Description of Research Expertise

My laboratory has 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. My group was the first to describe the extensive in vivo genetic variability of HIV-1 (Hahn et al., Science, 1986) and to discover that recombination between highly divergent viruses represents a major driving force of HIV/SIV diversification (Robertson et al., Nature, 1995). We also developed methods for the non-invasive detection of SIV in wild-living apes, which led to the identification of the chimpanzee and gorilla reservoirs of pandemic and non-pandemic HIV-1 (Gao et al., Nature, 1999; Keele et al., Science, 2006; d’Arc et al., PNAS, 2015). This work has recently come full circle with the discovery that a highly divergent SIVcpz Env may be suitable to immunofocus HIV-1 bNab responses to the Env trimer apex (Barbian et al., mBio, 2015; Andrabi et al., Cell Rep, 2019).

Although primate lentiviruses have long been thought to be harmless, long-term natural history studies in Gombe National Park, Tanzania, revealed that SIVcpz, like HIV-1, is pathogenic in its natural chimpanzee host (Keele et al., Nature, 2009). Mortality analyses revealed a 10- to 16-fold increased risk of death for SIVcpz infected chimpanzees, and post-mortem analyses confirmed CD4+ T cell depletion and other histopathological findings consistent with AIDS. We also discovered that the chimpanzee CD4 molecule, in contrast to the human CD4, is highly polymorphic in its D1 domain, resulting in nine distinct CD4 alleles that circulate in wild populations. Importantly, this CD4 diversity not only protects chimpanzees against SIVcpz, but also other SIV strains to which chimpanzees are routinely exposed through their hunting behavior (Bibollet-Ruche et al., PNAS, 2019). More recently, we discovered that CD4 receptor diversity represents an ancient protection mechanism against primate lentiviruses in general. We found that the primate CD4 receptor is under long-term balancing selection and that this diversification has been the result of a co-evolutionary arms race between primate lentiviruses and their hosts (Russell et al., PNAS, in press).

We also studied the origins of human malaria. Of the six Plasmodium species that cause malaria in humans, P. falciparum and P. vivax pose the greatest health risk. Until recently, P. falciparum and a single known chimpanzee parasite, P. reichenowi, were believed to have coevolved with their respective host species, while P. vivax was thought to have emerged in South East Asia following a cross-species transmission of a macaque parasite. Studying wild-living chimpanzees and gorillas, we showed that both of these hypotheses are incorrect, and that instead P. falciparum and P. vivax originated from parasites infecting African apes (Liu et al., Nature, 2009; Sundararaman et al., Nat Commun, 2016; Liu et al., Nat Commun., 2017; Loy et al., PNAS, 2018). We found that P. falciparum evolved following a single host switch of a gorilla parasite, while P. vivax emerged from within a Plasmodium species that infects both chimpanzees and gorillas.

We also characterized HIV-1 transmission at the molecular level, developing a theoretical framework that permits the identification and enumeration of transmitted founder HIV-1 and SIV strains (Keele et al., PNAS, 2008; Keele et al., J. Exp. Med., 2009). For this purpose, we developed single genome amplification (SGA) to derive viral sequences without PCR artifacts (Salazar et al., J Virol, 2008). This approach allowed us to dissect virus/antibody coevolution pathways in subjects who developed broadly cross-reactive neutralizing antibodies (bNabs) (Liao et al., Nature, 2013, Gao et al., Cell, 2014, Bonsignori et al., Sci. Transl. Med., 2017; Wagh et al., Cell Rep, 2019), provided a first understanding of the biological phenotype of transmitted founder viruses (Parrish et al., PNAS, 2013; Iyer et al., PNAS, 2017), and led to the development of a novel SHIV infection model that closely resembles HIV-1 infection of humans (Li et al., PNAS, 2016; Roark et a., Science, 2021). More recent studies revealed that HIV-1 resistance to IFN-I varies markedly over the course of the infection, but is highest during viral rebound following treatment interruption, indicating that IFN-mediated pressures shape the biology of viruses that reactivate in vivo from latency (Gondim et al., Sci. Trans. Med., 2021).

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. Exploiting the antigenic conservation of the Env trimer apex across primate lentiviral lineages for AIDS vaccine design. We will determine whether evolutionarily divergent SIV Envs, when expressed as chimeric simian-human immunodeficiency viruses (SHIVs), mRNA-encoded cell surface expressed gp160 trimers, and/or virus-like particles (VLPs), will elicit V2 apex bNabs in rhesus macaques that cross-react with HIV-1.

2. Improving HIV-1 Env immunogens. We will test the hypothesis that by minimizing distracting glycan hole epitopes, enhancing Env affinity for V2 apex bNAbs and their precursors, increasing epitope diversity coverage, and incorporating B cell lineage designs into our immunogens, we will improve V2 apex bNAb germline engagement and enhance bNab development.

3. Studies of ape Plasmodium infections. Mining publicly available whole genome databases of human and ape Plasmodium parasites, we will elucidate the origin and evolution of human P. malariae.

4. 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.

5. Characterizing the viral and host effector mechanisms that govern HIV-1 rebound. We recently discovered that rebounding HIV-1 strains are characterized by extraordinary levels of IFN-I resistance. Going forward, we will determine the kinetics and clinical impact of IFN-I resistance during rebound, define the viral determinants of IFN-I resistance and the host interferon stimulated genes (ISGs) that place pressure on the rebounding virus, and trace the provenance of IFN-I resistant rebound viruses.

6. Characterizing the SARS-CoV-2 neutralizing antibody response. We have isolated neutralizing monoclonal antibodies from memory B cells of COVID survivors and determined their breadth and potency against SARS-CoV-2 variants.

Members of the Hahn Lab

Senior Researchers:

Fred Bibollet-Ruche, Ph.D., Characterizing the biological properties of rebound HIV-1

Weimin Liu, M.D., Generation of V2-apex targeted HIV-1 Env immunogens

Yingying Li, M.D., Studies of the precursor of the human AIDS virus in its natural chimpanzee host

Laboratory Supervisor:

Fang-Hua Lee, Ph.D., Neutralizing antibody development in SHIV infected macaques

Students:

Ashwin Skelly, MSTP rotation student, Characterizing the SARS-CoV2 neutralizing antibody response

Daniel (Yong Hyun) Kim, MVP rotation student, Host interferon stimulated genes associated with the IFN-I resistance of rebound HIV-1


Postdocs:

Scott Sherill-Mix, Ph.D., Type 1 interferon responses in HIV-1 infection

Ronnie Russell, Ph.D., Exploiting the antigenic conservation of the Env trimer apex across primate lentiviral lineages for AIDS vaccine design


Bioinformatician:

Andrew Jesse Connell - Tracing of broadly cross-reactive neutralizing antibody lineages in SHIV infected rhesus macaques


Technicians:

Marie Stolz - Determinants of IFN resistance in HIV-1 infection

Amanda Moran - SHIV/HIV Env-antibody coevolution as a guide to iterative HIV/AIDS vaccine design


Former postdocs:

John Kappes, Ph.D., Associate Professor of Medicine and Microbiology, University of Alabama at Birmingham
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
Marvin Gondim, Ph.D., Scientist, Bristol-Myers Squibb


Former students:

Marcelo Soares, Ph.D., Professor of Genetics, Universidade Federal do Rio de Janeiro, Brazil
Mario L. Santiago, Ph.D., Associate Professor, University of Colorado
Rebecca Rudicell, Ph.D., Research Investigator, Sanofi, Cambridge, Massachusetts
Nicholas F. Parrish, M.D., Ph.D., Surgery Resident, Vanderbilt University
Sesh Sundararaman, M.D., Ph.D., Pediatric Resident, Children's Hospital of Philadelphia
Hannah Barbian, Ph. D., Postdoctoral Researcher, Rush University
Shilpa S. Iyer, Ph.D., Instructor, School of Medicine, University of Alabama, Birmingham
Elizabeth D. Loy, M.D., Ph.D., Internal Medicine Resident, University of Colorado
Edward F. Kreider, M.D., Ph.D, Internal Medicine Resident, University of Pennsylvania

Selected Publications

Keele, B.F., Jones, J.H., Terio, K.A., Estes, J.D., Rudicell, R.S., Wilson, M.L., Li, Y, Learn, G.H., Beasley, T.M., Schumacher-Stankey, J., Wroblewski, E., Mosser, A., Raphael, J., Kamenya, S., Lonsdorf, E.V., Travis, D.A., Mlengeya, T., Kinsel, M.J., Else, J.G., Silvestri, G., Goodall, J., Sharp, P.M., Shaw, G.M., Pusey, A.E., Hahn, B.H.: Increased mortality and AIDS-like immunopathology in wild chimpanzees infected with SIVcpz. Nature 460 (7254): 515-9, 2009.

Liu, W., Li, Y., Learn, G.H., Rudicell, R.S., Robertson, J.D., Keele, B.F., Ndjango, J-B.N., Sanz, C.M., Morgan, D.B., Locatelli, S., Gonder, M.K., Kranzusch, P.J., Walsh, P.D., Delaporte, E., Mpoudi-Ngole, E., Georgiev, A.V., Muller, M.N., Shaw, G.M., Peeters, M., Sharp, P.M., Rayner, J.C., Hahn, B.H.: Origin of the human malaria parasite Plasmodium falciparum in gorillas. Nature 467 (7314): 420-5, 2010.

Sundararaman, S.A., Plenderleith, L.J., Liu, W., Loy, D.E., Learn, G.H., Li, Y., Shaw, K.S., Ayouba, A., Peeters, M., Speede, S., Shaw, G.M., Bushman, F.D., Brisson, D., Rayner, J.C., Sharp, P.M., Hahn, B.H.: Genomes of cryptic chimpanzee Plasmodium species reveal key evolutionary events leading to human malaria. Nat. Comm. 7 : 11078, 2016.

Loy, D.E., Plenderleith, L.J., Sundararaman, S.A., Liu, W., Gruszczyk, J., Chen, Y-J., Trimboli, S., Learn, G.H., MacLean, O.A., Morgan, A.L.K., Li, Y., Avitto, A.N., Giles, J., Calvignac-Spencer, S., Sachse, A., Leendertz, F.H., Speede, S., Ayouba, A., Peeters, M., Rayner, J.C., Tham, W-H., Sharp, P.M., Hahn, B.H.: Evolutionary history of human Plasmodium vivax revealed by genome-wide analyses of related ape parasites. Proc. Natl. Acad. Sci. USA 115 (36): E8450-E8459,2018.

Bibollet-Ruche, F., Russell, R.M., Weimin, L., Stewart-Jones, G.B.E., Sherrill-Mix, S., Li, Y., Learn, G.H., Smith, A.G., Gondim, M.V.P., Plenderleith, L.J., Decker, J.M., Easlick, J.L., Wetzel, K.S., Collman, R.G., Ding, S., Finzi, A., Ayouba, A., Peeters, M., Leendertz, F.H., van Schijndel, J., Goedmakers, A., Ton, E, Boesch, C., Kuehl, H., Arandjelovic, M, Dieguez, P., Murai, M., Colin, C, Koops, K., Speede, S., Gonder, M.K., Muller, M.N., Sanz, C.M., Morgan, D.B., Atencia, R., Cox, D., Piel, A.K., Stewart, F.A., Ndjango, J.N., Mjungu, D., Lonsdorf, E.V., Pusey, A.E., Kwong, P.D., Sharp, P.M., Shaw, G.M., and Hahn, B.H.: CD4 receptor diversity in chimpanzees protects against SIV infection. Proc. Natl. Acad. Sci. USA 116 (8): 3229-3238,2019.

Gondim, M.V.P., Sherrill-Mix, S., Bibollet-Ruche, F., Russell, R.M., Trimboli, S., Smith, A.G., Yingying, L., Weimin, L., Avitto, A.N., DeVoto, J., Connell, J., Fenton-May, A.E., Pellegrino, P., Williams, I., Papasavvas, E., Lorenzi, J.C.C., Salantes, D.B., Mampe, F., Monroy, M.A., Cohen, Y.Z., Heath, S., Saag, M.S., Montaner, L.J., Collman, R.G., Siliciano, J.M., Siliciano, R.F., Plenderleith, L., Sharp, P.M., Caskey, M., Nussenzweig, M.C., Shaw, G.M., Borrow, P., Bar, K.J., Hahn, B.H.: Heightened resistance to type 1 interferons characterizes HIV-1 at transmission and following analytical treatment interruption Sci. Trans. Med. 13 (576): eabd8179,2021.

Sharp, P.M., Plenderleith, L.J., Hahn, B.H.: Ape Origins of Human Malaria Annu. Rev. Microbiol. 74 : 39-63,2020.

Roark, R.S., Li, H., Williams, W.B., Chug, H., Mason, R.D., Gorman, J., Wang, S., Lee, F-H., Rando, J., Bonsignori, M., Hwang, K-K., Saunders, K.O., Wiehe, K., Moody, M.A., Hraber, P.T., Wagh, K., Giorgi, E.E., Russell, R.M., Bibollet-Ruche, F., Liu, W., Connell, J., Smith, A.G., DeVoto, J., Murphy, A.I., Smith, J., Ding, W., Zhao, C., Chohan, N., Okumura, M., Rosario, C., Ding, Y., Lindemuth, E., Bauer, A.M., Bar, K.J., Ambrozak, D., Chao, C.W., Chuang, G-Y., Geng, H., Lin, B.C., Louder, M.K., Nguyen, R., Zhang, B., Lewis, M.G., Raymond, D., Doria-Rose, N.A., Schramm, C.A., Douek, D.C., Roederer, M., Kepler, T.B., Kelsoe, G., Mascola, J.R., Kwong, P.D., Korber, B.T., Harrison, S.C., Haynes, B.F., Hahn, B.H., and Shaw G.M.: Recapitulation of HIV-1 Env-Antibody Coevolution in Macaques Leading to Neutralization Breadth Science 371 (6525): eabd2638,2021.

Honjo, K., Russell, R.M., Li, R., Liu, W., Stolz, R., Tabengwa, E., Hua, Y., Prichard, L., Kombrust, A., Sterrett, S., Marques, M., Lima, J.L., Lough, C.M., McCarty, T.P., Ketas, T.J., Hatziioannou, T., Bieniasz, P.D., Redden, D.T., Moore, J.P., Goepfert, P.A., Heath, S.L., Hahn, B.H., Davis, R.S.: Convalescent Plasma-Mediated Resolution of Covid-19 in humoral Immunodeficiency Cell Rep. Med. 2 (1): 100164,2021.

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Academic Contact Information

Perelman School of Medicine
University of Pennsylvania
409 Johnson Pavilion
3610 Hamilton Walk
Philadelphia, PA 19104
Phone: 215-746-8512