Description of Research Expertise:
My laboratory has had a long-standing interest in elucidating the origins and evolution of human and simian immunodeficiency viruses, and in studying HIV/SIV gene function and disease mechanisms from an evolutionary perspective. Characterizing the evolutionary relationships of simian immunodeficiency viruses infecting different non-human primate species in sub-Saharan Africa, we found that Acquired Immunodeficiency Syndrome (AIDS) – one of the most devastating infectious diseases to have emerged in recent history – was the result of cross-species infections of humans by lentiviruses of primate origin. Specifically, we discovered that HIV-1 resulted from cross-species infections of SIVcpz and SIVgor naturally infecting chimpanzees (Pan troglodytes) and gorillas (Gorilla gorilla), respectively, while HIV-2 resulted from transmissions of SIVsmm infecting sooty mangabeys (Cercocebus atys). Moreover, we found that these viruses had entered the human population on multiple occasions, although only one of these transfers had spawned the HIV-1 pandemic. As we now know from molecular clock analyses, the main group of HIV-1, which has afflicted more than 70 million people and caused more than 30 million deaths worldwide, was transmitted to humans in the first third of the 20th century.
To further characterize the primate reservoirs of HIV-1 and HIV-2, we developed non-invasive methods of SIV detection and characterization. These novel (urine and fecal based) methods allowed us to pinpoint the geographic origin of epidemic HIV-2, trace the source of pandemic (group M) and non-pandemic (group N) HIV-1 to geographically isolated chimpanzee communities in southern Cameroon, and discover in wild gorilla populations viruses closely related to HIV-1 group O. We also performed the first natural history study of SIVcpz in Gombe National Park, determining the prevalence, transmission patterns and pathogenicity of this virus in both habituated and non-habituated chimpanzee communities. Combining virological, ecological, behavioral and necropsy data from over a decade, we found that SIVcpz, like HIV-1, causes significantly increased mortality and AIDS-like immunopathology in wild chimpanzees. We also found that in at least one instance high SIVcpz prevalence rates contributed to the decline of a chimpanzee community. This was a surprising finding, since until then it had been assumed for a long time that SIVcpz was non-pathogenic in its natural host.
More recently, we have employed our non-invasive detection methods to determine the origin of the human malaria parasites Plasmodium falciparum and Plasmodium vivax. Until recently, it was widely believed that P. falciparum had co-evolved with humans (and our ancestors) over millions of years, while P. vivax was assumed to have emerged in southeastern Asia following the cross-species transmission of a parasite from macaques. However, the discovery of a multitude of Plasmodium spp. in chimpanzees and gorillas has refuted these theories and instead revealed that both P. falciparum and P. vivax evolved from parasites infecting wild-living African apes. It is now clear that P. falciparum resulted from a recent cross-species transmission of a parasite infecting gorillas, while P. vivax emerged from an ancestral stock of parasites that infected chimpanzees, gorillas and humans in Africa, until the spread of the protective Duffy-negative mutation eliminated P. vivax from human populations there.
In the future, we will continue to work on emerging infectious diseases and build basic and translational research programs in global health. Current projects involve:
1. Studies of HIV-1 transmission. We have devised a way to infer the nucleotide sequence of HIV-1 strains that are responsible for initiating productive infection. We are interested in determining whether these transmitted/founder viruses have biological properties that render them uniquely suited for mucosal transmission.
2. Studies of ape Plasmodium infections. P. falciparum emerged in humans only once. Given the size of the ape Plasmodium reservoir, we will examine the parasite, host and ecological factors that control cross-species transmission.The lack of in vitro culture systems poses a significant challenge to the functional studies of ape Plasmodium parasites, but whole genome sequencing, even from suboptimal specimens such as subpatently infected unprocessed blood, represents a critical first step towards understanding their biology.
3. Studies of SIVcpz infection of wild chimpanzees. We are interested in the impact of SIVcpz infection on chimpanzee population dynamics and will continue our natural history studies in Gombe National Park and other sites in Tanzania.
4. Studies in HIV vaccine development. As part of the CHAVI-ID consortium, we are studying HIV-1 diversification. In particular, we will examine how understanding the pathways of virus and antibody coevolution can inform immunogen design to elicit broadly cross-reactive neutralizing antibodies.
Members of the Hahn Lab
Research Assistant Professors:
Fred Bibollet-Ruche, Ph.D. (01/98) Determinants of IFN resistance in HIV-1
Senior Research Investigators:
Weimin Liu, M.D. (06/02) Plasmodium infections of wild-living chimpanzees, gorillas, and bonobos
Yingying Li, M.D. (06/97) Molecular epidemiology of SIVcpz in wild-living chimpanzees
Gerald H. Learn, Ph.D. (03/08) Molecular evolution of HIV-1 and malaria parasites
Fang-Hua Lee, Ph.D. (07/15) Neutralizing antibody development in SHIV infected macaques
Dorothy Elizabeth Loy (05/12), MSTP Program, Evolution of ape and human Plasmodium vivax
Ronnie Russell (08/14), CAMB MVP Program, Adaptation of SIVcpz to the new human host
Marcos Vinícius P. Gondim, Ph.D. (02/16) Kinetics of type 1 interferon resistance during HIV-1 infection
Scott Sherill-Mix, Ph.D. Bioinformatic analyses of human and ape fecal microbiomes
Hannah Barbian, Ph.D. Understanding the consequences of SIVcpz infection in wild-living chimpanzees
Andrew Jesse Connell (12/16) Development of a nextgen sequencing pipeline for pathogen detection
Andrew G. Smith (07/11) Development of Oxford Nanopore Sequencing technologies
Alexa Avitto (07/16) Plasmodium infections in Cameroonian hunter-gatherer populations
Stephanie Trimboli (08/16) Characterization of IFN resistance in the HIV-1 latent reservoir
Jasmin Giles (06/17)
Mary K. Metch (07/17) Evolution and host adaptation of malaria parasites
John Kappes, Ph.D., Associate Professor of Medicine and Microbiology, University of Alabama
Feng Gao, M.D., Professor of Medicine, Duke University and Duke Human Vaccine Institute
David Robertson, Ph.D., Professor of Biology, University of Manchester, United Kingdom
Brandon Keele, Ph.D., Senior Scientist in the AIDS and Cancer Virus Program, SAIC-Frederick, NCI-Frederick
Former research associate:
Judith Straimer, Ph.D.
Marcelo Soares, Ph.D. Student., Professor of Genetics, Universidade Federal do Rio de Janeiro, Brazil
Mario L. Santiago, Ph.D. Student., Associate Professor of Medicine, University of Colorado
Rebecca Rudicell, Ph.D. Student, Research Investigator, Sanofi, Cambridge, Massachusetts
Nicholas F. Parrish, M.D., Ph.D. MSTP Student, Surgery Resident, Vanderbilt University
Sesh Sundararaman, M.D., Ph.D., Resident, Children's Hospital of Philadelphia
Edward Kreider, MSTP Student, University of Pennsylvania Perelman School of Medicine
Shilpa S. Iyer, Ph.D., Fogarty Global Health Fellow, Post-doctoral Researcher, Yale University / Centre for Infectious Disease Research in Zambia
Keele BF, Jones JH, Terio KA, Estes JD, Rudicell RS, Wilson ML, Li Y, Learn GH, Beasley TM, Schumacher-Stankey J, Wroblewski E, Mosser A, Raphael J, Kamenya S, Lonsdorf EV, Travis DA, Mlengeya T, Kinsel MJ, Else JG, Silvestri G, Goodall J, Sharp PM, Shaw GM, Pusey AE, Hahn BH: Increased mortality and AIDS-like immunopathology in wild chimpanzees infected with SIVcpz. Nature 460 (7254): 515-9,2009.
Liu W, Li Y, Learn GH, Rudicell RS, Robertson JD, Keele BF, Ndjango J-B N, Sanz CM, Morgan DB, Locatelli S, Gonder MK, Kranzusch PJ, Walsh PD, Delaporte E, Mpoudi-Ngole E, Georgiev AV, Muller MN, Shaw GM, Peeters M, Sharp PM, Rayner JC, Hahn BH: Origin of the human malaria parasite Plasmodium falciparum in gorillas. Nature 467 (7314): 420-5,2010.
Sundararaman SA, Liu W, Keele BF, Learn GH, Bittinger K, Mouacha F, Ahuka-Mundeke S, Manske M, Sherrill-Mix S, Li Y, Malenke JA, Delaporte E, Laurent C, Mpoudi Ngole E, Kwiatkowski DP, Shaw GM, Rayner JC, Peeters M, Sharp PM, Bushman FD, Hahn BH: Plasmodium falciparum-like parasites infecting wild apes in southern Cameroon do not represent a recurrent source of human malaria. Proc Natl Acad Sci U S A. 110 (17): 7020-5,2013.
Parrish NF, Gao F, Li H, Giorgi EE, Barbian HJ, Parrish EH, Zajic L, Iyer SS, Decker JM, Kumar A, Hora B, Berg A, Cai F, Hopper J, Denny TN, Ding H, Ochsenbauer C, Kappes JC, Galimidi RP, West AP, Bjorkman PJ, Wilen CB, Doms RW, O'Brien M, Bhardwaj N, Borrow P, Haynes BF, Muldoon M, Theiler JP, Korber B, Shaw GM, Hahn BH: Phenotypic properties of transmitted founder HIV-1. Proc Natl Acad Sci U S A. 110 (17): 6626-33,2013.
Liu W, Li Y, Shaw KS, Learn GH, Plenderleith LJ, Malenke JA, Sundararaman SA, Ramirez MA, Crystal PA, Smith AG, Bibollet-Ruche F, Ayouba A, Locatelli S, Esteban A, Mouacha F, Guichet E, Butel C, Ahuka-Mundeke S, Inogwabini B-I, Ndjango J-B N, Speede S, Sanz CM, Morgan DB, Gonder MK, Kranzusch PJ, Walsh PD, Georgiev AV, Muller MN, Piel AK, Stewart FA, Wilson ML, Pusey AE, Cui L, Wang Z, Färnert A, Sutherland CJ, Nolder D, Hart JA, Hart TB, Bertolani P, Gillis A, LeBreton M, Tafon B, Kiyang J, Djoko CF: African origin of the malaria parasite Plasmodium vivax. Nat Commun 5 : 3346,2014.
Sundararaman SA, Plenderleith LJ, Liu W, Loy DE, Learn GH, Li Y, Shaw KS, Ayouba A, Peeters M, Speede S, Shaw GM, Bushman FD, Brisson D, Rayner JC, Sharp PM, Hahn BH: Genomes of cryptic chimpanzee Plasmodium species reveal key evolutionary events leading to human malaria. Nature Communications 7 : 11078,2016.
Heigele, A., Kmiec, D., Regensburger, K., Langer, S., Peiffer, L., Stürzel, C.M., Sauter, D., Peeters, M., Pizzato, M., Learn, G.H., Hahn, B.H. and Kirchhoff, F.: The potency of Nef-mediated SERINC5 antagonism correlates with the prevalence of primate lentiviruses in the wild. Cell Host Microbe 20 : 381-391,2016.
Foster TL, Wilson H, Iyer SS, Coss K, Doores K, Smith S, Kellam P, Finzi A, Borrow P, Hahn BH, Neil SJ: Resistance of Transmitted Founder HIV-1 to IFITM-Mediated Restriction. Cell Host Microbe 20 (4): 429-442,2016.
Iyer SS, Bibollet-Ruche F, Sherrill-Mix S, Learn GH, Plenderleith L, Smith AG, Barbian HJ, Russell RM, Gondim MVP, Bahari CY, Shaw CM, Li Y, Decker T, Haynes BF, Shaw GM, Sharp PM, Borrow P, Hahn BH: Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness. Proceedings of the National Academy of Sciences of the United States of America 114 (4): E590-E599,2017.
Bonsignori M, Kreider EF, Fera D, Meyerhoff RR, Bradley T, Wiehe K, Alam SM, Aussedat B, Walkowicz WE, Hwang K-Ki, Saunders KO, Zhang R, Gladden MA, Monroe A, Kumar A, Xia S-M, Cooper M, Louder MK, McKee K, Bailer RT, Pier BW, Jette CA, Kelsoe G, Williams WB, Morris L, Kappes J, Wagh K, Kamanga G, Cohen MS, Hraber PT, Montefiori DC, Trama A, Liao H-X, Kepler TB, Moody MA, Gao F, Danishefsky SJ, Mascola JR, Shaw GM, Hahn BH, Harrison SC, Korber BT, Haynes BF: Staged induction of HIV-1 glycan-dependent broadly neutralizing antibodies. Science Translational Medicine 9(381) : eaai7514,2017.
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