POSITIVELY AWARE JANUARY/FEBRUARY 2011
Point of Origin
The discovery and spread of HIV
by Alicia M. Prater, PhD
Human retroviruses were thought to be non-existent prior to the discoveries of two human T-cell leukemia viruses (HTLVs) in the late 1970s. When the mysterious syndrome of chronic immunodeficiency spreading among gay men (and later intravenous drug users and hemophiliacs) was first recognized in 1981, researchers found a link with the new retroviruses—CD4 T-cell depletion.
As explained by Drs. Robert Gallo and Luc Montagnier in their December 2003 retrospective in the New England Journal of Medicine, the human retroviruses were clear candidates as the cause of the disease, but between 1982 and 1984 HTLV was ruled out as the causative agent. Instead, the researchers discovered yet another human retrovirus—HIV.
With the new field of human retrovirus study in the early 1980s, researchers were poised to deal with AIDS and to discover HIV, but how long did it go unrecognized in the human population, and where did the virus come from?
Lentiviruses, the family to which HIV belongs, have a long history of infecting several animal species, including cats (feline immunodeficiency virus, or FIV), horses (equine infectious anemia virus, or EIAV), and monkeys (simian immunodeficiency virus, or SIV). Several primate species in Africa, including chimpanzees and African green monkeys, have asymptomatic infections with SIV, similar to long-term non-progressor HIV-positive humans (elite controllers). In contrast, when some species that are not naturally infected, such as macaques, are exposed to the virus, they develop simian AIDS. Silvestri et al. reviewed the mechanisms underlying this difference in The Journal of Clinical Investigation in 2007. The differences appear to stem from variations in the CD4 co-receptors on T-cells, a mechanism now understood to contribute to differentiating the infectivity and course of HIV in humans.
Despite the speculation of when and where the first AIDS case appeared, the
virus had clearly become pandemic by the time the disease was recognized.
The first report of AIDS in the U.S. was published by the CDC in June 1981.
Because of this natural prevalence of the virus among monkeys, bushmeat in central Africa has a high rate of SIV infection, putting hunters and butchers in that region of the world at risk for zoonotic infections (diseases that normally exist in animals but can infect humans). Reporting in The Lancet in 2004, Wolfe et al. showed that simian viruses are capable of being readily transmitted to humans. Exposure to contaminated blood and meat is generally accepted as being the route by which HIV made its way into the human population.
HIV strains are genetically different from classical SIV strains due to the presence of an extra regulatory gene, which slightly differs among the two human strains due to crossover. Phylogenetic analyses of naturally occurring lentiviruses have identified recombinant lineages of HIV and SIV in central Africa. The years of genetic studies have shown that primates are the ancestral source of and reservoir for both HIV-1, the most prevalent strain worldwide, and HIV-2, a less common strain mostly isolated to western Africa. The HIV-1 species jump is thought to have occurred at least four times, allowing for the establishment of endemic human infections of different HIV-1 groups, similar to what is seen with influenza viruses that cross among birds, swine, and humans.
The virus begins to diversify once it has a human host, increasing genetic variability as it spreads. Multiple subgroups of the virus have developed, some more infectious and virulent than others, with HIV-1 group M (major group, as opposed to O, or outlier, and N, or non-M/non-O) gaining strength as a pandemic strain. As the birthplace of HIV, Africa still bears the brunt of AIDS globally—with more than three-fifths of all HIV infections occurring in the World Health Organization’s (WHO) African Region (as of the 2007 WHO Epidemiological Surveillance Report).
The ancestral sources of SIVcpz/HIV-1 and SIVmac/HIV-2 are arboreal guenons and sooty mangabey monkeys, respectively, according to a review in Clinical Microbiology Reviews in 2006. The National Institutes of Health (NIH) HIV sequence database suggests that HIV-1 M is the result of a single transmission event from chimpanzees, with the subtypes resulting from divergence in humans. HIV-1 O is thought to have been transmitted to humans from wild gorillas. A new group, P, was proposed in 2009 to describe a rare strain in Cameroon related to SIVgor. Similarly, HIV-2 is growing with new nomenclature for its own groups (A, B, C, F, G), each representing a unique transmission event between primates and humans.
The first transmission of the immunodeficiency virus from primate to human occurred prior to 1931, as reported in separate studies in Science in 2000 and 2006. The appearance of the human virus is dated to approximately that time (margin of error 15 years) based on HIV-1 reservoirs of specific SIV strains in chimpanzees. The virus then spread and mutated among the western and central African populations. A report in Nature in 1998 indicated the presence of HIV in a blood plasma sample obtained from an African in 1959 that resembled two subtypes of HIV-1 group M. Another report in Nature, in 2008, identified HIV in a tissue sample taken from a woman from the Belgian Congo in 1960, supporting measurable human infection with HIV by that time.
Other reports indicate that some individuals outside of Africa were infected with HIV-1, and possibly died from AIDS, around that same time, decades earlier than the pandemic spread of HIV to the United States. In 1997, the journal Virology published an analysis of blood from a Norwegian family that died in the mid-1970s after an AIDS-like illness. They were found to have been infected with HIV-1 group O prior to 1970.
According to a genetic analysis published in 2007 in the Proceedings of the National Academy of Sciences (PNAS) by the Department of Ecology and Evolutionary Biology at the University of Arizona and researchers at the University of Miami, the first epidemic of HIV outside of Africa started in the Caribbean in the 1960s. In 1979, the Miami medical community started reporting a mysterious illness in some Haitian immigrants. The researchers used stored blood samples from these patients and blood samples from early AIDS patients to trace the lineage of HIV in this immigrant population. The PNAS study found that HIV likely made its way to Haiti from Africa sometime around 1966, and then to the Unites States in approximately 1969, most likely in a single patient. HIV was circulating in the United States for at least a decade before AIDS was recognized.
Despite the speculation of when and where the first AIDS case appeared, the virus had clearly become pandemic by the time the disease was recognized. The first report in the United States of what was later called AIDS was published by the U.S. Centers for Disease Control and Prevention (CDC) in June 1981. As reviewed by the agency in June 2001, the Morbidity and Mortality Weekly Report from that time reviewed cases of Pneumocystis carinii pneumonia in healthy young men in Los Angeles, citing their cause as “cellular-immune dysfunction related to a common exposure,” which prompted additional reports from other major American cities, including New York and San Francisco. Eighteen months later, the CDC had a list of risk factors for the immune dysfunction, which by that point had been termed AIDS. The discovery of HIV was still not clear when the initial recommendations for preventing infection were issued in 1983.
The discovery of the virus known as HIV has been credited to the United States and France. In 2008, the Nobel committee decided that the French group consisting of Luc Montagnier and Francoise Barre-Sinoussi were the first to identify the new pathogen and awarded them the 2008 Nobel Prize for Physiology or Medicine. However, as explained by Richard Knox for NPR (National Public Radio) in 2008, many felt that American researcher Robert Gallo deserved to share in the prize. According to Gallo and Montagnier’s 2003 retrospective, Montagnier’s lab at the Pasteur Institute was the first to obtain a clear-cut isolate of the human retrovirus that causes AIDS. Gallo’s lab at the National Institutes of Health in Bethesda, Maryland, built on this 1983 discovery, finally unraveling the cause and effect in the development of the immune deficiency after infection. Gallo is the one credited with proving that HIV is the etiological agent underlying AIDS. By 1984, the work from these two laboratories finally illuminated the cause behind the tens of thousands of cases of AIDS being diagnosed in the United States at that time.
In 1985, this work led to a blood test for the presence of HIV, which was made available to blood transfusion centers, minimizing its transmission to hemophiliacs and surgical and trauma patients. The 1992 International Conference on AIDS estimated that 5% of hemophiliacs in the United States were HIV-positive due to blood transfusions or clotting products they received between 1978 and 1985.
The first FDA approved treatment for HIV infection and AIDS was Retrovir (AZT, zidovudine) in March 1987. That same year, a more specific blood test for HIV antibodies was approved and the first vaccine candidate tested. Almost 25 years later, a viable vaccine has yet to be found.
Many AIDS patients could not tolerate the antiretroviral therapy, so the FDA stepped up pre-approval procedures for drugs to treat the opportunistic infections, such as trimetrexate for pneumocystis pneumonia in 1988. Another problem with antiretroviral therapy was resistance. HIV has a high rate of mutation when it replicates. Drug cocktails were necessary to keep up with changes in the virus and prevent escalating infection. The mixture of three or more antiretroviral drugs is now known as HAART (highly active antiretroviral therapy), which was introduced as a standard regimen in 1996. However, the regimen needs constant medical surveillance for resistance, and Stanford University maintains a public HIV Drug Resistance Database to aid in the surveillance and treatment of infection.
In the 40 years that followed the arrival of the virus in the Caribbean, HIV-1 group M subtype B became the predominant strain in that region of the world and North America. HIV-1 M is divided into various clades, or subtypes, currently denoted by the letters A-K. As new strains are discovered, a new letter is used. Each strain has some genetic variability from the others, representing distinct lineages of HIV-1 M. However, retroviruses are capable of combining with genetically similar subtypes when present in the same host, resulting in recombinant forms. Circulating recombinant forms (CRFs) of HIV have been described since at least 1993, adding to the variability and survivability of the virus in the human population. CRFs have been identified in Asia, Africa, Russia, the Mediterranean, South America, Spain, Saudi Arabia, and Cuba according to the Los Alamos/NIH database of HIV sequences. The first HIV-2 CRF was identified last year.
New transmission events, mutation, and recombination among circulating strains are increasing the complexity of treating HIV. Over the last nearly three decades, research has traced the ancestry of the many HIV strains, finding more extensive and continuous spread than previously thought.
This is the first in a special three-part series sponsored by Abbott Molecular.
Alicia Prater has a PhD in Experimental Pathology, and has taught graduate level pathology, including infectious diseases and HIV/AIDS.
Special thanks to Michael Worobey for reviewing this article.
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