Download Article PDF/SlidesFor those lucky enough to be in attendance, the keynote lecture delivered at the 6th Conference on Retroviruses and Opportunistic Infections (CROI) at the end of January 1999 was nothing short of a jaw-dropping experience. Dr. Beatrice Hahn of the University of Alabama at Birmingham presented the first concrete evidence of the primate origin of HIV-1, the much more prevalent of the HIV types responsible for the AIDS pandemic. The official report of her team’s findings, published in a February 1999 issue of Science, was a no less captivating example of seminal scientific research (Gao, 1999).
Since 1999, Dr. Hahn's group has been working tirelessly in the laboratory and in the chimpanzee communities of sub-Saharan Africa to illuminate the pathways leading to the emergence of HIV-1, the adaptive changes that followed, and the mechanisms underlying its pathogenicity in humans. The genetic similarities between chimpanzees and humans-they share more than 98% sequence identity across their genomes (Watanabe, 2004)-and the newly demonstrated relationship between HIV and SIV may be useful to researchers searching for key differences in virus-host interactions that may explain why and how HIV causes immune deficiency in humans, while SIV is nonpathogenic to its natural host. It is this research that continues to guide current studies evaluating the susceptibility of humans to zoonoses such as AIDS and may guide the development of new treatments and vaccines.
| The Origin of HIV and SIV | Top of page |
There are two known genetically distinct AIDS viruses: human immunodeficiency virus-1 (HIV-1) and human immunodeficiency virus-2 (HIV-2). HIV-1 is divided into three major clades, groups M, N and O; group M is the clade most widely distributed and associated with the majority of disease globally. Both HIV-1 and HIV-2 are of primate origin. The origin of HIV-2 has been established to be the sooty mangabey (Cercocebus atys), an Old World monkey of Guinea Bissau, Gabon, and Cameroon (Hirsch, 1989; Gao, 1992). The origin of HIV-1 is the central common subspecies of chimpanzee (see Figure 1).
Figure 1.Pan troglodytes: The Primate Source of HIV-1
Both HIV-1 and HIV-2 are of primate origin. The origin of HIV-2 has been established to be the sooty mangabey, an Old World monkey of Guinea Bissau, Gabon, and Cameroon. The origin of HIV-1 is the central subspecies of chimpanzee, pictured here.
Photo courtesy of Karl Ammann. Published with permission of Goldray Consulting Group.
"The reason we know this is because these primates harbor viruses that are genetically very closely related to the human viruses," Dr. Hahn said. "What most people don't know is that there are at least 38 other primate species in sub-Saharan Africa, each harboring their own version of what is called simian immunodeficiency virus, or SIV." Chimpanzees acquired SIV from two smaller primates, the greater spot-nosed monkey (Cercopithecus petaurista) and the red-capped mangabey (Cercocebus torquatus). "The chimpanzee virus is a recombinant of ancestors of these other viruses," she added. "Chimpanzees acquired their infection like humans did, by hunting and consuming naturally infected primates."
Dr. Hahn pointed out the term SIV is a misnomer. "We called it SIV because it's so closely related to HIV, which we discovered first," she said. "However, SIV is not an immunodeficiency virus-it does not cause immune deficiency, or AIDS, in its natural host."
| Testing in the Wild | Top of page |
All of these factors suggested that collecting blood samples from chimpanzees was not feasible. In turn, Dr. Hahn’s group developed methods to identify SIVcpz-specific RNA and antibodies in chimpanzee urine samples and fecal matter collected from the forest. “We’re lucky because antibodies are present in both feces and urine,” Dr. Hahn explained.
In a pilot study of SIVcpz-infected captive chimpanzees, antibodies were found—using commercially available Western blot—in 63% of fecal and 100% of urine samples, suggesting that this approach was of sufficient sensitivity and specificity for field testing (Santiago, 2002; Santiago, 2003). SIV-RNA was also documented in 56% of fecal samples. While the sensitivity did not approach that of antibody testing, all of the SIVcpz-infected chimpanzees studied had at least one PCR-positive fecal sample, suggesting that SIV-RNA analysis could be used for molecular confirmation of infection, especially if multiple samples from the same individuals could be collected and tested.
| Prevalence of SIVcpz in P. t. troglodytes | Top of page |
Until recently, noninvasive testing of SIVcpz infection in wild-living chimpanzees from west central Africa—home to a sizeable population of P. t. troglodytes—has been limited, primarily because of a lack of established field sites with appropriate research infrastructure. Over the past few years, however, Dr. Hahn’s group, working with investigators from the University of Montpellier, have collected and analyzed samples collected from wild chimpanzees at different field sites in Cameroon.
They have confirmed the presence of P. t. vellerosus and P. t. troglodytes, using mitochondrial DNA analysis, and have used Western blot analysis to identify SIVcpz antibody-positive fecal samples. PCR analysis has also been performed to analyze fecal RNA, and microsatellite analysis has been completed for individual identification and sample enumeration. This has allowed for SIVcpz prevalence determinations at different sites and phylogenetic characterization of newly infected SIVcpz strains. However, these data have not yet been published in a peer-reviewed scientific journal and, as a result, cannot yet be reported in the pages of The PRN Notebook.
What can be discussed here is that, over the past decade, more than 100 wild-born P. t. troglodytes and 50 P. t. vellerosus chimpanzees have been screened in wildlife centers and sanctuaries (Sharp, 2005). While only a few naturally infected P. t. troglodytes were identified, molecular analysis of these viruses has yielded important insight into the evolutionary history of SIV—and HIV—in west central Africa.
First, SIVcpz infection has been identified in captive members of P. t. troglodytes but not P. t. vellerosus. While this cannot conclusively establish that P. t. vellerosus does not harbor SIVcpz, it does suggest that natural infection is rare in this subspecies. Second, SIVcpz strains from P. t. troglodytes in neighboring areas in southern Cameroon and northern Gabon were found to exhibit significant genetic diversity, suggesting longstanding infection in this area. Finally, phylogenetic analyses provided evidence of ancient recombination among members of the P. t. troglodytes SIVcpz lineage, at a time when the precursors of HIV-1 groups M, N, and O were still infecting chimpanzees. As Dr. Hahn’s group will demonstrate when its data are published, the significant clustering of HIV-1 groups M and N with SIVcpz in parts of Cameroon point to a geographic origin for these viruses.
| Conclusion | Top of page |
Even with emerging data regarding the geographical origins of HIV-1 groups M, N, and O, there are still unanswered questions regarding the natural SIV reservoirs that were the source of infection in chimpanzees. At the same time, very little is known about the biology of SIVcpz infection in chimpanzees, nor is there much data to elucidate the circumstances by which SIVcpz was transmitted to humans and gave rise to the HIV-1 epidemic. It is also unclear if SIVcpz underwent adaptive changes in order to become pathogenic and to spread as it did in the human population. If SIVcpz is nonpathogenic in chimpanzees, then elucidating the molecular basis for the differences between SIVcpz infection of apes and HIV-1 infection of humans demands attention. And if adaptive changes in SIVcpz were required, research into these changes may very well lead to a deeper understanding of HIV-1 transmission and pathogenesis, potentially guiding the ongoing search for novel prevention and treatment strategies.
| References | Top of page |
