|
|
REVIEW ARTICLE |
|
|
|
| Year : 2008 | Volume
: 29
| Issue : 1 | Page : 1-6 |
| |
HIV: Past, present and future
V Harindra
Department of GU Medicine, St. Mary's Hospital, Milton Road, Portsmouth PO3 6AD, United Kingdom
Correspondence Address:
V Harindra
Department of GU Medicine, St. Mary's Hospital, Milton Road, Portsmouth PO3 6AD
United Kingdom
 Source of Support: None, Conflict of Interest: None  | Check |
 Abstract | | |
The origin of acquired immune deficiency syndrome (AIDS) and human immunodeficiency virus (HIV) has puzzled scientists ever since the illness first came to light in the early 1980s. For over 25 years it has been the subject of fierce debate and the cause of countless arguments. It is now generally accepted that HIV is a descendant of a simian immunodeficiency virus and there are many theories about how this 'zoonosis' originated and how SIV became HIV in humans. Advances in treatment have steadily reduced the morbidity and mortality associated with HIV infection. However, in the low-income, high-prevalence countries, antiretroviral medication has taken a long time to reach the people who actually need it. Access to medication must greatly improve if millions of deaths are to be avoided. HIV is a preventable disease. Unless great progress is made in prevention, the number of people living with HIV will outstrip the resources available for treatment. The search for effective vaccines and microbicides must therefore be one of the very highest priorities. HIV is a global threat. Action needs to be taken to prevent it killing many more millions than those who have already died. This action needs not only to continue, but to be speeded up considerably.
Keywords: Human immunodeficiency virus, prevention
How to cite this article:
Harindra V. HIV: Past, present and future. Indian J Sex Transm Dis 2008;29:1-6 |
| Introduction | |  |
When acquired immune deficiency syndrome (AIDS) first emerged, no one foresaw how the epidemic would spread across the world and how it would change many millions of lives. There was no real idea of what caused it and, consequently, no real idea of how to protect against it. Human immunodeficiency virus (HIV) has devastated families, communities, and whole continents. We have seen the epidemic set back the development of countries by many decades, widen the gulf between rich and poor nations, and push already stigmatized groups closer to the margins of society.
The origin of HIV and AIDS has puzzled scientists ever since the illness first came to light in the early 1980s. For over 25 years it has been the subject of fierce debate and the cause of countless arguments.
The first recognized cases of AIDS occurred in the USA in 1981. A number of gay men in New York and San Francisco suddenly began to develop rare opportunistic infections and cancers that were stubbornly resistant to any treatment. It quickly became obvious that all the men were suffering from a common syndrome. The discovery of HIV was made 2 years later.
HIV is a lentivirus and, like all viruses of this type, it attacks the immune system. Lentiviruses are part of a larger group of viruses known as retroviruses. They have been found in a number of different animals, including cats, sheep, horses, and cattle. However, as far as the origin of HIV is concerned, the most interesting lentivirus is the simian immunodeficiency virus (SIV) that affects monkeys.
Although HIV came to light in the early 80s, there is evidence that HIV infection was prevalent much earlier. The earliest known instances of HIV infection are as follows:
- A plasma sample taken in 1959 from an adult male living in the Democratic Republic of Congo has been found to be positive for HIV.
- HIV has been found in tissue samples from an American teenager who died in St. Louis in 1969.
- HIV has been found in tissue samples from a Norwegian sailor who died around 1976.
A 1998 analysis of the plasma sample from 1959 has suggested that HIV-1 was introduced into humans sometime in the 1940s or the early 1950s, [1] much earlier than previously believed. Other scientists have dated the sample to an even earlier period -perhaps as far back as the end of the 19 th century. In January 2000, the results of a study carried out by Dr Bette Korber of the Los Alamos National Laboratory (which was presented at the 7 th Conference on Retroviruses and Opportunistic Infections) suggested that the first case of HIV-1 infection occurred around 1930 in West Africa.
It is now generally accepted that HIV is a descendant of an SIV because certain strains of SIV bear a very close resemblance to HIV-1 and HIV-2. HIV-1 corresponds to a strain of SIV found in chimpanzees [2],[3] and HIV-2 corresponds to a strain found in the sooty mangabey, which is indigenous to western Africa. [4] Viral transfer between animals and humans, known as zoonosis, is well recognized. There are many theories as to how HIV could have crossed species.
| The 'Hunter' Theory | | |
According to the hunter theory, SIV was transferred to humans when hunters ate the flesh of infected chimps or when the blood of the chimpanzee contaminated cuts or wounds on the body of the hunter. The fact that there were several different early strains of HIV, each with a slightly different genetic makeup, would support this theory; every time the virus was passed from a chimpanzee to a man, a slightly different strain was produced. Wolf et al . were able to show how retroviral transfer from primates to hunters still occurs. [5]
| The Oral Polio Vaccine (OPV) Theory | | |
In the late 1950s, an oral polio vaccine called CHAT was tested on about a million people in the Congo, Ruanda, and Urundi. Kidney cells from local chimps were used to produce this live polio vaccine. In his book, The River, Edward Hooper suggested that the origin of HIV could be traced to the testing of the CHAT oral polio vaccine, which was grown in kidney cells taken from local chimps infected with SIV. This, he claims, would have resulted in the contamination of the vaccine with chimp SIV, leading to a large number of people subsequently becoming infected with HIV-1. However, subsequent analysis of the vaccine in April 2001 showed no trace of either HIV or SIV. [6] A second analysis confirmed that only macaque monkey kidney cells, which cannot be infected with SIV or HIV, were used to make CHAT. [7] The fact that HIV probably existed in humans before the 1950s also suggests that the OPV theory is not tenable as the sole method of transmission.
| The Contaminated Needle Theory | | |
In developing countries, the practice of reusing syringes without adequate sterilization to inject multiple patients could have led to a rapid transfer of viral particles between patients. This would have created a huge potential for the virus to mutate and replicate in each new individual, thereby enhancing the spread of HIV.
| The Colonialism Theory | | |
An American specialist in primate behaviour, Jim Moore, first proposed this theory in 2000. [8] During the late 19 th and early 20 th century, much of Africa, including French Equatorial Africa and the Belgian Congo, were ruled by colonial forces. The labour camps were overcrowded, sanitation was poor, and the physical demands on the inmates were extreme, all of which would have weakened the immune systems of the camp inmates, paving the way for SIV to become HIV. Practices such as the use of unsterile needles to inoculate laborers against diseases such as smallpox and employing prostitutes to keep the workers 'happy,' would have created numerous opportunities for transmission. The fact that these labor camps were set up at around the same time that HIV is first believed to have passed into humans-the early part of the 20 th century-provides support for this theory.
| The Conspiracy Theory | | |
A significant number of African Americans believe HIV was created as part of a biological warfare programme that was designed to wipe out large numbers of black and homosexual people. [9] Some believe that the virus was spread worldwide through the smallpox inoculation programme or, alternatively, to gay men through hepatitis B vaccine trials.
The truth about the origin of HIV will continue to be debated for many more years. However, there is now clear evidence as to how HIV spread to USA. In March 2007, at the 14 th Conference on Retroviruses and Opportunistic Infections in Los Angeles, data was presented showing that the HIV had probably been brought to Haiti from Congo by a single infected person in around 1966. [10] Genetic analysis showed that the virus had spread slowly from person to person on the island before being transported to the US, probably by a single individual, at some point between 1969 and 1972. From this point on, the epidemic grew rapidly, with transmission occurring within and between the US and Haiti and also internationally.
| Twenty-Five Years of HIV/AIDS | | |
1981: (March) At least eight cases of an aggressive form of Kaposi's Sarcoma (KS) occurred amongst young gay men in New York. [11] At about the same time, both in California and New York, a number of cases of a rare lung infection Pneumocystis carinii pneumonia (PCP) was also diagnosed. [12] Early theories regarding the cause of these outbreaks included infection with cytomegalovirus, the use of amyl nitrite or butyl nitrate 'poppers,' and immune overload. [13],[14]
1982: The term acquired immune deficiency syndrome (AIDS) is first used.
1983: (May) Doctors at the Institut Pasteur in France reported that they had isolated a new virus; they named it lymphadenopathy-associated virus or LAV. [15]
1984: (April 23 rd ) Dr Robert Gallo of the National Cancer Institute, USA, isolated the virus and named it HTLV-III.
1985: An HIV antibody test became available.
1986: (May) The International Committee on the Taxonomy of Viruses recommended that the terms LAV and HTLV-III be dropped and a new name, human immunodeficiency virus (HIV), be used. [16]
1987: Zidovuidine (AZT), the first antiretroviral drug, got FDA approval. [17]
1989: ACTG019 showed that AZT could slow progression to AIDS in asymptomatic HIV-positive patients.
1993: The Anglo-French clinical trial Concorde concluded that AZT was not effective in treating in asymptomatic HIV-positive patients. [18]
1994: ACTG 076 showed that AZT reduced mother-to-child HIV transmission by two-thirds. [19]
1995: The Delta trial and the ACTG175 trial showed that combinations of AZT with didanosine (ddI) or zalcitabine (ddC) were more effective than AZT alone in delaying disease progression and prolonging life. The first protease inhibitor, saquinavir, became available.
1996: Introduction of the viral load test.
1997: For the first time, the number of deaths from AIDS dropped substantially across the developed countries.
2003: Fuzeon gained FDA approval. This was the first of a new type of anti-HIV drug that was designed to prevent the entry of HIV into human cells.
2006: Two African trials of male circumcision as an HIV prevention method were halted early for ethical reasons because preliminary analysis showed that they reduced HIV transmission by around 50%.
Since the start of the HIV epidemic, a series of antiretroviral drugs have been developed which have significantly prolonged the lives of HIV-positive people. But there have been associated challenges such as the increase in pill burden, problems with adherence to treatment, drug toxicities, development of resistance, treatment failure, and increase in cost of care.
There are currently five main classes of drugs, operating at different points in the HIV cycle:
- Nucleoside reverse transcriptase inhibitors: Disrupt the copying process by blocking the enzyme reverse transcriptase.
- Non-nucleoside reverse transcriptase inhibitors: These drugs attach themselves to the enzyme, reverse transcriptase, which controls the copying process.
- Protease inhibitors: Acts by interrupting the assembly of the new virus particle.
- Entry inhibitors: Binds to the proteins on the outside of the HIV virus, preventing it from attaching itself to and entering a CD4+ cell.
- Integrase inhibitor: Prevents integration of viral RNA to cellular DNA.
The goal of HIV therapy is to reduce the viral load to undetectable levels (i.e., below 50 copies/ml). This would help to restore immune function, reducing HIV-related morbidity and mortality and thus aid in achieving the ultimate goal of improving quality of life. Currently, over 27 antiretroviral (ARV) agents are available and many more are in development. Until recent times the side effects, both short and long term, have been a concern but the newer agents are addressing these issues. In the Highly active anti retroviral therapy (HAART) era, as the life expectancy of HIV-infected individuals continues to increase, cardiovascular disease, hepatic disease, and malignancy have become important issues among this population. The wide use of ARV has also resulted in the emergence of viral resistance. In order to combat this, newer agents are being developed, with higher genetic barrier and better efficacy against resistant strains.
The key development in HIV care in high-income countries has been the elimination of mother-to-child transmission (MTCT) of HIV. This has been achieved by introducing effective voluntary testing and counseling, enabling access to ARV therapy, instituting safe delivery practices, and by making available safe breast-milk substitutes. Even in resource-limited countries, a reduction in MTCT is seen with limited interventions.
It is very unlikely that HIV and AIDS will ever be eradicated without new scientific developments. For every person who starts treatment with ARV, another six become infected. Unless great progress is made in prevention, the number of people living with HIV will outstrip the resources available for treatment.
Current methods for preventing HIV infection are far from perfect. Education has been proved to be effective and necessary, both for people who are not infected with HIV and for those who are infected. Behavior therapy, condom use, voluntary HIV testing, and treatment of sexually transmitted infections are proven methods of HIV prevention. In theory, if everyone abstained from sex or remained faithful to one partner and always used condoms and nobody injected drugs, then HIV and AIDS might be eradicated. However, in the real world behavior change and condoms alone will not eliminate the virus, they will only help to control its spread. A number of promising HIV prevention approaches are currently available or are in late stage clinical trials.
| Male Circumcision | | |
Since the 1980s, scientists have suspected that male circumcision might reduce the chances of HIV transmission during sex. Circumcised men are less likely to have HIV than uncircumcised men, and countries with higher rates of male circumcision have lower rates of HIV infection. Removal of HIV target cells from the foreskin, keratinization of skin surface, and reduction of Sexually Transmitted infections (STIs) are the key factors through which circumcision exerts its protective effect. [20],[21] We now have conclusive evidence from studies in Africa that male circumcision, if performed safely in a medical environment, brings about a 65% reduction in the risk of a man becoming infected with HIV through heterosexual sex.
| Microbicides | | |
A microbicide is a chemical product applied in the vagina to inactivate HIV. Anal application is also been studied. They act as a physical barrier, maintain vagina flora, and prevent STIs. A number of second-generation microbicide candidates, including tenofovir-containing microbicides, are in the early stages of research. Nine HIV microbicide trials were in progress at the start of February 2007. [22] Three microbicide candidates are undergoing phase III trials to test their effectiveness; these are:
- BufferGel, which maintains acidity in the vagina
- Carraguard, an entry inhibitor based on carrageenan, which is derived from seaweed
- PRO 2000, another entry inhibitor
In August 2006, Family Health International decided to halt a phase III trial of a surfactant called SAVVY after preliminary results showed no evidence of a protective effect. [23] Two phase III trials of an entry inhibitor called cellulose sulphate (also known as Ushercell™) were halted in January 2007 after some sites recorded a higher HIV infection rate among women who used the gel compared to those in the placebo group. It is not yet known why cellulose sulphate was associated with an increased risk of infection; this result was entirely unexpected. [24]
| Cervical Barrier | | |
Cervical barriers such as diaphragms may help protect women from HIV and others STIs. An efficacy trial of the diaphragm for HIV prevention is nearing completion in South Africa and Zimbabwe.
| Herpes Suppression | | |
Genital herpes simplex infection significantly increases the risk of HIV acquisition as well as the risk of transmission to others. [25],[26] Trials are being conducted in Africa and the US to test the effectiveness of suppression of herpes with acyclovir in lowering HIV risk.
| Preexposure Prophylaxis with Antiretrovirals | | |
Efficacy trials of Truvada™ (Tenofovir and Emtricitabine) in preexposure prophylaxis are being conducted in Botswana, Thailand, and Peru. [27] Proof of this concept derives from the use of ARV to prevent MTCT of HIV. A significant disadvantage of this approach could be the development of drug resistance.
| HIV Vaccine | | |
The aim of vaccination is to induce either neutralizing antibody or a T-cell response or both. Although the search for an effective vaccine has been continuing for more than 25 years, it has remained elusive. The genetic diversity of HIV; its ability to infect the cells of the immune system, to spread from cell to cell, and to integrate its genome into the host cell; and viral resistance are the main challenges in producing an effective vaccine. Currently, 30 HIV vaccine candidates are in clinical trials.
There is no 'magic bullet' for HIV prevention. None of the new methods being tested currently is likely to be 100% effective in prevention and all will need to be used in combination with existing approaches. However, even a partially effective vaccine or microbicide could save many millions of lives. Experts have calculated that a vaccine that is 50% effective, given to just 30% of the population, could reduce the number of HIV infections in the developing world by more than half over 15 years. Greater access to existing HIV prevention tools could avert half of the new infections projected to occur over the next decade.
| Future of HIV Care - The Next 10 Years | | |
Including more people in HIV screening in clinics and primary care and other healthcare settings will result in a situation where very few patients infected with HIV will be unaware of their diagnosis. This would help in controlling HIV transmission as well as in identifying HIV infection before advanced immunosuppression has set in.
Increased awareness of HIV status; increase in condom use; increase in use of female-initiated HIV prevention methods, such as the use of microbicides of potency and cervical diaphragm; and increase in male circumcision in high-prevalence countries will all help to reduce sexual transmission of HIV.
Health manpower shortage and inadequate infrastructure will result in limited HIV treatment programmes in resource-limited countries. In spite of this, most of those found to be infected will have access to care. Antiretroviral drugs will be more widely available and treatment will be extremely convenient. Evidence shows that treatment should be initiated at a higher CD4 lymphocyte count than is currently practiced. The availability of cheaper ARV drugs, increase in the choice of drugs, less toxicity, higher genetic barrier, and convenience of treatment would result in all cases being treated. Antiretroviral drugs will also be widely used to prevent HIV transmission.
MTCT will be completely eliminated in high-income countries. Antiretroviral therapy will be continued after delivery, both to treat the mother's disease and to allow safe breastfeeding.
The HIV pandemic remains the most serious infectious disease challenge in public health. AIDS is a preventable disease. Every day over 6800 persons become infected with HIV and over 5700 die from AIDS. Most deaths are the result of inadequate access to HIV prevention and treatment services. [28] People need empowerment to negotiate safe and responsible sexual relationships; gender inequalities must be confronted, and those who choose to have sex need access to condoms. Needle exchange programs should be encouraged, as they have proven to be highly effective at preventing HIV transmission among injecting drug users. The search for effective vaccines and microbicides must be one of the very highest priorities in scientific research.
| References | | |
| 1. | Zhu T, Korber BT, Nahmias AJ, Hooper E, Sharp PM, Ho DD. An African HIV-1 sequence from 1959 and implications for the origin of the epidemic. Nature 1998;391:594-7.  [PUBMED] [FULLTEXT] |
| 2. | Bailes E, Gao F, Bibollet-Ruche F, Courgnaud V, Peeters M, Marx PA, et al . Hybrid origin of SIV in Chimpanzees. Science 2003;300:1713. [PUBMED] [FULLTEXT] |
| 3. | Gao F, Bailes E, Robertson DL, Chen Y, Rodenburg CM, Michael SF, et al . Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature 1999;397:436-44. [PUBMED] [FULLTEXT] |
| 4. | Lemey P, Pybus OG, Wang B, Saksena NK, Salemi M, Vandamme AM. Tracing the origin and history of the HIV-2 epidemic. Proc Natl Acad Sci USA 2003;100:6588-92. [PUBMED] [FULLTEXT] |
| 5. | Wolfe ND, Switzer WM, Carr JK, Bhullar VB, Shanmugam V, Tamoufe U, et al . Naturally acquired simian retrovirus infections in Central African Hunters. Lancet 2004;363:932-7. [PUBMED] [FULLTEXT] |
| 6. | Blancou P, Vartanian JP, Christopherson C, Chenciner N, Basilico C, Kwok S, et al . Polio vaccine samples not linked to AIDS. Nature 2001;410:1045-6. [PUBMED] [FULLTEXT] |
| 7. | Berry N, Davis C, Jenkins A, Wood D, Minor P, Schild G, et al . Vaccine safety: Analysis of oral polio vaccine CHAT stocks. Nature 2001;410:1046-7. [PUBMED] [FULLTEXT] |
| 8. | Chitnis A, Rawls D, Moore J. Origin of HIV type 1 in Colonial French Equatorial Africa? AIDS Res Hum Retroviruses 2000;16:5-8. [PUBMED] [FULLTEXT] |
| 9. | Fears D. Study: Many blacks cite AIDS conspiracy. The Washington Post: 2005. |
| 10. | Carter M. CROI: Haiti is the source of HIV subtype B. Available from: http://www.aidsmap.com. [cited on 2007 Mar 2]. |
| 11. | Hymes KB, Cheung T, Greene JB, Prose NS, Marcus A, Ballard H, et al . Kaposi's sarcoma in homosexual men: A report of eight cases. Lancet 1981;2:598-600. [PUBMED] |
| 12. | Centers for Disease Control (CDC). Kaposi's sarcoma and pneumocystis pneumonia among homosexual men-New York City and California. MMWR Morb Mortal Wkly Rep 1981;30:305-8. [PUBMED] |
| 13. | Goedert JJ, Neuland CY, Wallen WC. Amyl Nitrite may alter T lymphocytes in homosexual men. Lancet 1982;1:412-6. |
| 14. | Gottlieb MS, Schroff R, Schanker HM, Weisman JD, Fan PT, Wolf RA, et al . Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: Evidence of a new acquired cellular immunodeficiency. N Engl J Med 1981;305:1425-31. [PUBMED] |
| 15. | Barre-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, et al . Isolation of a T-Lymphotropic retrovirus from a patient at risk for Acquired Immune Deficiency Syndrome (AIDS)', Science; 1983. |
| 16. | Coffin J, Haase A, Levy JA, Montagnier L, Oroszlan S, Teich N, et al . What to call the AIDS virus? Nature 1986;321:10. [PUBMED] |
| 17. | Approval of AZT. News release, Public Health Service. [cited on 1987 Mar 20]. Available from: http://fda.gov/bbs/topics/NEWS/NEW00217.html. |
| 18. | Aboulker JP, Swart A. Preliminary analysis of the Concorde trial. Lancet 1993;341:889-90. |
| 19. | Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O'Sullivan MJ, et al . Reduction of maternal-infant transmission of Human Immunodeficiency Virus type 1 with zidovudine treatment. N Engl J Med 1994;331:1173-80. [PUBMED] [FULLTEXT] |
| 20. | Soilleux EJ, Coleman N. Expression of DC-DIGN in human foreskin may facilitate sexual transmission of HIV. J Clin Pathol 2004;57:77-8. [PUBMED] [FULLTEXT] |
| 21. | Hussain LA, Lehner T. Comparative investigation of Langerhans' cells and potential receptors for HIV in oral, genitourinary and rectal epithelia. Immunology 1995;85:475-84. [PUBMED] [FULLTEXT] |
| 22. | Candidate Products database, Alliance for Microbicide Development. |
| 23. | Phase 3 trial in Nigeria evaluating the effectiveness of SAVVY Gel in preventing HIV infection in women will close. Family Health International; 28 August 2006. |
| 24. | Polydex pharmaceuticals reports phase III trial of ushercell for HIV prevention halted. Press Release; 2007. |
| 25. | Corey L, Wald A, Celum CL, Quinn TC. The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: A review of two overlapping epidemics. J Acquir Immune Defic Syndr 2004;35:435-45. [PUBMED] [FULLTEXT] |
| 26. | Celum CL, Robinson JN, Cohen MS. Potential effect of HIV type 1 antiretroviral and herpes simplex virus type 2 antiviral therapy on transmission and acquisition of HIV type 1 infection. J Infect Dis 2005;191:S107-14. |
| 27. | Peterson L, Taylor D, Clarke EE, et al . Findings from a double-blind, randomized, placebo-controlled trial of tenofovir disoproxil fumarate (TDF) for prevention of HIV infection in women. Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Ontario, Canada. Abstract THLB0103. |
| 28. | UNAIDS, 2007 Global summary of the AIDS epidemic, December 2007. |
|
|
|
|
|
|
|
|
