the mutants and the wild types resulting in increased persistence of the virus. Another pathway of evolution of the drug-resistant HIV virus is observed in atypical variants. This occurs in the transmission of a drug-resistant HIV to a new host where a novel amino acid may be selected (Little et al. 2008). The atypical variants exhibit an increased replication cycle and increased selectivity to the thymidine analogues. This further evidences the fact that evolution plays a major role for the genetic variability of HIV in hosts and the increased persistence of the infection due to drug-resistant strains. Evolution of the drug resistance HIV virus can also be explained by looking at the persistence of transmission of the resistant mutants. Persistence of HIV infection can be due to a minimal reduction in the replication cycle (Gerretti, 2006). As seen earlier, during reversion of mutants to the wild type, the replication cycle may be reduced. However, if the replication cycle of the variants is almost equal to that of the wild types, mutations of the virus may persist. Another mechanism leading to the persistence of the virus is compensatory fixation (an example is observed in PI patients who interrupt their PI therapy resulting in maintained combinations of the mutated strains) (Pingen et al. 2011).

Implications of Evolution of the HIV virus The biological implications of evolution of the HIV virus are the persistence of the infection and introduction of drug-resistant variants (Gerretti, 2006). However, the full picture cannot be painted until what happens biologically is translated to humans. One of the implications of evolution of the evolution of HIV is the costs incurred (Cohen et al. 2008). Diagnosis of the specific type of HIV variant requires advanced medical testing that is expensive. The medical costs bear down heavily on the family of patients and also on the nation at large. Evolution also results in drug resistant variants. This impacts on the health of patients and affects their quality of life. There is also stigmatization in the society of people diagnosed with HIV/AIDS (Rambaut et al. 2008). This impacts negatively on their lives of affected persons, and it results in emotional and physical deterioration. Another impact is death when the infection is fully blown. The attack on the immune system allows for opportunistic infection, which in addition to lowering the quality of life can be fatal.

Conclusion A lot of literature has evidenced the role of evolution in the spread and persistence of HIV/ AIDS. In this case, evolution is responsible for the existence of different variants of the virus. A consequence of the evolution of the virus is the development of drug-resistant variants. The high rate of replication cycle, errors made during the replication and transcription processes, and recombinant strains all contribute to the evolution of the virus. Existing pharmacological interventions focus on targeting the viral cycle, and this has proved futile as the rate of evolution surpasses that of the research being carried out. This is worrying as it means even that the cure is not within reach, and the fatalities are almost 100%. The persistence and spread of HIV infection impact on the society negatively, hence there is need to drive research so as to obtain a cure. '''

work citation Bold text'''

Cohen, M. S., Hellman, N., Levy, J. A., DeCock, K., & Lange, J. (2008). The Spread, Treatment, and Prevention of HIV-1: Evolution of a Global Pandemic. The Journal of Clinical Investigation, 118(4):1244–1254. Retrieved from, http://www.jci.org/articles/view/34706 Cotton et al. (2014). Genotypic and Functional Impact of HIV-1 Adaptation to its Host Population during the North American Epidemic. Retrieved from, http://www.plosgenetics.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pgen.1004295&representation=PDF Gerretti, A. M. (2006) Antiretroviral Resistance in Clinical Practice. London: Mediscript. Retrieved from, http://www.ncbi.nlm.nih.gov/books/NBK2239/ King, D. J. S., & Larsson-sciard, E-L. (2001). Clonal Evolution of CD8+ T-Cell Expansions in HIV-Infected Patients on Long-Term HAART. The Journal of Translational Immunology, 126(2): 280–286. Retrieved from, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1906198/ Little, S.J., et al. (2008). Persistence of Transmitted Drug Resistance among Subjects with Primary Human Immunodeficiency Virus Infection. Journal of Virology, vol. 82 no. 11 5510-5518. Retrieved from, http://jvi.asm.org/content/82/11/5510.full.pdf+html Overbaugh, J., & Morris, L. (2012). The Antibody Response Against HIV-1. National Center for Biotechnology Information. Retrieved from, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253031/ Pingen, M., Nijhuis, M., Bruin, J. A., Boucher, C. A., & Wensing, A. M. (2011). Evolutionary Pathways of Transmitted drug-Resistant HIV-1. Journal of Antimicrobial Chemotherapy. Retrieved from, http://hivdb.stanford.edu/surveillance/refs/Pingen_2011_The%20Journal%20of%20antimicrobial%20chemotherapy.pdf Rambaut, A., Posada, D., Crandall, K. A., & Holmes, E. C. (2004). The Causes and Consequences of HIV Evolution. Nature Reviews: Genetics, (5) 55-61. Van de Vijver, D. A., Wensing, A. M., & Boucher, C. A. B. (2012). The Epidemiology of Transmission of Drug Resistant HIV-1. HIV Sequence Database. Retrieved From, http://www.hiv.lanl.gov/content/sequence/HIV/REVIEWS/2006_7/VAN/van.html

the contribution to the wikipedia article starts here The biological implications of evolution of the HIV virus are the persistence of the infection and introduction of drug-resistant variants ([20]. However, the full picture cannot be painted until what happens biologically is translated to humans. One of the implications of evolution of the evolution of HIV is the costs incurred [21]. Diagnosis of the specific type of HIV variant requires advanced medical testing that is expensive. The medical costs bear down heavily on the family of patients and also on the nation at large. Evolution also results in drug resistant variants. This impacts on the health of patients and affects their quality of life. Drug resistance by the HIV is a consequence arising from its evolution ([22]. This resistance is central to the disease as it impacts on the health status of individuals, their emotional well-being and also on their finances. This is in that a disease with resistance to pharmacological interventions translates to management of the condition rather than curing the diseases that have negative impacts. Highly active antiretroviral therapy (HAART) targets various stages of the viral life cycle is being applied as a managerial intervention [23] The pooling of the virus in cells such as T lymphocytes, follicular dendritic cells, and macrophages has contributed to the failure of the therapy [24] The rapid evolution of drug-resistant strains is due to exchange of resistant mutations in a nonlinear fashion due to high rates of recombinants taking place in the above cell reservoirs. An example of a hypothetical scenario is where a mutation in one strain results in resistance to drug Y and another strain mutates and is resistance to drug Z. The two mutated strains bearing drug resistance can then recombine during replication to give rise to a strain showing double resistance. Hence, evolution leading to drug resistance will have taken place. Inter-host evolution where partners can acquire different strains (sexual transmission) has been used to explain the evolution of drug-resistance and also the existence of various strains within an individual [25] Various studies have been conducted to explore various ways to explain the evolution of drug-resistant HIV virus in an attempt to curb the HIV/AIDS plague.

References:

1. Cohen, M. S., Hellman, N., Levy, J. A., DeCock, K., & Lange, J. (2008). The Spread, Treatment, and Prevention of HIV-1: Evolution of a Global Pandemic. The Journal of Clinical Investigation, 118(4):1244–1254. Retrieved from, http://www.jci.org/articles/view/34706 this article tackles the most up-to-date estimates demonstrate very heterogeneous spread of HIV-1. Also talks about The efficiency of transmission of HIV-1 depends primarily on the concentration of the virus in the infectious host.

2. Cotton et al. (2014). Genotypic and Functional Impact of HIV-1 Adaptation to its Host Population during the North American Epidemic. Retrieved from, http://www.plosgenetics.org/article/fetchObject.action?uri=info%3Adoi%2F10.1371%2Fjournal.pgen.1004295&representation=PDF In this article talks about HLA-restricted immune escape mutations that persist foll owing HIV transmission could gradually spread through the viral population, thereby compromising host antiviral immunity as the epidemic progresses.

3.Gerretti, A. M. (2006) Antiretroviral Resistance in Clinical Practice. London: Mediscript. Retrieved from, http://www.ncbi.nlm.nih.gov/books/NBK2239/ this article talks about the evolution of drug resistance and how to use available diagnostic assays and interpret their results optimally are important aspects of the management of HIV-1-infected patients.

4. King, D. J. S., & Larsson-sciard, E-L. (2001). Clonal Evolution of CD8+ T-Cell Expansions in HIV-Infected Patients on Long-Term HAART. The Journal of Translational Immunology, 126(2): 280–286. Retrieved from, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1906198/ how HIV-1 continually replicates in spite of long-term highly active anti-retroviral therapy (HAART) and therefore, it is conceivable that the low level, persistent viral activity could continue to stimulate the hosts immune system despite remaining below the detection limit of the current assays.

5.Little, S.J., et al. (2008). Persistence of Transmitted Drug Resistance among Subjects with Primary Human Immunodeficiency Virus Infection. Journal of Virology, vol. 82 no. 11 5510-5518. Retrieved from, http://jvi.asm.org/content/82/11/5510.full.pdf+html

talks about how interruption of antiretroviral therapy among individuals with acquired drug resistance, preexisting drug-sensitive virus emerges relatively rapidly.

OCTOBER 1st assingment 1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253031/ 2. This article can be improved by providing specific mechanisms through which viral evolution takes place. It should also factor in the biology of the virus and factors that propagate the evolution of different viruses. Also a clearer definition and differences between intra-host and inter-host 3. Antibodies have the potential to block HIV-1 replication through multiple pathways, and they exert immune pressure on the virus that leads to escape Overbaugh, J., & Morris, L. (2012). The Antibody Response Against HIV-1. National Center for Biotechnology Information. Retrieved from. 4. Overbaugh, J., & Morris, L. (2012). The Antibody Response Against HIV-1. National Center for Biotechnology Information. Retrieved from, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253031/

Zeyad Alsaeed. the Ohio State University