Research

We use a variety of techniques to understand the implications of HIV's extraordinary genetic diversity for the pathogenesis of AIDS, and apply this information to the development of more effective therapies and vaccines. Current intensive research topics include:


Computational Methods for HIV Research

The pace of AIDS research has been astounding over the past quarter century, leading to many new insights into normal as well as disease processes, as well as means of counteracting disease processes. The advent of increasingly massive parallel technologies for acquiring experimental data, and the multidisciplinary nature of modern biomedical research, cries out for software solutions for the acquisition, retention and multi-parameter evaluation of clinical, laboratory and genetic data derived from pathogens such as HIV and their infected human hosts. With the goal of discovering mechanisms of disease causation and means of preventing infection and disease, such an infrastructure would significantly enhance the discovery process. To this end, we are developing a software infrastructure, termed Viroverse, that will capture and integrate and assist query of databases from the patient bedside, to the laboratory, to the bioinformaticist's computers. Along the way, we continue to develop a series of stand alone tools and make them freely available to the research community on our website. Our publications in this area include the following:

Deng W, Maust BS, Nickle DC, Learn GH, Liu Y, Heath L, Kosakovsky Pond SL, Mullins JI 2010 DIVEIN: a web server to analyze phylogenies, sequence divergence, diversity, and informative sites. BioTechniques485405-8 pubmed

Nickle DC, Jojic N, Heckerman D, Jojic V, Kirovski D, Rolland M, Kosakovsky Pond S, Mullins JI 2008 Comparison of immunogen designs that optimize peptide coverage: reply to Fischer et al. PLoS computational biology41e25 pubmed

Deng W, Nickle DC, Learn GH, Maust B, Mullins JI 2007 ViroBLAST: a stand-alone BLAST web server for flexible queries of multiple databases and user's datasets. Bioinformatics (Oxford, England)23172334-6 pubmed

Rolland M, Jensen MA, Nickle DC, Yan J, Learn GH, Heath L, Weiner D, Mullins JI 2007 Reconstruction and function of ancestral center-of-tree human immunodeficiency virus type 1 proteins. Journal of virology81168507-14 pubmed

Bhattacharya T, Daniels M, Heckerman D, Foley B, Frahm N, Kadie C, Carlson J, Yusim K, McMahon B, Gaschen B, Mallal S, Mullins JI, Nickle DC, Herbeck J, Rousseau C, Learn GH, Miura T, Brander C, Walker B, Korber B 2007 Founder effects in the assessment of HIV polymorphisms and HLA allele associations. Science (New York, N.Y.)31558181583-6 pubmed

Nickle DC, Heath L, Jensen MA, Gilbert PB, Mullins JI, Kosakovsky Pond SL 2007 HIV-specific probabilistic models of protein evolution. PLoS ONE26e503 pubmed

Jensen MA, Coetzer M, van 't Wout AB, Morris L, Mullins JI 2006 A reliable phenotype predictor for human immunodeficiency virus type 1 subtype C based on envelope V3 sequences. Journal of virology80104698-704 pubmed

Jensen MA, Li FS, van 't Wout AB, Nickle DC, Shriner D, He HX, McLaughlin S, Shankarappa R, Margolick JB, Mullins JI 2003 Improved coreceptor usage prediction and genotypic monitoring of R5-to-X4 transition by motif analysis of human immunodeficiency virus type 1 env V3 loop sequences. Journal of virology772413376-88 pubmed

Nickle DC, Jensen MA, Shriner D, Brodie SJ, Frenkel LM, Mittler JE, Mullins JI 2003 Evolutionary indicators of human immunodeficiency virus type 1 reservoirs and compartments. Journal of virology7795540-6 pubmed

Rodrigo AG, Goracke PC, Rowhanian K, Mullins JI 1997 Quantitation of target molecules from polymerase chain reaction-based limiting dilution assays. AIDS research and human retroviruses139737-42 pubmed

HIV Pathogenesis

Our long-standing interest in the pathogenesis of HIV infection emerged from our earlier work in animal model systems of retroviral infections. Notably, these included feline leukemia and feline immunodeficiency viruses studies done in collaboration with Dr. Edward A. Hoover and his laboratory at Colorado State University, and simian immunodeficiency viruses studied in collaboration with Dr. Hoover and several other collaborators. Our work in this area continues to center on defining milestones occurring within the asymptomatic period of HIV infection in an effort of defining the critical determinants of progression as well as identify new targets for and means of evaluating new therapeutic interventions. A summary of our findings are shown in this animation Link. Fundamental as well as recent publications include:

Herbeck JT, Müller V, Maust BS, Ledergerber B, Torti C, Di Giambenedetto S, Gras L, Günthard HF, Jacobson LP, Mullins JI, Gottlieb GS 2012 Is the virulence of HIV changing? A meta-analysis of trends in prognostic markers of HIV disease progression and transmission. AIDS1426193-205 pubmed

Herbeck JT, Gottlieb GS, Li X, Hu Z, Detels R, Phair J, Rinaldo C, Jacobson LP, Margolick JB, Mullins JI 2008 Lack of evidence for changing virulence of HIV-1 in North America. PLoS ONE32e1525 pubmed

Rolland M, Brander C, Nickle DC, Herbeck JT, Gottlieb GS, Campbell MS, Maust BS, Mullins JI 2007 HIV-1 over time: fitness loss or robustness gain? Nature reviews. Microbiology59C1 pubmed

Gottlieb GS, Hawes SE, Nickle DC, Herbeck JT, Kiviat NB, Mullins JI, Sow PS 2007 Presenting plasma HIV RNA level and rate of CD4 T-cell decline. JAMA : the journal of the American Medical Association2978805; author reply 806-7 pubmed

Shriner D, Shankarappa R, Jensen MA, Nickle DC, Mittler JE, Margolick JB, Mullins JI 2004 Influence of random genetic drift on human immunodeficiency virus type 1 env evolution during chronic infection. Genetics16631155-64 pubmed

Gottlieb GS, Nickle DC, Jensen MA, Wong KG, Grobler J, Li F, Liu SL, Rademeyer C, Learn GH, Karim SS, Williamson C, Corey L, Margolick JB, Mullins JI 2004 Dual HIV-1 infection associated with rapid disease progression. Lancet3639409619-22 pubmed

Pathogenesis Intervention using Antiretrovial Therapy (ART)

Prior work done in collaboration with Dr. Lawrence Loeb at the University of Washington resulted in the development of a new class antiretroviral drugs now under development at Koronis Pharmaceuticals, Inc. In collaboration with the laboratory of Drs. Anthony Fauci and Tae-Wook Chun at the NIH we have been seeking out cellular reservoirs responsible for the rebound of virus that occurs upon cessation of ART. Our most recent and current work consists of collaborations with Drs. Lisa Frenkel and Tuofu Zhu at the University of Washington in which we seek to identify sites of residual viral replication under ART. The goal of these studies are to identify "therapy shadows" within the body for specific targeting by new ART approaches and drugs. Fundamental as well as recent publications include:

Mullins JI, Heath L, Hughes JP, Kicha J, Styrchak S, Wong KG, Rao U, Hansen A, Harris KS, Laurent JP, Li D, Simpson JH, Essigmann JM, Loeb LA, Parkins J 2011 Mutation of HIV-1 Genomes in a Clinical Population Treated with the Mutagenic Nucleoside KP1461. PloS one61e15135 pubmed

Xu Y, Zhu H, Wilcox CK, van't Wout A, Andrus T, Llewellyn N, Stamatatos L, Mullins JI, Corey L, Zhu T 2008 Blood monocytes harbor HIV type 1 strains with diversified phenotypes including macrophage-specific CCR5 virus. The Journal of infectious diseases1972309-18 pubmed

Chun TW, Justement JS, Moir S, Hallahan CW, Maenza J, Mullins JI, Collier AC, Corey L, Fauci AS 2007 Decay of the HIV reservoir in patients receiving antiretroviral therapy for extended periods: implications for eradication of virus. The Journal of infectious diseases195121762-4 pubmed

Holte SE, Melvin AJ, Mullins JI, Tobin NH, Frenkel LM 2006 Density-dependent decay in HIV-1 dynamics. Journal of acquired immune deficiency syndromes (1999)413266-76 pubmed

Tobin NH, Learn GH, Holte SE, Wang Y, Melvin AJ, McKernan JL, Pawluk DM, Mohan KM, Lewis PF, Mullins JI, Frenkel LM 2005 Evidence that low-level viremias during effective highly active antiretroviral therapy result from two processes: expression of archival virus and replication of virus. Journal of virology79159625-34 pubmed

Chun TW, Nickle DC, Justement JS, Large D, Semerjian A, Curlin ME, O'Shea MA, Hallahan CW, Daucher M, Ward DJ, Moir S, Mullins JI, Kovacs C, Fauci AS 2005 HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir. The Journal of clinical investigation115113250-5 pubmed

Fulcher JA, Hwangbo Y, Zioni R, Nickle D, Lin X, Heath L, Mullins JI, Corey L, Zhu T 2004 Compartmentalization of human immunodeficiency virus type 1 between blood monocytes and CD4+ T cells during infection. Journal of virology78157883-93 pubmed

Zhu T, Hu SL, Feng F, Polacino P, Liu H, Hwangbo Y, Learn GH, Mullins JI, Corey L 2004 Persistence of low levels of simian immunodeficiency virus in macaques that were transiently viremic by conventional testing. Virology3232208-19 pubmed

Zhu T, Corey L, Hwangbo Y, Lee JM, Learn GH, Mullins JI, McElrath MJ 2003 Persistence of extraordinarily low levels of genetically homogeneous human immunodeficiency virus type 1 in exposed seronegative individuals. Journal of virology77116108-16 pubmed

Frenkel LM, Wang Y, Learn GH, McKernan JL, Ellis GM, Mohan KM, Holte SE, De Vange SM, Pawluk DM, Melvin AJ, Lewis PF, Heath LM, Beck IA, Mahalanabis M, Naugler WE, Tobin NH, Mullins JI 2003 Multiple viral genetic analyses detect low-level human immunodeficiency virus type 1 replication during effective highly active antiretroviral therapy. Journal of virology77105721-30 pubmed

Zhu T, Muthui D, Holte S, Nickle D, Feng F, Brodie S, Hwangbo Y, Mullins JI, Corey L 2002 Evidence for human immunodeficiency virus type 1 replication in vivo in CD14(+) monocytes and its potential role as a source of virus in patients on highly active antiretroviral therapy. Journal of virology762707-16 pubmed

Primary HIV-1 Infection

Campbell MS, Kahle EM, Celum C, Lingappa JR, Kapiga S, Mujugira A, Mugo NR, Fife KH, Mullins JI, Baeten JM, 2013 Plasma viral loads during early HIV-1 infection are similar in subtype C- and non-subtype C-infected African seroconverters. The Journal of infectious diseases20771166-70 pubmed

Herbeck JT, Rolland M, Liu Y, McLaughlin S, McNevin J, Zhao H, Wong K, Stoddard JN, Raugi D, Sorensen S, Genowati I, Birditt B, McKay A, Diem K, Maust BS, Deng W, Collier AC, Stekler JD, McElrath MJ, Mullins JI. 2011 Demographic processes affect HIV-1 evolution in primary infection before the onset of selective processes. Journal of Virology85157523-34 pubmed

Liu Y, Curlin ME, Diem K, Zhao H, Ghosh AK, Zhu H, Woodward AS, Maenza J, Stevens CE, Stekler J, Collier AC, Genowati I, Deng W, Zioni R, Corey L, Zhu T, Mullins JI 2008 Env length and N-linked glycosylation following transmission of human immunodeficiency virus Type 1 subtype B viruses. Virology3742229-33 pubmed

Liu Y, McNevin J, Zhao H, Tebit DM, Troyer RM, McSweyn M, Ghosh AK, Shriner D, Arts EJ, McElrath MJ, Mullins JI 2007 Evolution of human immunodeficiency virus type 1 cytotoxic T-lymphocyte epitopes: fitness-balanced escape. Journal of virology812212179-88 pubmed

Liu Y, McNevin J, Cao J, Zhao H, Genowati I, Wong K, McLaughlin S, McSweyn MD, Diem K, Stevens CE, Maenza J, He H, Nickle DC, Shriner D, Holte SE, Collier AC, Corey L, McElrath MJ, Mullins JI 2006 Selection on the human immunodeficiency virus type 1 proteome following primary infection. Journal of virology80199519-29 pubmed

Herbeck JT, Nickle DC, Learn GH, Gottlieb GS, Curlin ME, Heath L, Mullins JI 2006 Human immunodeficiency virus type 1 env evolves toward ancestral states upon transmission to a new host. Journal of virology8041637-44 pubmed

Liu Y, Mullins JI, Mittler JE 2006 Waiting times for the appearance of cytotoxic T-lymphocyte escape mutants in chronic HIV-1 infection. Virology3471140-6 pubmed

Vaccine Design

The practical benefits we derive from understanding both the dynamics of viral evolution and the host immune responses that occur during primary HIV infection and throughout the course of disease include an increasingly sophisticated understanding of the necessary features for a vaccine to provide protective immunity. Our current work in this area is devoted to identifying components of each viral protein which should be included or excluded in a vaccine and evaluating the impact of prior vaccination on the HIV strains that subsequently infect vaccinees. Recent publications include work on approaches focusing on conserved elements as well as incorporating ancestral features and viral diversity into the vaccine.

Ancestral Sequence Approach

Rolland M, Jensen MA, Nickle DC, Yan J, Learn GH, Heath L, Weiner D, Mullins JI 2007 Reconstruction and function of ancestral center-of-tree human immunodeficiency virus type 1 proteins. Journal of virology81168507-14 pubmed

Doria-Rose NA, Learn GH, Rodrigo AG, Nickle DC, Li F, Mahalanabis M, Hensel MT, McLaughlin S, Edmonson PF, Montefiori D, Barnett SW, Haigwood NL, Mullins JI 2005 Human immunodeficiency virus type 1 subtype B ancestral envelope protein is functional and elicits neutralizing antibodies in rabbits similar to those elicited by a circulating subtype B envelope. Journal of virology791711214-24 pubmed

Nickle DC, Jensen MA, Gottlieb GS, Shriner D, Learn GH, Rodrigo AG, Mullins JI 2003 Consensus and ancestral state HIV vaccines. Science (New York, N.Y.)29956121515-8; author reply 1515-8 pubmed

Conserved Elements Approach

Kulkarni V, Rosati M, Valentin A, Ganneru B, Singh AK, Yan J, Rolland M, Alicea C, Beach RK, Zhang GM, Le Gall S, Broderick KE, Sardesai NY, Heckerman D, Mothe B, Brander C, Weiner DB, Mullins JI, Pavlakis GN, Felber BK 2013 HIV-1 p24(gag) Derived Conserved Element DNA Vaccine Increases the Breadth of Immune Response in Mice. PloS one83e60245 pubmed

Rolland M, Manocheewa S, Swain JV, Lanxon-Cookson EC, Kim M, Westfall DH, Larsen BB, Gilbert PB, Mullins JI 2013 HIV-1 conserved-element vaccines: relationship between sequence conservation and replicative capacity. Journal of virology87105461-7 pubmed

Rolland M, Nickle DC, Mullins JI 2007 HIV-1 group M conserved elements vaccine. PLoS pathogens311e157 pubmed

Rolland M, Heckerman D, Deng W, Rousseau CM, Coovadia H, Bishop K, Goulder PJ, Walker BD, Brander C, Mullins JI 2008 Broad and Gag-biased HIV-1 epitope repertoires are associated with lower viral loads. PLoS ONE31e1424 pubmed

Rolland M, Nickle DC, Deng W, Frahm N, Brander C, Learn GH, Heckerman D, Jojic N, Jojic V, Walker BD, Mullins JI 2007 Recognition of HIV-1 peptides by host CTL is related to HIV-1 similarity to human proteins. PLoS ONE29e823 pubmed

Variation-Inclusive Approach

Nickle DC, Jojic N, Heckerman D, Jojic V, Kirovski D, Rolland M, Kosakovsky Pond S, Mullins JI 2008 Comparison of immunogen designs that optimize peptide coverage: reply to Fischer et al. PLoS computational biology41e25 pubmed

Nickle DC, Rolland M, Jensen MA, Pond SL, Deng W, Seligman M, Heckerman D, Mullins JI, Jojic N 2007 Coping with viral diversity in HIV vaccine design. PLoS computational biology34e75 pubmed

Department of Microbiology
School of Medicine
University of Washington
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