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PUBLIC HEALTH: ON THE ORIGIN OF AIDS

The following points are made by Jim Moore (American Scientist 2004 92:540):

1) Shortly after the 1983 discovery of the human immunodeficiency virus (HIV), the pathogen responsible for AIDS, investigators became aware of a strangely similar immune deficiency disease afflicting Asian monkeys (macaques) held in captivity in various US research labs. Soon, virologists identified the culprit: a simian immunodeficiency virus (SIV) that is found naturally in a West African monkey species, the sooty mangabey (Cercocebus atys), but is harmless to that host. This virus, denoted SIVsm, is genetically similar to a weakly contagious form of the AIDS virus that is largely restricted to parts of West Africa, HIV-2, and thus is considered its likely precursor. More recent work has shown that the closest relative of the primary human immunodeficiency virus (HIV-1) is another simian immunodeficiency virus, one carried by chimpanzees (SIVcpz).

2) After comparing the SIVs in chimpanzees and sooty mangabeys with HIV-1 and HIV-2 strains, investigators concluded that there must have been multiple transmission "events" from simians to humans -- at least seven for HIV-2 (some of which are known from only a single person who lives near mangabeys carrying a uniquely similar SIV) and three for HIV-1, the virus now infecting some 40 million people worldwide.

3) How did SIVcpz and SIVsm cross over into humans and become pathogenic? Given the lack of historical references to AIDS-like disease in Africa prior to the mid-20th century, as well as its absence previously in the New World (which imported some 10 million African slaves during the 16th through 19th centuries), that transfer appears to have happened relatively recently --exactly when is a point of considerable debate. And why did two distinct simian viruses with which humans have apparently coexisted for centuries, or even millennia, suddenly pass into humans multiple times within a few decades?

4) The answers to these questions have been slow in coming, despite the considerable efforts of molecular biologists to understand the nature and evolution of primate immunodeficiency viruses. The solution almost certainly will come from one or more of four competing theories.

5) Theory 1: Tainted Polio Vaccine: The first theory is the most controversial. In a 1992 article in the magazine Rolling Stone, journalist Tom Curtis suggested that HIV could have resulted from the use in Africa of an experimental oral polio vaccine (OPV), one contaminated by a then-unknown SIV carried most probably (Curtis supposed) by African green monkeys. Green-monkey kidney cells were widely used as a substrate to grow viruses for research and vaccine production. And one of the first major trials of an experimental oral polio virus vaccine took place from 1957 to 1960 in what are now the Democratic Republic of the Congo, Burundi and Rwanda, seemingly the "hearth" of the global AIDS epidemic.

6) Theory 2: Cut Hunter: The main competing theory posits that SIV is occasionally transmitted to hunters via blood-to-blood contact with an infected primate. According to this view, the virus is usually cleared in its human host, but at least several times during the 20th century it survived and became established as HIV. It is not hard to imagine hunters suffering cuts or being injured by a wounded mangabey or chimpanzee, and some form of natural transfer between species presumably accounts for the widespread distribution of SIVs in African primates. Hence, one has the "cut hunter" or "natural transfer" theory, which is probably the most accepted idea today.

7) Theory 3: Contaminated Needles: The next proposal, a refinement of the cut-hunter theory, comes from Preston A. Marx, a virologist who holds positions at Tulane University and at the Aaron Diamond AIDS Research Center. In 1995 he noted that a big change in medical practice took place in the 1950s with the worldwide introduction of disposable plastic syringes, making guaranteed sterile use possible and dropping the cost of syringe production by almost two orders of magnitude. The result was that the medical use of injections went up astronomically. Because doses can be measured and there is no possibility of patients losing or selling the medicine, injections became a popular way for doctors in the developing world to administer medicines, including vitamins, analgesics and other common drugs.

8) Theory 4: Heart of Darkness: Together with two undergraduate students, the author is responsible for another variant to the cut-hunter theory. The background of this variant theory is that more Africans probably died as a result of colonial practices in French Equatorial Africa and neighboring Belgian Congo between 1880 and the onset of World War II than had been taken from Africa as slaves during the preceding 400 years. During the years prior to World War I, forced labor camps of thousands had poor sanitation, poor diet, and exhausting labor demands. It is hard to imagine better conditions for the establishment of an immune-deficiency disease. To care for the health of the laborers, well-meaning but undersupplied doctors routinely inoculated workers against smallpox and dysentery, and they treated sleeping sickness with serial injections. The problem is that the multiple injections given to arriving gangs of tens or hundreds were administered with only a handful of syringes. The importance of sterile technique was known but not regularly practiced: Transfer of pathogens would have been inevitable. And to appease the laborers, in some of the camps, sex workers were officially encouraged.

References (abridged):

1. Apetrei, C., D. L. Robertson and P. A. Marx. 2004. The history of SIVs and AIDS: Epidemiology, phylogeny and biology of isolates from naturally SIV infected non-human primates (NHP) in Africa. Frontiers in Bioscience 9:225-254

2. Chitnis, A., D. Rawls and J. Moore. 2000. Origin of HIV-1 in colonial French Equatorial Africa? AIDS Research and Human Retroviruses 16:5-8

3. Cohen, J. 2001. Disputed AIDS theory dies its final death. Science 292:615

4. Curtis, T. 1992. The Origin of AIDS. Rolling Stone issue 626 (19 March):54-59

5. Dicko, M., A.-Q. O. Oni, S. Ganivet, S. Kone, L. Pierre and B. Jacquet. 2000. Safety of immunization injections in Africa: Not simply a problem of logistics. Bulletin of the World Health Organization 78:163-169

American Scientist http://www.americanscientist.org

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PUBLIC HEALTH: AIDS EPIDEMIC UPDATE

The following points are made by Robert Steinbrook (New Engl. J. Med. 2004 351:115):

1) In the 24th year of the AIDS pandemic, the number of people living with human immunodeficiency virus (HIV) infection continues to increase steadily.(1) Two thirds of infected persons are in Africa, where the epidemic exploded during the 1990s, and one fifth are in Asia, where the epidemic has been growing rapidly in recent years. As of the end of 2003, an estimated 34.6 million to 42.3 million people throughout the world were living with HIV infection, and more than 20 million had died of AIDS.(2) In that year alone, approximately 4.8 million people became infected with HIV, and approximately 2.9 million died of AIDS.

2) The challenge of the epidemic is that despite the increases in funding, global attention, and political will, more infections and more deaths continue to occur. The Joint United Nations Program on HIV/AIDS (UNAIDS) has updated its global statistics.(2) On the basis of better data than have previously been available from many countries, the estimation of the number of people living with HIV infection as of the end of 2003 has been revised downward -- to a point estimate of 37.8 million from an earlier estimate of about 40 million. The estimated number of deaths due to AIDS has also been revised downward. Nonetheless, the statistics are merely estimates that reflect many assumptions and uncertainties; the situation in particular countries, such as those where accurate data are hardest to obtain, may be better or worse. Of all people between 15 and 49 years of age worldwide, 1.1 percent are now infected with HIV.

3) The global statistics make it clear that the burden remains greatest in Africa, although it is home to only 11 percent of the world's population. On that continent, AIDS has single-handedly reversed gains in life expectancy and reductions in childhood mortality. Botswana, a country of less than 2 million people, has an HIV prevalence rate among adults of 37.3 percent. Of the nine countries that have the most HIV-infected people, eight are in sub-Saharan Africa: South Africa (5.3 million), Nigeria (3.6 million), Zimbabwe (1.8 million), the United Republic of Tanzania (1.6 million), and four others where more than 1 million people are infected (the Democratic Republic of Congo, Ethiopia, Kenya, and Mozambique). An estimated 950,000 people are living with HIV in the United States, 860,000 in the Russian Federation, 840,000 in China, 680,000 in Brazil, 570,000 in Thailand, 400,000 in Sudan, 360,000 in Ukraine, 330,000 in Myanmar, 280,000 in Haiti, and 220,000 in Vietnam. (All these figures are based on a range of high and low estimates, but the estimates for India -- which is one of the countries with the most infections -- and for China are particularly imprecise: estimates range from 2.2 million to 7.6 million for India and from 430,000 to 1.5 million for China.)

4) The primary modes of transmission of HIV have changed little over the years: unprotected intercourse, unprotected penetrative sex between men, injection-drug use, unsafe injections and blood transfusions, and transmission from mother to child during pregnancy, labor and delivery, or breast-feeding. Direct blood contact, such as the sharing of drug-injection equipment, is a particularly efficient means of transmitting the virus. The specific nature of the epidemic, however, continues to vary both among regions and within countries. Globally, "unprotected sexual intercourse between men and women is the predominant mode of transmission of the virus," according to the World Health Report 2004, which the World Health Organization (WHO) released in May 2004.(1) "In sub-Saharan Africa and the Caribbean, women are at least as likely as men to become infected." In India, many infected persons are sex workers and long-distance truck drivers.(3) There are parts of China, India, Thailand, and Vietnam where the epidemic is being driven primarily by injection-drug use. In parts of Cambodia, Myanmar, Thailand, and Vietnam, men who have sex with sex workers are a major factor.(4)

References:

1. The world health report 2004 -- changing history. Geneva: World Health Organization, May 2004

2. 2004 Report on the global AIDS epidemic. Geneva: Joint United Nations Program on HIV/AIDS, July 2004

3. Chase M. Gates Foundation bets it can stem India's AIDS crisis. Wall Street Journal. May 3, 2004:A1

4. LaFraniere S. Mandatory testing bolsters Botswana in combating AIDS. New York Times. June 14, 2004:A1

New Engl. J. Med. http://www.nejm.org

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EPIDEMIOLOGY: ON THE ORIGINS OF HIV

The following points are made by J. Stebbing et al (New Engl. J. Med. 2004 350:1872):

1) The worldwide dissemination of human immunodeficiency virus (HIV) over the past four decades is one of the most catastrophic examples of the emergence, transmission, and propagation of a microbial genome.(1) We now know that the cellular and anatomical sites of HIV replication influence the course of the infection, the ability of antiretroviral therapy to reduce viremia, and the establishment of the viral reservoir. This highly mutable virus inserts its genome into the genomes of crucially important cells of the host and, despite therapy, maintains a reservoir of latent HIV within the body.(2) The virus has a predilection for activated HIV-specific CD4+ T cells, although other cells are also susceptible to the virus. This tropism for particular cells is determined mainly by cellular receptors to which HIV attaches in order to enter cells.

2) The earliest documented case of HIV infection in humans was identified in a sample of serum from Kinshasa (Democratic Republic of Congo) that was stored in 1959.(3) On the basis of the HIV type 1 (HIV-1) sequences obtained from this and numerous other, more recent isolates, it has been estimated that the main (M) group of HIV-1 strains diversified in humans in about 1931 (95 percent confidence interval, 1911 to 1941).(4) Similarly, the most recent common ancestors of HIV type 2 (HIV-2) subtypes have been dated to the 1940s.(5)

3) There is persuasive evidence that HIV-1 came to humans from the chimpanzee (Pan troglodytes), which harbors the related simian immunodeficiency virus (SIVcpz) and lives in central Africa. HIV-2, whose DNA has 40 to 60 percent homology with HIV-1 DNA, originated from the SIVsm of the sooty mangabey (Cercocebus atys) monkeys of coastal West Africa, from Senegal to the Ivory Coast, the endemic epicenter of HIV-2. In these areas, nonhuman primates are kept as pets and butchered for food, suggesting routes of transmission -- monkey and ape to human -- that are in accord with phylogenetic data implying cross-species infection. Estimates of when HIV was introduced into the human population, on the basis of a molecular clock and the distribution of SIV genomic sequences among the chimpanzees of central Africa, render it highly improbable that contaminated poliovirus vaccines were the source of HIV.

4) It is striking that in all known instances of infection of the natural primate host of SIV, neither a disease resembling the acquired immunodeficiency syndrome (AIDS) nor a profound depletion of CD4+ T cells develops, despite the presence of very high viral loads. In contrast, transmission of SIV to unnatural hosts, such as the rhesus macaque (Macaca mulatta) or humans, causes a progressive loss of CD4+ T cells and a high degree of susceptibility to opportunistic infections. The importance of this point cannot be overstated and must surely lie at the core of the pathogenic mechanisms of HIV, which is in effect a zoonotic infection. It is unclear why SIV infection of its natural hosts fails to cause disease, but recent studies have shown that SIV does not elicit the prominent T-cell activation that is seen in chronic HIV infection. Other studies that analyzed polymorphisms in major-histocompatibility-complex genes suggest that present-day animals, which have SIV infection but no disease, may in fact represent the survivors of an ancient retroviral pandemic.

References (abridged):

1. Ho DD, Huang Y. The HIV-1 vaccine race. Cell 2002;110:135-138

2. Siliciano JD, Kajdas J, Finzi D, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med 2003;9:727-728

3. 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;391:594-597

4. Korber B, Muldoon M, Theiler J, et al. Timing the ancestor of the HIV-1 pandemic strains. Science 2000;288:1789-1796

5. 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 U S A 2003;100:6588-6592

New Engl. J. Med. http://www.nejm.org

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