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P.Falciparum in Chimpanzees (Duval Et Al) Apes and origin of HIV and malaria Martine© by authorPeeters IRD and University of Montpellier, ESCMID OnlineFrance Lecture Library HIV/AIDS :The most important infectious disease to have emerged in the past century. • 1979-1981: First cases of unusual immune deficiency in USA • 1983: HIV-1 identified as the cause of AIDS • 1985: second HIV virus identifed in West Africa (HIV-2) AIDS in captive macaques (SIVmac) simian origin of AIDS? • 2012 34 million© people by infectedauthor with HIV (+ > 20 million deaths) 70% in sub- saharan Africa ESCMID Online Lecture Library Origin of HIV? Where, when, how? HIV/AIDS: Cross-species transmission of Simian Immunodeficiency viruses (SIV) from Non-human primates SIVcol Evidence of SIV infection >45 African NHP Each primate species infected with a species specific SIV SIVery SIVmon SIVrcm SIVmnd-1 SIVsun HIV-1 O SIVlho HIV-1 from SIVcpz/SIVgor in © by authorchimpanzees and gorillas in Central Africa SIVcpz/SIVg or/HIV-1 ESCMID OnlineSIVsmm/HI Lecture Library V-2 HIV-2 from SIVsmm in sooty mangabeys in West Africa How did cross-species transmission with simian retroviruses occur? Cutaneous or mucous membrane exposure to infected blood or tissues Injury by hunting and butchering M.Peeters primates S.Ahuka-Mundeke © by author S.Ahuka-Mundeke B.Abela ESCMIDBiting by primates Online Lecture Library Pets or hunting S.Ahuka-Mundeke B.Abela How many cross-species transmissions? How many epidemics? HIV-1 HIV-1 4 transmissions HIV-2 4 groups of HIV-1 HIV-1 M global epidemic HIV-1 O 1% of HIV-1 in Cameroon 8 transmissions © by author HIV-1 N <20 in Cameroon HIV-1 P 2 from Cameroon 8 groups of HIV-2 Only HIV-2 ESCMIDA and Online Lecture Library B spread in West Africa HIV-2 Adapted from Tebit & Arts, 2011 How long is HIV present in human population? • 20 years before recognition of first AIDS cases in the US: HIV circulated in Africa – 1960/1959: Kinshasa, DRC HIV-1 M subtype A and B/D – 1964 : norvegian sailor HIV-1 O most likely contaminated in Cameroon • Most common recent ancestors (MRCA) – HIV-1 group M early 1900 (1908) group O around 1920 Group N © byaround author 1960 Group P described in 2009 - HIV2ESCMID group A and B Online around Lecture 1940 Library Other groups No spread, mainly in rural areas more recent? Where are the reservoirs of the HIV-1/2 ancestors? Identify the prevalence and genetic diversity of SIV in wild primate populations? Primates are highly endangered species, Large scale studies only© possible by author using non -invasive approach detectionESCMID of antibodies Online and viralLecture RNA in faecesLibrary (Santiago et al, 2003) Non-invasive detection of SIV infection in faecal samples Faecal samples on track, at nest and feeding sites Foot print F.Liegeois S.Locatelli S.Locatelli Storage: Max 3 weeks in the field at ambiant temp in RNA- later , -80° in the lab C.Neel Chimpanzee nest © by author Antibody detection mtDNA: F.Liegeois after dialysis species/subspecies Feeding site ESCMID Online LectureViral RNA detection: Library RT-PCR, Sequence Microsatellite and phylogenetic analysis: analysis Enumeration of SIV positive samples F.Liegeois Reservoirs of HIV-1 are in Chimpanzees and Gorillas from West Central Africa Chimpanzees: N >6500 Only 2/4 subspecies SIV+ (adapted from P. Sharp et al. 2011) SIVcpzPtt: 5%(0>40%) 0.1 * * SIVcpzPts:13% (0>40%) * HIV-1 M * HIV-1 N SIVcpzPtt P. t. verus HIV-1 M and N fall in the P. t. ellioti P. t. troglodytes SIVcpzPtt radiation * P. t. schweinfurtii * P. paniscus SIVcpz+ SIVcpz - * * * Bonobos: N>800 NO SIV * SIVgor * © by author * * Prevalence: 1.6% (0-25%) * HIV-1 P HIV-1 O * HIV-1 O and P most closely * SIVcpzPts * ESCMID Online Lecture Libraryrelated to SIVgor Not transmitted to humans Gorillas: N>3500 Chimpanzees at origin of SIV infection in gorillas Reservoirs of HIV-1 M and N in chimpanzees in Cameroon High genetic diversity of SIVcpz Phylogeographic clusters Highest prevalences in chimpanzee populations infected with ancestors of HIV-1 M and N GP41 SIVcpzLB7 SIVcpzLB715 SIVcpzLB714 SIVcpzMB803 SIVcpzMB801 SIVcpzMB23 SIVcpzMB771 SIVcpzMB802 HIV-1 M SIVcpzMB192 SIVcpzMB750 TK gp41 SIVcpzMB749 SIVcpzLB730 SIVcpzMB317 MF SIVcpzMB897 HIV-1 M/B HX2B MP HIV-1 M/A U455 WE SIVcpzMB248 SIVcpzMB245 MG SIVcpzMB66 MT SIVcpzSL995 SIVcpzMT115 DG SIVcpzMT145 KG SIVcpzGAB1 © by author SIVcpzCAM13 SIVcpzDP206 SIVcpzDP25 DP BQ SIVcpzGAB2 SL SIVcpzDP943 SIVcpzDP942 BM EK LM SIVcpzCAM5 SIVcpzCAM3 SIVcpzUS BB HIV-1 N YBF106 CP Ancestors Ancestors HIV-1 N YBF30 NK MB ESCMIDSIVcpzBM1034 Online Lecture Library LB SIVcpzEK516 of HIV-1 M SIVcpzEK505 HIV-1 N of HIV-1 N SIVcpzEK519 SIVcpzEK502 HIV-1 O MVP5180 HIV-1 O ANT70 SIVcpzTAN3 SIVcpzTAN2 SIVcpzTAN1 SIVcpzANT 0.1 Ancestors of HIV-1 and epidemic Ancestor HIV-1 O and P ?? Ancestor HIV-1 N, O, and P low and HIV-1 N local spread Ancestor in areas where reservoirs HIV-1 M of ancestors are suspected ? © by author Epicenter of HIV-M epidemic 1000 km below reservoir of ESCMID OnlineEpicenter Lecture Library HIV-1 M ancestors. How did virus arrive from southern Cameroun to Kinshasa around 1900? Ancestor Kinshasa 1912 1960 2008 HIV-1 M Kinshasa 1960 Human migration: Exchange between Mouloundou and Kinshasa in early 1900 Population growth in Mouloundou and Kinshasa (De souza et al, 2012; Pepin 2011) © by author Behaviour associated with efficient sexual and blood to blood transmission (Pepin, 2011)ESCMID Online Lecture Library Initial M/F sexratio 10/1: Prostitution, High prevalence of STDs and GUD iatrogenic factors: Unsterile needles, Mass vaccination and treatment Non invasive sampling and understanding origin of other major diseases Origin of the human malaria parasite © byPlasmodium author falciparum in gorillas (Liu et al, 2010) ESCMID Online Lecture Library Human malaria parasites Plasmodium species infecting humans: P. falciparum most deathly P. vivax most common P. malariae P. ovale P. knowlesi (macaque© byparasite) author OtherESCMID Plasmodium Online species Lecture known infecting Library other mammals, birds and reptiles Origin of P. falciparum? Before 2009 Only 1 isolate (P.reichnowi) in a chimpanzee close to P.falciparum Host-parasite co-divergence : Plasmodium species diverged at the same time as humans and chimpanzees separated, between 5 million and 7 million years ago (Escalante & Ayala 1994) 2009/2010 Several studies on blood of captive and wild apes Higher genetic diversity than initially suspected in chimpanzees (Ollomo et al) Origin of malignant malaria in chimpanzees© by (Richauthor et al) African great apes are natural hosts of multiple related malaria species, Plasmodium falciparum in Gorillas Before 2009 After 2009 (PrugnolleESCMID et al) Online Lecture Library Origin of P.falciparum in Bonobos (Krief et al) PRUGNOLLE et al. (2010) P.falciparum in chimpanzees (Duval et al) Plasmodium infections of wild apes: QUESTIONS • How many different Plasmodium species are circulating in the wild? • How prevalent is ape malaria? • Are chimpanzees, gorillas or bonobos the source of the human malaria parasite ? P. falciparum? © by author ESCMID Online Lecture Library Non-invasive detection of malaria in apes Faecal samples in RNA-Later F.Liegeois F.Liegeois Storage: Max 3 weeks in the field at ambiant temp in RNA-later , -80° in the lab DNA extraction mt DNA Analysis: species/subspecies© by author Microsatellite analysis: Enumeration of individuals ESCMID Online Lecture Library Plasmodium detection: diagnostic PCR, 950 bp cytB fragment Malaria is widespread in african apes 1,827 chimpanzees, 805 gorillas and 107 bonobos © by author ESCMID Online Lecture Library (Liu et al, 2010) chimpanzees - all samples negative gorillas RED – both chimps & gorillas pos both Prevalence of Plasmodium Infection in African apes © by author Prevalences calculated by taking into account sample degradation, oversampling rates and sensitivity ESCMID Online Lecture Library 70% of wild chimpanzees (P.t.verus) from West Africa are infected with Plasmodium spp (Kaiser et al, EID 2010) UMI 233 TRANSVIHMI, IRD and UM1, Montpellier Phylogenetic tree analysis of cytb (mtDNA) P. t. ellioti P. t. troglodytes P. t. schweinfurthii G. g. gorilla P.falciparum © by author ESCMIDP.reichnowi Online Lecture Library Multiple sequences in one sample? Phylogenetic analysis of cytB sequences after Single Genome Amplification (SGA) P. t. ellioti chimpanzee P. t. troglodytes P. t. schweinfurthii gorilla G. g. gorilla chimpanzee gorilla Laverania clade: Laverania ©chimpanzee by author 3 chimpanzee-specific Plasmodium species 3 gorilla-specific ESCMID Online Lecture PlasmodiumLibrary species: gorilla P. falciparum is of Gorilla Origin chimpanzee gorilla chimpanzee gorilla Laverania ©chimpanzee by author ESCMID Online Lecture Library gorilla Gorillas and not Bonobos are at the origin P. falciparum in humans 980 aa 2,447 bp Captive © by author bonobos Captive bonobos Strains resistant to antimalaria drugs ESCMID Online Lecture Library NO P.falciparum or P.falciparum-like strains in wild chimpanzees and bonobos Liu et al , 2010 Futur questions Proximity of Plasmodium-infected wild living apes to human habitation © by author great apes may constitute a reservoir of Plasmodium ? ESCMID Online Lecture Library Ape malaria variants in humans? Plasmodium falciparum-like parasites infecting wild apes in southern Cameroon do not represent a recurrent source of human malaria. (Sundararaman et al, 2013) 1402 blood samples Plasmodium species specific PCR 71% infected no ape malaria species 454 sequencing (n=514) to detect minority infections no ape malaria
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