Introduction
Figure one: A graph produced by the WHO showing the worldwide population living with HIV has increases from 9 million to 34 million on average over a 20-year period, this is a 378% increase over a 20-year period, showing that understanding how HIV works is important to determining how it can induce various cancers, as it effects a wide range of people throughout the world in various geographical locations. (8)
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)
Figure 2: The graph produced by George Washington school of medicine and health sciences, showing how the amount of CD4+ T lymphocytes decreases over time due to HIV progression, with a significant decrease after 3 weeks post infection. (9)(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)
Figure 3: A graph showing the frequency and incidence rate for the amount of veterans observed by the North Texas Healthcare System where found to be HIV positive and HIV negative infected with cancer over a 5 year period, although there are multiple factors that cause cancer, it’s evident given the data collected from this study that HIV negative patients have a much lower frequency and incidence rate of developing cervical cancer in comparison with those who are HIV positive, it’s also evident that people who are HIV positive have a much higher chance of developing Hodgkin lymphoma and Kaposi sarcoma, both cancers are caused by viruses known to be more prevalent in HIV positive individuals. (15) (16)
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)
Figure 4: An illustration showing how HIV infects an immune system cell and then replicates itself using the replication mechanism of the host cell, HIV inserts its viral RNA into the host cell, and manipulates its DNA replication mechanism to replicate its own viral DNA. This illustration highlights the docking, fusion and receptors involved when a cell encounters a HIV. (3)(18)
CD4+ T cells
Figure 5: A graph from the HIV and AIDS clinic study, showing how a reduction in CD4+ T Lymphocyte count can increase the bodies susceptibility to various pathologies including a range of cancers able to effect multiple organ systems throughout the body. At 0 to 3 years after initial infection we can see the body has a sustained decrease in its CD4+ T lymphocyte count, with it falling from 600 to 400 over an average 4-year period, Kaposi sarcoma, and mycobacterium tuberculosis are two commonly seen infections in some individuals at this stage of infection. (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)
Figure 6: A picture taken by a junior doctor treating a patient, showing extensive oncogenic HPV infection of a 38-year-old, HIV positive man from a rural village in south Africa who was born with HIV, due to his lack of treatment the infection has spread from his genital region to his leg and developed into Kaposi sarcoma making him unable to walk properly. (28)
Figure 7: A graph showing data from a study conducted within the multicentre AIDS cohort study and women interagency HIV study, displaying how the chance of contracting any form of Human Papilloma Virus increase as your CD4+ T lymphocyte count decreases and is significantly higher in HIV positive patients, the chance of contracting HPV increases from 25% in HIV negative patients to 59% in HIV positive patients with a CD4+ T lymphocyte count of less than 200 cells per mm3. (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)
Figure 8: A graph showing HIV positive and HIV negative patients with non-Hodgkin’s Lymphoma seen at Chris Hani Baragwanath Academic Hospital in South Africa. (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)
Figure 9: A world map created by WHO, showing an average distribution of HIV positive people in various countries throughout the world, it shows that the Asian, African and North American continents make up a large proportion of the worlds HIV positive population. (30) (31) (32) (34)
Figure 10: A world map created by WHO showing the mortality rates of people infected with cervical cancer, we see the highest mortality rates of more than 17.5 % in the African, South American and Asian continents, other continents such as North America and Europe have very low mortality rates of 2.4 to 5.8% in comparison, due to the better medical treatment available in these countries. (32)
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.
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