2. Question

9. An Exception - Not Baboons Only 2 of 279 baboons in Tanzania and Ethiopia were found to harbor SIV Subsequently shown to be SIVagm phylogenetically matched to the green monkeys in the region Baboons are known to kill and eat green monkeys A good research project - how is it that baboons have been able to exclude endemic SIV infection

11. Natural Infection of Non-human Primates LentivirusType D Retrovirus African old world YesNo Asian old world NoYes New World No ?

13. Cross-species transmissions Sooty mangabeys -> humans SIVsmm -> HIV-2 Sooty mangabeys -> macaques SIVsmm -> SIVmac Chimpanzees -> humans SIVcpz -> HIV-1

14. Evidence that HIV-2 in humans arose by cross species transmission from sooty mangabeys HIV-2 isolates cannot be distinguished from SIVsm isolates at the genetic level The natural habitat of sooty mangabeys is the coastal forest regions of western Africa, exactly where HIV-2 is endemic Humans in western Africa sometimes keep sooty mangabeys as pets and sometimes capture and eat sooty mangabeys

16. HIV-2 vs HIV-1 Most highly prevalent in west Africa and in those with roots or ties to west Africa Prevalence? Certainly much less than HIV-1, but may be as high as 1,000,000 or more. Less pathogenic Low viral loads 85% - 95% are considered long term non-progressors Originated by cross-species transmission from sooty mangabeys, probably within the last 100 years 8 phylogenetic groupings, but 6 of these have only one member

17. Cross-species transmissions Sooty mangabeys -> humans SIVsmm -> HIV-2 Sooty mangabeys -> macaques SIVsmm -> SIVmac Chimpanzees -> humans SIVcpz -> HIV-1

18. Natural hosts of SIV by and large do NOT develop disease from their SIV infections It is quite clear with HIV-1 in humans and SIVmac in rhesus macaques that: high viral loads - bad prognosis low viral loads - better prognosis It is quite natural to predict that natural hosts of SIV infection have evolved an ability to maintain low viral loads Sorry, that is not the case

20. To everyone’s surprise, natural hosts of SIV infection (e.g. AGMs, SMs) have high SIV viral loads Natural hosts appear to resist SIV-induced disease by other means Chronic lymphoid activation Breakdown of the gut mucosal barrier microbial translocation

21. It is not always cross-species - interesting historical anecdotes Karakul sheep were imported from Germany to Iceland in 1933 Was followed by gradual transmission over decades of a chronic wasting disease in the Icelandic sheep Led to the discovery of the first lentivirus in 1954: Maedi-Visna Virus (MVV) MVV was eradicated from Iceland with the slaughter of hundreds of thousands of Icelandic sheep in the 1960s. This story was essentially repeated in the 1960s on the island of Bali in the South Pacific with the introduction of the bovine lentivirus (BIV) into Bali cattle and the subsequent outbreak of Jembrana Disease

22. What? African Green Monkeys in the Caribbean?? Three islands in the Caribbean have free- roaming troops of African Green Monkeys: Barbados, Nevis, and St Kitts They were brought there in the 1600s and 1700s in conjunction with the slave trade (pets/companionship) All green monkeys in the Caribbean are free of SIV Tempting to conclude that SIV was introduced to AGMs in Africa after 1600, but probably not true. Founder effects: monkeys brought 3 years of age

24. Can modern medicine benefit from this information? We have already learned the critical importance of microbial translocation and chronic lymphoid activation for SIV-induced and HIV-induced AIDS The dangers associated with cross-species transmission of lentiviruses are a warning shot across the bow of public health and modern medicine We now have a useful animal model for AIDS

25. SIVmac -> macaques as an animal model for HIV/AIDS SIVmac targets CD4+ lymphocytes and macrophages for replication SIVmac uses the CD4 molecule as its first receptor and CCR5 as the second receptor for entry into target cells SIVmac has a similar set of auxiliary genes as HIV-1 SIVmac produces a chronic disease course, CD4 depletion, immunodeficiency, AIDS and death in rhesus macaques A similar set of opportunistic infections in macaques with AIDS as in humans with AIDS: PCP; CMV; thrush; EBV lymphomas; etc Availability of an infectious, pathogenic, molecular clone; 10,279 base pairs; allows application of mutations (genetics) to address questions of tropism, pathogenesis, and most importantly vaccine development

26. Why is it useful to have a relevant animal model? Better understanding of the pathogenesis of disease; why the virus does what it does and why it does it; will help fuel novel therapeutic and prevention approaches Testing of radical, potentially dangerous, therapeutic interventions or prevention approaches, with the possibility of home run outcomes Vaccine development, vaccine development, vaccine development

27. Some important uses of the SIVmac/rhesus model Relative importance and functional role of auxiliary genes Critical role for restriction factors in limiting cross-species transmission and limiting replication once infection is established Priviliged sites for viral replication Is replication in macrophages essential for the development of AIDS Vaccine Development, Vaccine Development, Vaccine development

28. Some important uses of the SIVmac/rhesus model Relative importance and functional role of auxiliary genes

31. Some important uses of the SIVmac/rhesus model Priviliged sites for viral replication

33. Some important uses of the SIVmac/rhesus model Vaccine Development, Vaccine Development, Vaccine development

35. Some important uses of the SIVmac/rhesus model Relative importance and functional role of auxiliary genes Critical role for restriction factors in limiting cross-species transmission and limiting replication once infection is established Priviliged sites for viral replication Is replication in macrophages essential for the development of AIDS Vaccine Development, Vaccine Development, Vaccine development

36. Some of the lessons from today Related lentiviruses are present in sheep, goats, horses, cattle, cats, monkeys and man The importance of cross-species transmissions for causing new endemics and epidemics How phylogenetic analyses can help identify nearest viral relatives and the origins of cross-species transmissions Of the different groups of HIV-1 and HIV-2, group M of HIV-1 is far and away the major player in the AIDS epidemic The importance of animal models in moving forward in our fight against HIV/AIDS

37. Why are lentiviruses in African but not Asian nonhuman primates??