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Introduction

The human immunodeficiency virus (HIV) is a lentivirus that infects our white blood cells compromising the immune system of the host organism it infects (5), resulting in the infected organism becoming susceptible to other viral infections which can cause various neoplasms throughout the body. These viral infections include Epstein-Barr Virus which can lead to the development of Barkitt’s lymphoma, Human Papilloma Virus which can lead to the development of cervical cancer and Kaposi’s sarcoma, additionally there is evidence to suggest that HIV secretes oncogenic proteins such as Tat. In this study we will review how these three aspects of HIV infection have an oncogenic role in cancer development. (1) Figure 1 shows how the rate of HIV infection has increased worldwide from an average of 9 million people in 1990 to an average of 34 million people in 2010, third world countries make up a large proportion of those infected with HIV, at around 70%, this is could be a result of poor education, a lack of suitable sanitation, a poorer economy, which means they are unable to buy contraception and provide sexual health checks for people who are sexually active. (6)(7)(8) (34)

HIV:

HIV is transmitted via the blood during sexual intercourse or sharing needles with a HIV positive individual, the most common form of infection is via sexual intercourse, due to the fact there is no known cure for HIV, clinicians focus mainly on prevention of the disease rather than a cure, HIV develops into acquired immunodeficiency virus (AIDS) when the CD4+ T lymphocyte count falls below 200 cells per mm3 in the blood, this can be measured with a blood test, at this stage of infection the body becomes vulnerable to advanced infections, viral infections and progressive cancers. (11)(12) HIV infects CD4+ T lymphocyte cells, macrophages and dendritic cells which subsequently causes immune system failure and increased vulnerability of the host organism to advantageous infections, due to the hosts immune systems inability to identify and kill invading pathogens. Figure one show CD4+ T cell count has a progressive decline over a 11-year period due to HIV infection, upon initial infection its evident there is no sudden fall in T cell numbers until the third year where we see wide dissemination of the virus that begins seeding lymphoid organs and this allows the virus to spread to multiple organs and structures throughout the body. This ultimately results in death due to the diminished CD4+ T lymphocyte population, at this point HIV would have progressed to AIDS, allowing a range of exotic and advanced diseases to infect the host. (1) Figure two shows us that we have an average count of 1000 CD4+ T Lymphocyte cells/mm3 in our body when initially exposed to HIV, at this stage both our bodies primary and secondary immune response are efficient and capable of eliminating most pathogens, 2 weeks after infection we begin to see an increase in the presence of HIV RNA copies in the plasma, this is seen at its peak within 6 to 9 weeks after initial infection with the HIV, at this stage the level of HIV RNA copies has reached an average of 1 million per ml of plasma, there is wide dissemination of the HIV due to the seeding of the bodies lymphoid organs, once HIV infects the lymphatic system it is able to quickly and easily spread throughout the body infecting our white blood cells, specifically, CD4+ T lymphocyte and macrophages, it’s this increase in HIV RNA copies causing a rapid decline in the CD4+ T lymphocyte count in our body, this decline is typically significant around 3 to 6 weeks after initial infection where we can see the count CD4+ T lymphocyte count drops an average of 48% from 900 cells/mm3 to 490 cells/mm3, historically we observe flu like symptoms as a result of this rapid decline in CD4+ T lymphocyte count. (10) (34) More importantly the body’s ability to identify and destroy malignant cells is compromised at around 8 years when the CD4+ T lymphocyte count falls below 200 cells per mm3, where we see AIDS has developed. (12) (10)

Cancer

Cancer is the term used to describe a disease characterised by random, unregulated cell growth, cancers also known as malignancies typically form tumours that inhibit or press against vital structures in our body which can cause pain, cancer is caused by random gene mutations however external factors can increase a person’s risk of developing cancer such as viral infection, smoking, exposure to ionising radiation, carcinogens and obesity. (13) Although anyone can become infected with cancer as gene mutations are completely random, some cancers, such as skin cancers are more prevalent in Caucasian people due to the lack of melanin in their skin, causing reduced protection from ultraviolet radiation from the sun, additionally individuals who contract lung cancer increase their risk by smoking multiple times a day, this is in contrast to people in many third world countries that may develop cancer due to malnourishment or the fact they are HIV positive, many children in third world countries inherit HIV from their mother, increasing their susceptibility to various cancers from  birth. (2) (14) (16) (35) (36) Figure 3 shows HIV positive patients monitored by the North Texas Healthcare System having a higher chance of anal cancer, Hodgkin lymphoma, liver cancer, Kaposi sarcoma, non – Hodgkin lymphoma and cervical cancer, cancers associated with HIV infection. When analysing the incidence rate of anal cancer with HIV positive individuals we see a 1403% increase from an incidence rate of 7.4 in HIV negative individuals compared to an incidence rate of 111.2 in HIV positive individuals, this is further reinforced by the 572% increase in the frequency of cancer infections from 29 in HIV negative individuals to 195 in HIV positive individuals, anal cancer is common amongst people who perform anal sex and having HPV can increase your chances of infection by 90%, HIV infection also increases your risk of HPV infection. (15)

HIV mechanism of infection

HIV typically infects white blood cells, more specifically CD4+ T lymphocyte cells, the mechanism of how it infects these cells must be understood to accurately evaluate how HIV infection causes various other viral infections, that ultimately result in the development of unique cancers. (3) 1.	HIV attaches to a white blood cell (WBC) releasing its RNA into the target cell. 2.	Reverse transcriptase produced by HIV converts viral RNA into viral DNA which is then inserted into the nucleus of the target cell. 3.	Integrase is an enzyme HIV uses to allow the viral DNA to integrate into the host cell’s DNA. 4.	The infected cell now produces viral DNA and proteins required to produce a new HIV. 5.	The HIV will then bud out of the infected CD4+ T lymphocyte cell taking some of the host cells protein coat with it making it undetectable from the organism’s immune system cells. 6.	HIV protease cuts structural proteins in a newly formed HIV for it to mature into a HIV capable of infecting other cells. The main cells targeted in this process are the immune systems CD4+ T lymphocyte cells, so as HIV replicates, it causes the destruction of these immune system cells, weakening the bodies defence against further HIV infection. The roles of these cells must be properly understood to assess the implications it will have on the rest of the body and why a reduction in these cells increases the bodies chance of developing cancers. (3) (17) (18)

CD4+ T cells

T helper cells play an essential role in the adaptive immune response, this is a part of the immune response that would recognise a virus if it attempted to re-infect an organism, CD4+ T lymphocyte cells are also the main target for HIV, so the number of these cells present is a strong indicator of the progression of HIV infection. (20) CD4+ T cells promote the interaction between CD8+ T cells with dendritic cells in secondary lymphoid tissue, this leads to recruitment of innate and antigen specific effector cells at the site of viral replication. (21) Figure 5 shows how a reduction in CD4+ T lymphocyte count due to HIV infection can increase the chance of Kaposi’s sarcoma and other lymphomas developing within just 4 years of infection, the rate of infection becomes more frequent and more severe because of the sustained decrease in CD4+ T lymphocyte count and many pathologies begin to develop when T-cell numbers drop below 500 cells per mm3. (4) After 10 years we see a CD4+ T lymphocyte count of less than 100 cells per mm3, at this stage AIDS has developed however it’s important to highlight that at each milestone where the CD4+ T lymphocyte count drops, there’s an increased chance of new cancers developing. (19)

Macrophages:

Macrophages are a class of white blood cell involved in the innate immune response and their numbers are significantly reduced over several years due to infection with HIV. Macrophages are involved in tumour cell destruction as well as protection from viral infections so a reduction in macrophage cell count will ultimately result in an ineffective innate immune response and reduced destruction of malignant cells. HIV infects a macrophage through binding of a gp120 and CD4, it can also bind to a second membrane receptor called CCR5, once infected with HIV macrophages can act as a reservoir for the HIV to replicate. (22) Macrophages play a key role in the development of blood vessels and tumour destruction, once activated macrophages become tumoricidal when they interact with liposomes containing immunomodulators, tumoricidal macrophages can recognise and destroy neoplastic cells without harming non-neoplastic cells. (23) Reducing the number of macrophages present in the body will have a direct effect on the bodies capacity to destroy any malignancies. This will result in the rapid and unrestricted growth of malignancies throughout the body, thus increasing the chance of a potentially small tumour progressing into a larger tumour that may restrict the function of a vital organ and have fatal effects on the host organism. (24)

Dendritic cells:

Dendritic cells recognise cancerous cells and target them for destruction, they present these cells to T cells which destroy the malignant cells, this is known as T cell mediated cancer immunity. Conventional dendritic cells type one (cDC1s) are required to produce anti-tumour T cell responses, CDC1 can deliver tumour antigens to draining lymph nodes, they also have the capacity to cross present antigens to active cytotoxic T lymphocytes capable of destroying cancer cells. HIV reduces the volume of dendritic cells available and therefore reduces their ability to identify malignant cells, it also highlights the fact that more normal cells have the chance of developing into cancerous cells as the body has an impaired ability to identify dying cells and mark them for destruction. (25)

Human Papilloma Virus - Kaposi sarcoma

The physiological effects of the Human Papilloma virus (HPV) are enhanced in individuals infected with HIV due to immune system cell destruction, the type of HPV that causes malignancies are the HPV 16 and 18 strains. Infection with HIV increase the frequency of HPV infections, resulting in a higher chance of infection with an oncogenic HPV strain (HPV 16 and 18) and subsequently a higher chance of developing Kaposi’s sarcoma, which infects multiple regions throughout the body including the cervix, vulva, vagina in women and penile and anal infections in men, commonly associated with cancer of the anus and cervix. (26) Figure 7 shows there is a significant increase in HPV infection in HIV positive individuals compared to HIV negative individuals, more specifically we observe a noticeable increase in the frequency of oral oncogenic HPV infection in HIV positive patients, from a 13% average in HIV negative patients to a 48% average in HIV positive patients. Oncogenic HPV is more common in HIV positive individuals with a CD4+ T Lymphocyte count of less than 200 cells per mm3, this is shown in figure 6 where the HPV infection has become malignant and spread down to the patients leg, this is a prime example of an induvial who has received little or no treatment for HIV infection hence the exuberated effects of HPV shown in figure 6. (27)

Non-Hodgkin lymphoma:

Hodgkin’s Lymphoma infects the white blood cells called lymphocytes and the lymph nodes, immune suppression due to HIV infection can drastically reduce the number of immune cells present, thus making the host more susceptible to severe infection. Lymphomas are an interesting class of cancer due to its ability to infect the lymph system and can rapidly spread to a variety of regions all around the body. Figure 8 shows an increase in the number of HIV positive individuals infected with non – Hodgkin lymphoma, highlighting a significant increase in 2001, where 20 HIV positive patience’s where infected with non – Hodgkin lymphoma compared to the 4 HIV negative patients infected with the disease, improved treatment for non – Hodgkin lymphoma compared to HIV means the effects of non – Hodgkin lymphoma are worse in HIV positive individuals, this idea is further reinforced in figure 8 where 67 HIV positive patients were infected with non – Hodgkin lymphoma compared to the 10 HIV negative individuals that has the same disease in 2008. The data in figure 8 only shows HIV positive patients having a higher frequency of infection with non – Hodgkin lymphoma after 2001, this was a result of poor testing and understanding about HIV, this could also be because as more people became infected with HIV they went to the hospital and found they developed opportunistic infections as result of unknowingly living with HIV for a number of years, reducing their CD4+ T lymphocyte count to less than 250 cells per mm3, meaning they’d be more susceptible to infection with non – Hodgkin lymphoma and other advanced diseases due to HIV progressing into AIDS. (29)

Pre-cancerous cervical changes and invasive cervical cancer

Infection with HIV increases your chance of developing cervical cancer, it also causes increases risk of HPV infection which further increases your risk of developing cervical cancer. Worldwide, we see countries with a high proportion of people who are HIV positive and have cervical cancer however we see these effects enhanced in patients living in certain third world countries where treatment for HIV and HIV prevention or detection is unsatisfactory. Figure 9 shows more than 1 million people are HIV positive in America, India and many east African countries when compared with the data shown in figure 10, which shows that the mortality rate for people in America living with cervical cancer is much lower compared to India and various east African countries, we see mortality rates of more than 17.5% in India, South America and Africa, in comparison to a mortality rate of 5.8% to 9.8% seen in America additionally both figure 9 and 10 shows a correlation of countries with a large population of HIV positive people and having a high mortality rate of people infected with cervical cancer, countries such as Brazil, South Africa, Mozambique, Tanzania, Kenya and India all have more than 1 million people living with HIV and a mortality rate of more than 17.5%, compared to countries such as Australia where 10 to 50 thousand people are HIV positive and have a mortality rate of less than 2.5% due to cervical cancer infection, therefore we can say there is a strong correlation between countries having a large HIV positive population with little treatment and high mortality rates due to cervical cancer infection. (30) (31) (32) (34)

HIV proteins that cause cancer

The HIV-1 tat protein is an 86-amino acid chain which is encoded by two exons that can modulate the expression of a range of cellular genes and functions within cells. The tumour cells derived from patients with Kaposi Sarcoma (KS) and AIDs proliferate and differentiate in response to the tat protein produced by HIV-1 infected individuals, the progenitors of the KS cells are normal vascular cells which acquire a spindle structure to respond to the mitogenic effect of the HIV-1 protein tat, after it has been cultured with inflammatory cytokines. Tat promotes the adhesion of KS cells and normal vascular cells, this is induced by the exposure of these cells to inflammatory cytokines. (33)

Other risk factors for cancer other than HIV

There multiple risk factors for developing cancer, these include aging, smoking, radiation exposure, exposure to chemicals, certain hormones, alcohol abuse, poor nutrition and being overweight, can all cause a higher risk of developing cancer. Although each factor has a different mechanism to that of HIV it’s important to understand that the causes of cancer aren’t always clear cut. Infections make up an average 7% of all external sources that increase the chance of cancer development however due to better control and regulation over HIV many other factors now contribute to the development of various malignancies in a HIV positive individual. (35) (36) Summary:

In conclusion, HIV has a direct oncogenic effect on the human body, firstly by weakening our immune system, reducing the body’s ability to clear malignant cells which increases the frequency of unmodulated tumour development due to reduced tumour suppression and identification by our body’s immune system. HIV also has an indirect oncogenic effect by increasing the bodies susceptibility to other cancer causing viral infections such a HPV. The secretion of oncogenic proteins such as HIV-1 tat promotes the growth and differentiation of tumour cells in vivo and in vitro. HIV weakens our immune system, lowering our CD4+ T lymphocyte count. Improved treatment and management of HIV means many people are living longer which increases the chance of cancer being caused by other factors rather than viral infection however the body’s ability to deal with any new potentially malignant mutations is restricted due to HIV infection and many people living in less developed countries where access to medicine isn’t readily available are dying due to the effects of HIV associated cancers, which makes HIV infection the overriding cause of more frequent and advanced cancer infections, the data in this study shows there is a strong correlation between people being infected with HIV and having cancer, infection with HIV can cause cancer or provide an excellent environment for viruses that stimulate the maturation of cancer cells in the body to grow, furthermore we have analysed data from developed and developing countries in different parts of the world, the data shows that more HIV positive patients develop some form of cancer in their lifetime compared to HIV negative patients.

Reference list:

1.	Sam S. (2016). About HIV. Available: https://www.hiv-monitoring.nl/english/patients-and-public/about-hiv/. Last accessed 01 November 2017. 2.	K L Grogg. (2007). Hiv infection and lymphoma. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2095580/. Last accessed 1st November 2017. 3.	Edward R. Cachay, MD, MAS, Professor of Clinical Medicine, Department of Medicine and Division of Infectious Diseases–Owen Clinic, University of California, San Diego. (2015). Human Immunodeficiency Virus (HIV) Infection. Available: http://www.msdmanuals.com/en-gb/home/infections/human-immunodeficiency-virus-hiv-infection/human-immunodeficiency-virus-hiv-infection. Last accessed 1st November 2017. 4.	Greta Hughson. (2017). Factsheet CD4 cell counts. Available: http://www.msdmanuals.com/en-gb/home/infections/human-immunodeficiency-virus-hiv-infection/human-immunodeficiency-virus-hiv-infectionhttps://www.aidsmap.com/CD4-cell-counts/page/1044596/. Last accessed 1st November 2017.

5.	Hannah T. (2015). What are HIV and AIDS? Available: http://www.tht.org.uk/sexual-health/about-hiv/what-are-hiv-and-aids_qm_. Last accessed 20th November 2017.

6.	Farid D. (2016). HIV. Available: https://www.fpa.org.uk/sexually-transmitted-infections-stis-help/hiv. Last accessed 20th November 2017. http://www.rtltuition.com/

7.	Abi T. (2017). HIV AND AIDS IN EAST AND SOUTHERN AFRICA REGIONAL OVERVIEW. Available: https://www.avert.org/professionals/hiv-around-world/sub-saharan-africa/overview. Last accessed 20th November 2017

8.	K Daniels. (2009). WHO/UNAIDS/UN The Millennium Development Goals Report. Available: http://www.who.int/hiv/data/global_data/en/. Last accessed 20th November 2017.

9.	Ileke I. (2015). nfection with HIV-1 is associated with a progressive decrease of the CD4+ T cell count and an increase in viral load.Available: http://www.nairaland.com/646183/300000-infected-hiv-aids-akwa. Last accessed 20th November 2017.

10.	Henner F. (2015). Why Does HIV Cause AIDS? Available: https://smhs.gwu.edu/timetoendhiv/hiv-aids/why-hiv-causes-aids. Last accessed 12th November 2017.

11.	Smith W. (2015). CD4 count (or T-cell count). Available: https://www.hiv.va.gov/patient/diagnosis/labs-CD4-count.asp. Last accessed 5th November 2017.

12.	Taylor D. (2015). How CD4 Counts Help Treat HIV and AIDS. Available: https://www.webmd.com/hiv-aids/cd4-count-what-does-it-mean#1. Last accessed 5th November 2017.

13.	Grey K. (2016). Cancer. Available: https://www.nhs.uk/conditions/cancer/. Last accessed 1st November 2017.

14.	Hamilton C. (2016). What is cancer? Available: http://www.cancerresearchuk.org/about-cancer/what-is-cancer. Last accessed 1st November 2017.

15.	Bedimo, Roger J MD, MS, FACP; McGinnis, Kathleen A MS; Dunlap, Melinda MD; Rodriguez-Barradas, Maria C MD; Justice, Amy C MD, PhD From the *Department of Medicine, Veterans Affairs North Texas Health. (2009). Incidence of Non-AIDS-Defining Malignancies Higher in HIV-Infected Versus Noninfected Patients in the HAART Era: Impact of Immunosuppression. JAIDS Journal of Acquired Immune Deficiency Syndromes. 5 (2), p10-22.

16.	Michael J. Silverberg, PhD, MPH (*); Bryan Lau, PhD, MHS (*); Chad J. Achenbach, MD, MPH; Yuezhou Jing, MS; Keri N. Althoff, PhD, MPH; Gypsyamber D'Souza, PhD; Eric A. Engels, MD, MPH; Nancy A. Hessol. (2010). Cumulative Incidence of Cancer Among Persons with HIV in North America: A Cohort Study. Available: http://annals.org/aim/article-abstract/2450214/cumulative-incidence-cancer-among-persons-hiv-north-america-cohort-study. Last accessed 20th November 2017.

17.	Davis L. (2014). HIV Tutorial. Available: https://library.med.utah.edu/WebPath/TUTORIAL/AIDS/HIV.html. Last accessed 20th November 2017.

18.	Coffin JM, Hughes SH, Varmus HE, editors. Cold Spring Harbor. (1997). Immunopathogenic Mechanisms of HIV Infection. Available: https://www.ncbi.nlm.nih.gov/books/NBK19451/. Last accessed 20th November 2017.

19.	Robers J. (2016). Human immunodeficiency virus (HIV) facts.Available: http://www.hivaidsclinic.co.in/content.php?id=43. Last accessed 20th November 2017.

20.	Janeway CA Jr, Travers P, (2001). T Cell-Mediated Immunity.Available: https://www.ncbi.nlm.nih.gov/books/NBK10762/. Last accessed 20th November 2017.

21.	Hunter J. (2013). Beginners Guide to T cells. Available: http://www.tcells.org/beginners/tcells/. Last accessed 20th November 2017.

22.	Saldana J. (2016). Macrophages. Available: https://www.immunology.org/public-information/bitesized-immunology/cells/macrophages. Last accessed 20th November 2017.

23.	Mosser D. (2010). Macrophages: The 'defense' cells that help throughout the body. Available: https://www.sciencedaily.com/releases/2010/08/100826141232.htm. Last accessed 12th November 2017.

24.	Whitworth PW1, Pak CC, Esgro J, Kleinerman ES, Fidler IJ. (1990). Macrophages and cancer. Cancer Metastasis Rev. 4 (4), p319-351.

25.	Roghanian A. (2015). Dendritic Cells. Available: https://www.immunology.org/public-information/bitesized-immunology/cells/dendritic-cells. Last accessed 12th November 2017.

26.	Huang YQ1, Li JJ, Rush MG, Poiesz BJ, Nicolaides A, Jacobson M, Zhang WG, Coutavas E, Abbott MA, Friedman-Kien AE.. (1992). HPV-16-related DNA sequences in Kaposi's sarcoma. Pubmed. 4 (6), p515-518.

27.	Daniel C. Beachler, Kathleen M. Weber, Joseph B. Margolick, Howard D. Strickler, Ross D. Cranston, Robert D. Burk, Dorothy J. Wiley, Howard Minkoff, Susheel Reddy, Emily E. Stammer, Maura L. Gillison. (2012). Risk Factors for Oral HPV Infection among a High Prevalence Population of HIV-Positive and At-Risk HIV-Negative Adults. Cancer Epidemiology, Biomarkers & Prevention. 21 (1), p22-34.

28.	Craver D. (2012). Dom in South Africa. Available: http://domcraver.blogspot.co.uk/2012/12/. Last accessed 20th November 2017.

29.	Moosa Patel (2012). Hodgkin’s Lymphoma and Human Immunodeficiency Virus Infection, Immunodeficiency, Prof. Krassimir Metodiev (Ed.), InTech, DOI: 10.5772/51671. Available from: https://www.intechopen.com/books/immunodeficiency/hodgkin-s-lymphoma-and-human-immunodeficiency-virus-infection

30.	Newton H. (2008). A global view of HIV infection in 2007. Available: http://www.who.int/hiv/facts/hiv2007/en/. Last accessed 20th November 2017.

31.	Reffery S. (2015). n 2011 34 million people were living with HIV and AIDS.. Available: https://sites.google.com/a/students.shrewsbury.k12.ma.us/the-case-for-hiv-aids/. Last accessed 20th November 2017.

32.	Johnson I. (2017). Estimated Cervical Cancer Mortality Worldwide in 2012. Available: http://globocan.iarc.fr/old/FactSheets/cancers/cervix-new.asp. Last accessed 20th November 2017

33.	Alan D. Frankel, John A. T. Young. (1998). HIV-1: Fifteen Proteins and an RNA.Available: http://www3.uah.es/farmamol/Public/AnnReviews/PDF/Biochemistry/HIV1.pdf. Last accessed 20th November 2017.

34.	Niccols C. (2016). Many of the most common cancers are attributable to infection. Available: http://canceratlas.cancer.org/risk-factors/infection/. Last accessed 20th November 2017.

35.	Jakes D. (2016). Cancer Risk Factors. Available: https://www.medicinenet.com/cancer_causes/article.htm. Last accessed 20th November 2017.

36.	Jones R. (2015). Cancer. Available: https://www.mayoclinic.org/symptoms-causes/syc-20370588. Last accessed 20th November 2017.