Our lab focuses on understanding the fundamental viral-host interactions that determine the outcome of RNA virus translation, replication and packaging. These events in the RNA virus lifecycle have specific points of integration with cellular responses such as innate immune sensing, host gene expression, apoptosis and autophagy activation. Our work defines these cellular events in the context of fundamental RNA viral life cycle events. We primarily study flaviviruses, such as West Nile virus, and HIV as important human viruses with significant impact on human health. With a detailed understanding of host-viral interactions, we anticipate that unique and novel therapeutic targets can be leveraged for development of new therapeutics.
J. David Beckham MD
PI -Assistant Professor of Medicine
PhD Candidate, Microbiology
Professional Research Assistant, Lab Manager
Beatman E, Oyer R, Shives KD, Hedman K, Brault AC, Tyler KL, Beckham JD. ‘West Nile replication is Independent of Autophagy activation’. Virology. 2012. 433: 262-272. DOI 10.1016.
Davis LE, Oyer R, Beckham JD, KL Tyler. Elevated CSF cytokines in the Jarisch-Herxheimer reaction of general paresis. JAMA Neurology. 2013. 79(8):1060-4.
Shives K, Beatman E, Hall MN, Beckham JD. West Nile virus activates mTOR signaling in support of viral protein synthesis. PLoS Pathogens. 2013.
Beatman E, Shives K, Kleinschmidt-DeMasters BK, Beckham JD. Subcortical neuronal populations exhibit increased West Nile virus growth and apoptosis in association with alpha-synuclein expression. Journal of Infectious Diseases. 2013.
Main Research Focus
I conduct clinical and
translational investigations of HIV/AIDS and AIDS-KS in domestic and
international settings. Since 1998, I have collaborated with Dr. Margaret
Borok to study the epidemiology and treatment of Kaposi’ sarcoma and Kaposi's
sarcoma herpesvirus (KSHV or HHV-8) in Zimbabwe. These ongoing
collaborations have defined risk factors for HHV-8 infection, described the
molecular epidemiology of HHV-8 and investigated HHV-8 viremia as a marker of
KS disease outcomes in Zimbabwe. We are currently conducting a
community-based clinical of an intervention funded by the National Cancer
Institue to improve KS diagnosis in primary care settings in Zimbabwe.
Personnel and titles
Rick Rapaport, Professional
Beth White, Professional
Selected Publications (citations)
- Erlandson KM, Allshouse
A, Duong S, MaWhinney S, Kohrt WM, Campbell TB. HIV, Aging, and
Advance Care Planning: Are We Successfully Planning for the Future?
J Palliat Med 2012;15:1124-9. [PMCID: PMC 3438835]
- Campbell TB, Smeaton L, De Gruttola
V, Eshleman SH, Klingman K, Martinez A, Grinsztejn B, Hosseinipour M, Kumwenda
J, Lalloo U, Reverie C, Sanchez J, Firnhaber C, Santos BR, Supparatpinyo
K, Tripathy T, Moran L, Safren S, Snowden W, Petrella L, Rooney JF, Uy J,
Schooley RT, Flanigan T, Kumarasamy N, Hakim J for the PEARLS study team
of the ACTG. Efficacy and Safety of Once-Daily Antiretroviral Therapy for
Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse
Multinational Settings. PLOS Medicine 2012;9:1-12. [PMCID: PMC 3419182]
- Erlandson KM, Allshouse
A, Jankowski CM, Duong S, MaWhinney S, Kohrt WM, Campbell TB. A
Comparison of Functional Status Instruments in HIV-Infected Adults on
Effective Antiretroviral Therapy. HIV Clin Trials 2012;13:324-34. [PMID:
- Erlandson KM, Allshouse
AA, Jankowski CM, Duong S, MaWhinney S, Kohrt WM, Campbell TB. Risk
factors for recurrent falls in HIV-infected persons. J Acquir Immune Defic
Syndr. 2012;61:484-9. [PMCID: PMC 3496187]
- Erlandson KM, Allshouse
AA, Jankowski CM, Lee EJ, Rufner KM, Palmer B, Wilson CC, MaWhinney S,
Kohrt WM, Campbell TB. Association of impaired physical function
with inflammation and immune activation in HIV-1-infected adults on
effective antiretroviral therapy. J Infect Dis 2013;208:249-59.
- Erlandson KM, Allshouse
AA, Jankowski CM, MaWhinney S, Kohrt WM, Campbell TB. Functional
impairment is associated with low bone and muscle mass among persons aging
with HIV-infection. J Acquir Immune Defic Syndr 2013;63:209-15. [PMCID:
- Fiscus SA, Cu-Uvin S,
Eshete AT, Hughes MD, Hosseinipour M, Grinsztejn B, Badal-Faesen S,
Dragavon J, Coombs RW, Braun K, Moran L, Hakim J, Flanigan T, Kumarasamy
N, Campbell TB and the A5185s Team. Changes in HIV-1 subtypes
B and C genital tract RNA in women and men after initiation of
antiretroviral therapy. Clin Infect Dis 2013;57: 290-297. [PMCID:
- Nelson BC, Borok MZ,
Ndhlovu CE, Mhlanga T, Makadzange T, Campbell TB. AIDS-associated
Kaposi’s sarcoma: Outcomes after initiation of antiretroviral therapy at a
university-affiliated hospital in urban Zimbabwe. Int J Infect Dis
2013;17:e902-6. [PMID: 23809198; PubMed - in process]
- Lozupone CA, Li M, Campbell
TB, Flores SC, Linderman D, Gebert MJ, Knight R, Fontenot AP, Palmer
BE. Alterations in the gut microbiota associated with HIV-1 infection.
Cell Host Microbe 2013;14:329-39. [PMCID: PMC3864811]
- Périssé A, Smeaton L,
Chen Y, La Rosa A, Walawander A, Nair A, Grinsztejn B, Santos B, Kanyama
C, Hakim J, Nyirenda M, Kumarasamy N, Lalloo U, Flanigan T, Campbell TB,
Hughes MD. Outcomes among HIV-1 infected individuals first starting
antiretroviral therapy with concurrent active TB or other AIDS-defining
disease. PLoS One 2013;8:e83643. [PMCID:PMC3877069]
- Mollan KR, Smurzynski M,
Eron JJ, Daar ES, Campbell TB, Sax PE, Gulick GM, Na L, O’Keefe L,
Robertson KR, Tierney C. Association between Efavirenz as Initial Therapy
for HIV-1 Infection and Increased Risk of Suicidal Ideation, Attempted, or
Completed Suicide. Ann Intern Med 2014;161:1-10. [PMID: 24979445;
PubMed - in process]
- Erlandson KM, Gudza I,
Fiorillo S, Ndemera B, Schooley RT, Gwanzura L, Borok M, Campbell TB.
Relationship of vitamin D insufficiency to AIDS-associated Kaposi's
sarcoma outcomes: Retrospective analysis of a prospective clinical trial
in Zimbabwe. Int J Infect Dis. 2014;24:6-10. [PMCID: PMC4070314]
- Erlandson KM, Schrack
JA, Jankowski CM, Brown TT, Campbell TB. Functional Impairment,
Disability, and Frailty in Adults Aging with HIV-Infection. Current
HIV/AIDS Reports 2014;11:279-90. [PMCID: PMC4125474]
- Erlandson KM, Allshouse
AA, Jankowski CM, Mawhinney S, Kohrt WM, Campbell TB. Relationship
of Physical Function and Quality of Life among Persons Aging with HIV
Infection. AIDS 2014 (in press)
- Safren S, Biello KB,
Smeaton L, Mimiaga MJ, Walawander A, Lama JR, Rana A, Nyirenda M, Kayoyo
VM, Samaneka W. Joglekar A, Celentano D, Martinez A, Remmert JE, Nair A,
Lalloo UG, Kumarasamy N, Hakim J, Campbell TB. Psychosocial
predictors of non-adherence and treatment failure in a large scale
multi-national trial of antiretroviral therapy for HIV: Data from the ACTG
A5175/PEARLS trial. PLOS One. 2014 (in press)
Castillo-Mancilla is a clinical researcher who is focused on improving clinical
outcomes of HIV therapy, with a particular interest in developing new
strategies to measure drug adherence and understanding individual host factors
that lead to unique responses to antiretroviral treatment. Accurately measuring
drug adherence has proven very difficult in routine clinical practice, thus
implementing new approaches to advance in this field is of critical importance.
Dr. Castillo-Mancilla works in close collaboration with the Colorado Antiviral
Pharmacology Laboratory at the Skaggs School of Pharmacy and Pharmaceutical
Sciences, which is world-renowned for its contributions in the field of
clinical pharmacology of antiretrovirals and anti-hepatitis treatment.
Castillo-Mancilla J, Zheng JH,
Rower JE, Meditz A, Gardner E, Predhomme J, Fernandez C, Langness J, Kiser J,
Bushman LR, Anderson PL. Tenofovir, emtricitabine, and tenofovir-diphosphate in
dried blood spots for determining recent and cumulative drug exposure. AIDS Res
Hum Retroviruses. 2013;29:384-90. (Citations 8).
Zheng JH, Guida LA, Rower C, Castillo-Mancilla
J, Meditz A, Klein B, Kerr BJ, Langness J, Bushman L, Kiser J, Anderson PL.
Quantitation of Tenofovir and Emtricitabine in Dried Blood Spots (DBS) with
LC-MS/MS. J Pharm Biomed Anal. 2014;88:144-51. (Citations 3).
Kile DA, Mawhinney S, Aquilante C, Rower JE, Castillo-Mancilla J, Anderson PL. A population pharmacokinetic-pharmacogenetic
analysis of atazanavir. AIDS Res Hum Retroviruses. 2012;28:1227-1234.
Castillo-Mancilla JR, Campbell TB. Comparative
effectiveness of efavirenz-based antiretroviral regimens in resource-limited
settings. J Comp Eff Res. 2012;1:157-170. (Citations 1).
Main Research Focus
Connick laboratory investigates the immunopathogenesis of HIV infection in 3
distinct areas: 1) identifying
strategies employed by the virus to evade the immune system; 2) the influence
of sex and sex hormones on sex differences in disease outcome; and 3) the role
of inflammation on comorbidities in HIV infection, particularly cardiovascular
disease. Because most HIV replication
occurs in secondary lymphoid tissues, our work has largely concentrated on
understanding the biology of HIV replication within lymphoid tissues and unique
features of the host immune response in those tissues. Ongoing studies evaluate secondary lymphoid
tissues from both HIV-infected humans and SIV-infected rhesus macaques using
disaggregated cells as well as intact tissues.
Another area of focus involves the investigation of virus-host
interactions in the female genital tract and the influence of female sex
hormones. A better understanding of the mechanisms that prevent immune
elimination of HIV is essential for development of a prophylactic vaccine as
well as a cure for HIV infection.
Personnel and personnel titles (academic and job
Joy Folkvord, MS –
Senior Professional Research Associate
Brodie Miles, PhD – Postdoctoral Fellow
Shannon Miller, BS – Graduate Student
Selected Publications (citations)
JM, Armon C, Connick E. Lymphoid follicles are sites of heightened
human immunodeficiency virus type 1 (HIV-1) replication and reduced
antiretroviral effector mechanisms. AIDS
Research and Human Retroviruses 2005;21:363-70.
2. Folkvord JM, McCarter MD, Ryder J, Meditz AL, Forster JE, Connick E. Alpha-Defensins
1, 2, and 3 are expressed by granulocytes in lymphoid tissues of HIV-1
seropositive and seronegative individuals.
J AIDS 2006; 42:529-36.
3. Connick E, Mattila T, Folkvord JM,
Schlichtemeier R, Meditz AL, McCarter MD, MaWhinney S, Hage A, White C, Skinner
PJ. Cytotoxic T cells fail to accumulate
at sites of HIV-1 replication in lymphoid tissue. J Immunol 2007; 178:6975-83.
4. Meditz A, Schlichtemeier R, Folkvord J, Givens M, Lesh K, Ray G,
McCarter M, Connick E. SDF-1a is a Potent Inducer of HIV-1-specific CD8+ T-cell
Chemotaxis, but Migration of CD8+ T Cells is Impaired at High Viral Loads. AIDS
Research and Human Retroviruses 2008;24:977-85.
E, Bosch RJ, Aga E, Schlichtemeier R, Demeter LM, Volberding P and the ACTG 709
Team. Augmented HIV-specific
Interferon-gamma Responses, but Impaired Lymphoproliferation During
Interruption of Antiretroviral Treatment Initiated in Primary HIV
Infection. J AIDS 2011;58:1-8.
AL, MaWhinney S, Allshouse A, Feser W, Markowitz M, Little S, Hecht R, Daar ES,
Collier AC, Margolick J, Kilby JM, Routy J, Conway B, Kaldor J, Levy
J, Schooley R, Cooper DA, Altfeld M, Richman D, Connick E. Sex,
Race, and Geographic Region Influence Clinical Outcomes Following Primary HIV-1
Infection. J Infect Dis 2011;203:442-51.
7. Meditz AL, Haas MK, Folkvord
AJM, Melander K, Young R, McCarter M, MaWhinney S, Campbell T, Lie Y, Coakley
E, Levy DN, Connick E. HLA-DR+CD38+CD4+ T Lymphocytes Have Elevated
CCR5 Expression and Produce the Majority of R5-tropic HIV-1 RNA in Vivo. J Virol 2011;85:10189-10200.
8. Meditz AL, Moreau KL,
MaWhinney S, Gozansky WS, Melander K, Kohrt, WM, Wierman, ME, Connick E. CCR5 Expression is Elevated
on Endocervical CD4+ T-Cells in Healthy Postmenopausal Women. J AIDS
RA, Mudd JC, Savoye Anne-Laure, Perreau M, van Grevenynghe J, Metcalf T, Connick E, Meditz AL, Freeman GJ, Abesada-Terk G, Jacobson JM, Brooks AD,
Crotty S, Estes JD, Pantaleo G, Lederman MM, Haddad EK. Inadequate T follicular
cell help impairs B cell immunity during HIV infection. Nature Medicine 2013;
19:494-9. PMCID: PMC3843317
10. Meditz AL, Folkvord JM, Lyle NH, Searls K, Lie
Y, Coakley E, McCarter
M, MaWhinney S, Connick E. CCR5 Expression is Reduced in Lymph Nodes of
HIV-1-Infected Women Compared to Men, But Does Not Mediate Sex Differences in
Viral Loads. J Infect Dis 2014;
209:922-30. PMCID: PMC3935472
Haas MK, Levy DN, Folkvord JM, Connick E.
Distinct Patterns of Bcl-2 Expression Occur in R5- and X4-tropic
HIV-1-Producing Lymphoid Tissue Cells Infected Ex Vivo. AIDS Research and Human Retroviruses (in
12. Connick E, Folkvord JM, Lind KT, Rakasz
EG, Miles B, Wilson NA, Santiago ML, Schmitt K, Stephens EB, Kim
HO, Wagstaff R, Li S, Abdelaal HM, Kemp N, Watkins DI, Samantha
MaWhinney S, Skinner PJ. Compartmentalization
of SIV Replication Within Secondary Lymphoid Tissues of Rhesus Macaques is
Linked to Disease Stage and Inversely Related to Localization of Virus-Specific
CTL. J Immunol (in press).
Information coming soon!
Dr. Frank’s research program investigates how interactions between commensal microorganisms, pathogens, and the mucosal immune system contribute to human health and disease. This work uses a variety of genomic and metagenomic technologies to study the mechanisms by which the human host and its associated microbial communities adapt and respond to one another. Current research projects examine these issues in the context of 1) Mother to child HIV transmission, 2) Staphylococcus aureus and Streptococcus pneumoniae carriage and infection, 3) Inflammatory bowel disease, and 4) Maternal and infant nutrition. Through the Microbiome Resource Consortium (MiRC), Dr. Frank is committed to making the resources and infrastructure required for microbiome studies readily available to the research community at UC-Denver and at-large.
Selected Recent Publications:
• Robertson, C.E., Harris, J.K., Wagner, B.D., Granger, D., Browne, K., Tatem, B., Feazel, L.M., Park, K., Pace, N.R., and Frank, D.N. 2013. Explicet: Graphical user interface software for metadata-driven management, analysis, and visualization of microbial ecology data. Bioinformatics. In Press.
• Krebs, N.F., Sherlock, L.G., Westcott, J., Culbertson, D., Hambidge, K.M., Miller, L.V., Robertson, C.E., Feazel, L.M., and Frank, D.N. 2013. Effects on the Infant Intestinal Microbiome of Complementary Feeding Regimes with Different Iron (Fe) Exposure. J. Peds. 163(2):416-423
• Khailova, L., Wischmeyer, P.E., Frank, D.N., and Dominguez, J.A. 2013. Probiotic Administration Reduces Mortality and Improves Intestinal Epithelial Homeostasis in Experimental Sepsis. Anesthesiology. 119(1):166-77.
• Robertson, C.E., Baumgartner, L.K., Harris, J.K., Peterson, K.L., Stevens, M.J., Frank, D.N., Pace, N.R. 2013. Culture-Independent Analysis of Aerosol Microbiology in a Metropolitan Subway System. Appl. Env Microbiol. 79(11): 3485-3493.
• Markle, J.G.M., Frank, D.N., Mortin-Toth, S., Robertson, C.E., Feazel, L.M., Rolle-Kampczyk, U., vonBergen, M., McCoy, K.D., Macpherson, A.J., and Danska, J.S. 2013. Sex Differences in the Gut Microbiome Drive Hormone-Dependent Regulation of Autoimmunity. Science. 339(6123):1084-1088.
• Rodriguez de Evgrafov, M. Frank, D.N., Koll, P., Baumgartner, L.K., Hernandez, M.T., and Pace, N.R. 2013. Culture-Independent Microbiological Analysis of Bioaerosols in Concentrated Animal Feeding Operations. Aer. Sci. Technol. 47:755-766.
• Ramakrishnan, V.R., Feazel, L.M., Abrass, L.J., and Frank, D.N. 2013. Prevalence and abundance of Staphylococcus aureus in the middle meatus of patients with chronic rhinosinusitis, nasal polyps, and asthma. Intl Forum Allergy Rhinol. 3(4):267-271. 10 OCT 2012, DOI: 10.1002/alr.21101
• Nelson, A.W., Feazel, L.M., Robertson, C.E., Spear, J.R. and Frank, D.N. 2012. Microbiological water quality monitoring in a resource-limited urban area: a study in Kumbo, Cameroon. J. Pub. Health in Africa. 3(2):e19.
• Frank, D.N., Manigart, O., Van de Perre, P., Meda, N., Leroy, V., Valea, D., Zhang, W., Dabis, F., Pace, N.R., and Janoff, E.N. 2012. Altered Vaginal Microbiota in African Women with HIV Infection from Burkina Faso is Associated with Risk of Perinatal Mother-to-Child HIV Transmission. J. AIDS. 60(3):299-306.
• Kelley, C.J., Colgan, S.P. and Frank, D.N. 2012. Of Microbes and Meals: The Health Consequences of Dietary Endotoxemia. Nutr Clin Pract. 27(2):215-225.
• Zhang, T, DeSimone, R.A., Jiao, X., Rohlf, F.J., Zhu, W, Gong, Q.Q., Hunt, S.R., Dassopoulos, T., Newberry, R.D., Sodergren, E., Weinstock, G.M., Robertson, C.E., Frank, D.N., Li, E. 2012. Host genes related to Paneth cells and xenobiotic metabolism are associated with shifts in human ileum-associated microbial composition. PLoS ONE. 7(6):e30044. PMCID: PMC3374611
• Li, E., Hamm, C.M., Gulati, A., Sartor, R.B., Chen, H., Wu, X., Zhang, Tianyi Z., Rohlf, F.J., Zhu, W., Gu, C., Robertson, C.E., Pace, N.R., Sartor, R.B., Boedeker, E.C., Harpaz, N., Yuan, J., Weinstock, G.M., Sodergren, E., and Frank, D.N. 2012. Inflammatory Bowel Disease Phenotype, C. difficile, and NOD2 Genotype are Associated with Shifts in Human Ileum Associated Microbial Composition. PLoS ONE. 7(6)e26284. PMCID: PMC3374607
• Xiong, X., Frank, D.N., Robertson, C.E., Hung, S., Markle, J., Canty, A., McCoy, K.D., Macpherson, A.J., Poussier, P., Danska, J., and Parkinson, J. 2012. Generation and Analysis of A Mouse Model Metatranscriptome Through Illumina Based RNA-Sequencing. PLoS ONE. 7(4):e36009. PMCID: PMC3338770
• Feazel, L.M., Robertson, C.E., Ramakrishnan, V.R., and Frank, D.N. 2012. Microbiome complexity and Staphylococcus aureus in chronic rhinosinusitis. The Laryngoscope. 122(2):467-472. PMCID: PMC3398802
• Hara, N., Alkanani, A.K., Ir, D., Robertson, C.E., Wagner, B., Frank, D.N., and D. Zipris. 2012. Prevention of Virus-Induced Type 1 Diabetes with Antibiotic Therapy. J. Immunol. 189(8): 3805-3814.
• Frank, D.N., Zhu, W., Sartor, R.B., and Li, E. 2011. Investigating the Biological and Clinical Significance of Human Dysbioses. Trends Microbiol. 19(9):427-434. PMCID: PMC3164499
• Frank, D.N., Roberstson, C.E., Hamm, C.M., Kpadeh, Z., Zhang, T., Chen, H., Zhu, W., Sartor, R.B., Harpaz, N., Pace, N.R. and Li, E. 2011. Disease Phenotype and Genotype are Associated with Shifts in Intestinal-associated Microbiota in Inflammatory Bowel Diseases. Inflam Bowel Dis. 17(1):179-184.
• Frank, D.N., Feazel, L.M., Bessesen, M.T., Price, C.S., Janoff, E.N, and Pace, N.R. 2010. The Human Nasal Microbiota and Staphylococcus aureus Carriage. PLoS One. 5(5):e10598. PMCID: PMC2871794
Information coming soon!
HIV/AIDS infects 35 million people worldwide but an
effective HIV-1 vaccine has remained elusive. Vaccines work by eliciting
protective adaptive immune responses that include antibodies that can directly
neutralize viruses, and cytotoxic T cell responses that can kill infected
cells. Thus, unraveling basic mechanisms that could enhance antibody and T cell
responses could significantly assist vaccine development efforts. A key may be
found in the mysterious events during the earliest stages of infection, a
timeframe that is governed by the innate arm of the immune system. In fact, the
importance of the innate immune response is encoded in the HIV-1 genome.
HIV-1 encodes the proteins Vif and Vpu that counteract innate host proteins
that could directly inhibit retroviruses. Vif counteracts APOBEC3G, a cytidine
deaminase that can block reverse transcription, whereas Vpu counteracts
Tetherin, a protein that ‘tethers’ virion and cell membranes to prevent virus
release. While much effort has been invested in investigating molecular aspects
of the Vif:APOBEC3G interaction and Vpu:Tetherin interactions, the
immunobiology of APOBEC3G and Tetherin remains unclear. Our laboratory aims to
fill this important conceptual gap using three experimental systems.
Immunobiology of Retrovirus Restriction Factors. (Top) HIV-1 encodes the proteins Vif and
Vpu which antagonize APOBEC3G and Tetherin, respectively. Vif links APOBEC3G to
the E3 Ligase ubiquitination machinery, leading to its degradation. Vpu may
link Tetherin for degradation or mislocalization. (Bottom) APOBEC3 restriction results in the production of
non-infectious virus particles that may prime B cell responses. On the other
hand, Tetherin-mediated endocytosis of virions may promote viral peptide
presentation to MHC molecules, resulting in improved T cell responses. (Photo
credit for panels on Vif and Vpu protein interactions: Warner Greene and John
1. Immunology of
retrovirus restriction factors in mice
Major breakthroughs in immunology utilized mouse models due
to the plethora of immunological tools available and the many possibilities for
genetic studies. Using a well-described mouse model of retrovirus infection,
the Friend retrovirus complex, we obtained evidence that APOBEC3 could
influence the retrovirus-specific neutralizing antibody response, whereas
Tetherin can influence cell-mediated immunity. A major focus of the laboratory
is to decipher the underlying mechanisms. Our hypothesis is that APOBEC3,
through direct and indirect mechanisms, may influence immunoglobulin somatic
hypermutation, a mutagenic process in B cells that results in higher antibody
binding. On the other hand, we hypothesize that Tetherin-mediated endocytosis
may enhance antigen presentation to Major Histocompatibility Complex molecules
to prime T cell responses. These mechanisms are being investigated in
collaboration with Dr. Kim Hasenkrug (NIAID)
and colleagues with diverse expertise in Friend retrovirus infection
adaptive immunity in the SIV/rhesus macaque model
SIV infection of rhesus macaques is the gold standard for
AIDS pathogenesis studies. It has two major advantages: (a) the timing, dose
and route of infection can be controlled; and (2) molecular clones of SIV can
be genetically manipulated. In collaboration with Dr.Edward Stephens (University of Kansas), we have generated SIV molecular
clones with defects in Vif and Nef that would allow for the evaluation of the
resulting adaptive immune response. We are particularly interested in tracking
how SIV would evolve in the context of these responses. To facilitate these
studies, we generated novel tools to investigate SIV innate and adaptive
immunity, such as the characterization of the rhesus macaque APOBEC3 locus, and quantifying viral and
antibody mutation rates through next-generation sequencing approaches.
3. Genetics and
regulation of innate antiretroviral restriction factors in humans
Early in the HIV-1 epidemic, Interferon-a was
administered in HIV-1 infected individuals and have shown significant clinical
potency. However, the mechanism for how IFN-a inhibited HIV-1 remains unknown. Among
hundreds of Interferon-Stimulated Genes (ISGs), potential IFN-a
effectors are the 7 APOBEC3 proteins and Tetherin, but also Mx2, Ribonuclease
L, Viperin, and several others. To identify the primary effectors of IFN-a
against primary HIV-1 strains, we utilize the highly physiologically-relevant
Lamina Propria Aggregate Culture (LPAC) model developed by Dr. Cara Wilson (University of Colorado). In a
separate study, we also obtained DNA from individuals resistant to HIV-1
infection based on nearly 2 decades of studies on HIV discordant couples by Dr. Eric Hunter (Emory University) and colleagues in
the Zambia. Our goal is to determine if polymorphisms in the human APOBEC3 locus play a role as to why some
individuals who are repeatedly exposed to HIV-1 remain uninfected.
Current (in alphabetical order)
Brad Barrett, MS (Senior Research Associate)
Chemistry, Illinois State University, 2000
2010 – present
Research: Host genetic control of Friend
Kejun Guo, PhD (Instructor)
Microbiology, Auburn University, AL, 2004
2010 – present
factor biology by next-generation sequencing
Kalani Halemano (Graduate Student, PhD Microbiology)
Biochemistry & Molecular Biology, Whitman College, WA, 2008
D. Watkins Pre-doctoral Fellow, American Society for Microbiology
2010 – present
Research: Mechanism of retroviral antibody
Michael S. Harper (Graduate Student, MSTP/PhD
Neuroscience, College of William & Mary, VA, 2009
2011 – present
Pre-doctoral Fellow, Tim Gill Endowment for HIV/AIDS
Research: Interferon-mediated control of
Drs. Charles Dinarello and Cara Wilson)
Sam X. Li (Graduate Student, PhD Microbiology)
Biology, University of Kansas, Lawrence, KS, 2009
2011 – present
(2012) Colorado Clinical &
Translational Science Institute TL1 TR000155
(2013) Molecular Pathogenesis of
Infectious Disease T32 AI052066
Research: Role of myeloid restriction factors
in retroviral immunity
Karl J. Heilman (Research Associate)
Political Science, University of St Louis, MO, 2009
2010 – present
Research: Novel physiological roles of APOBEC3
Diana S. Smith, MS (Lab Manager/ Senior Research
Mol Cell Dev Biology, University of Colorado Boulder, 1977
2009 – Dec 2011
Research: Mechanisms underlying the Apobec3/Rfv3 phenotype
Current: Lab Manager (Beck laboratory),
VA Medical Center
Jessica Diaz-Rivera (Undergraduate Trainee)
University of Puerto Rico in Cayey
2012 – Aug 2012
Graduate Education for Multicultural Students (GEMS) Program
Research: Innate sensing and
retrovirus-specific antibody development
1. Bradley S. Barrett*, Kejun Guo*,
Michael S. Harper, Sam X. Li, Karl J. Heilman, Nicholas O. Davidson and Mario
L. Santiago. 2014. Reassessment of murine APOBEC1 as a retrovirus restriction
factor in vivo. Virology, in press.
2. Elizabeth Connick, Joy M. Folkvord,
Katherine T. Lind, Eva G. Rakasz, Nancy A. Wilson, Mario L. Santiago, Edward B.
Stephens, Hyeon Kim, Reese Wagstaff, Hadia Mohamed, Nathan Kemp, Samantha
MaWhinney and Pamela J. Skinner. 2014. Compartmentalization of SIV replication
within secondary lymphoid tissues of rhesus macaques is linked to disease stage
and inversely related to localization of virus-specific CTL. J Immunol, in press.
3. Miki Katuwal*, Yaqiong Wang*, Kimberly
Schmitt, Kejun Guo, Kalani Halemano, Mario L. Santiago§ and Edward
B. Stephens. 2014. Cellular HIV-1 restriction by truncated Old World monkey
APOBEC3A proteins lacking an intact deaminase domain. Virology 468-470C:532-544. PMID: 25262471.
4. Sam X. Li, Bradley S. Barrett, Karl J.
Heilman, Ronald J. Messer, Rachel A. Liberatore, Paul D. Bieniasz, George
Kassiotis, Kim J. Hasenkrug and Mario L. Santiago. 2014. Tetherin promotes the
innate and adaptive cell-mediated immune response against retrovirus infection in vivo. J Immunol 193(1): 306-16. PMID:
5. Kalani Halemano*, Kejun Guo*, Karl J.
Heilman, Bradley S. Barrett, Diana S. Smith, Kim J. Hasenkrug and Mario L. Santiago.
Immunoglobulin somatic hypermutation by APOBEC3/Rfv3 during retroviral
infection. Proc Natl Acad Sci USA
111(21): 7759-64. PMID: 24821801.
6. Amanda K. Steele, Eric J. Lee, Jennifer
A. Manuzak, Stephanie M. Dillon, J. David Beckham, Martin D. McCarter, Mario L.
Santiago and Cara C. Wilson. 2014. Microbial alteration of HIV-1 mediated
mucosal CD4+ T cell death pathways ex
vivo. Retrovirology 11:14. PMID:
7. Marielle Cavrois, Jason Neidleman,
Mario L. Santiago, Cynthia A. Derdeyn, Eric Hunter and Warner C. Greene. 2014.
Enhanced fusion and virion incorporation for HIV-1 subtype C envelopes with
compact V1/V2 domains. J Virol 88(4):
2083-94. PMID: 24335304.
8. Sam X. Li, Bradley S. Barrett, Michael
S. Harper, Karl J. Heilman, Kalani Halemano, Amanda L. Steele, Kejun Guo,
Robert H. Silverman and Mario L. Santiago. 2013. Ribonuclease L is not critical
for innate restriction and adaptive immunity against Friend retrovirus
infection. Virology 443(1):134-42.
9. Kimberly Schmitt, Kejun Guo, Miki
Katuwal, Darayu Wilson, Courtney Prochnow, Ronda Bransteitter, Xiaojiang S.
Chen, Mario L. Santiago and Edward B. Stephens. 2013. Lentivirus restriction by
diverse primate APOBEC3A proteins. Virology
442(1): 82-96. PMID: 23648232.
10. Kalani Halemano, Bradley S. Barrett, Sam
X. Li, Michael S. Harper, Diana S. Smith, Karl J. Heilman, and Mario L.
Santiago. 2013. Fv1 restriction and
retrovirus vaccine immunity in Apobec3-deficient
129P2 mice. PLOS One 8(3):e60500.
11. Michael S. Harper, Bradley S. Barrett,
Diana S. Smith, Sam X. Li, Kathrin Gibbert, Ulf Dittmer, Kim J. Hasenkrug and Mario
L. Santiago. 2013. Interferon-alpha treatment inhibits acute Friend retrovirus
replication primarily through the antiviral effector molecule Apobec3. J Immunol 190(4): 1583-90. PMID:
12. Kalani Halemano, Michael S. Harper,
Kejun Guo, Sam X. Li, Karl J. Heilman, Bradley S. Barrett, and Mario L.
Santiago. 2013. Humoral immunity in the Friend retrovirus infection model. Immunologic Research 55(1): 249-260. PMID:
13. Bradley S. Barrett, Diana S. Smith, Sam
X. Li, Kejun Guo, Kim J. Hasenkrug and Mario L. Santiago. 2012. A single
nucleotide polymorphism in Tetherin
promotes retroviral restriction in vivo.
PLOS Pathogens 8(3): e1002596. PMID:
14. Will Fischer, Christian Apetrei, Mario
L. Santiago, Yingying Li, Rajeev Gautam, Ivona Pandrea, George M. Shaw,
Beatrice H. Hahn, Norman L. Letvin, Gary J. Nabel and Bette T. Korber. 2012.
Distinct evolutionary pressures underlie diversity in simian and human
immunodeficiency virus lineages. J Virol
86(24): 13217-31. PMID: 23055550.
15. Diana S. Smith, Kejun Guo, Bradley S.
Barrett, Karl J. Heilman, Leonard H. Evans, Kim J. Hasenkrug, Warner C. Greene
and Mario L. Santiago. 2011. Noninfectious retrovirus particles drive the
Apobec3/Rfv3 dependent neutralizing
antibody response. PLOS Pathogens
7(10): e1002284. PMID: 21998583.
16. Kimberly Schmitt, Kejun Guo, Malinda
Algaier, Autumn Ruiz, Fang Cheng, Jianming Qiu, Silke Wissing, Mario L.
Santiago and Edward B. Stephens. 2011. Differential virus restriction patterns
of rhesus macaque and human Apobec3A: implications for lentivirus evolution. Virology 419(1): 24-42. PMID: 21868050.
17. Mario L. Santiago, Diana S. Smith, Bradley
S. Barrett, Mauricio Montano, Robert L. Benitez, Roberta Pelanda, Kim J.
Hasenkrug and Warner C. Greene. 2011. Persistent Friend virus replication and
disease in Apobec3 deficient mice
expressing functional B cell activating factor receptor. J Virol 85(1): 189-199. PMID: 20980520.
18. Gilad Doitsh, Marielle Cavrois, Kara G.
Lassen, Orlando Zepeda, Yang Z, Mario L. Santiago, Andrew M. Hebbeler and
Warner C. Greene. 2010. Abortive HIV infection mediates CD4+ T cell depletion
and inflammation in human lymphoid tissue. Cell
143(5): 789-801. PMID: 21111238.
19. Angelo Kolokithas, Kyle Rosenke, Frank
Malik, Duncan Hendrick, Lukas Swanson, Mario L. Santiago, John L. Portis, Kim
J. Hasenkrug and Leonard H. Evans. 2010. The glycosylated Gag protein of a
Murine Leukemia Virus inhibits the anti-retroviral function of Apobec3. J Virol 84(20): 10933-6. PMID: 20702647.
20. Mario L. Santiago, Robert L. Benitez,
Mauricio Montano, Kim J. Hasenkrug and Warner C. Greene. 2010. Innate
retroviral restriction by Apobec3 promotes antibody affinity maturation in vivo. J Immunol 185(2): 1114-23. PMID: 20566830.
21. Kara G. Lassen, Silke Wissing, Michael
A. Lobritz, Mario L. Santiago and Warner C. Greene. 2010. Identification of two
APOBEC3F splice variants displaying HIV-1 antiviral activity and differential
Vif-sensitivity. J Biol Chem 285(38):
29326-35. PMID: 20624919.
22. Julie M. Decker, Kenneth P. Zammit,
Juliet L. Easlick, Mario L. Santiago, Denise Bonenberger, Beatrice H. Hahn,
Olaf Kutsch and Frederic Bibollet-Ruche. 2009. Effective activation alleviates
the replication block of CCR5-tropic HIV-1 in chimpanzee CD4+ lymphocytes. Virology 394(1): 109-118. PMID:
23. Mario L. Santiago, Mauricio Montano,
Robert L. Benitez, Ronald J. Messer, Wes Yonemoto, Bruce Chesebro, Kim J.
Hasenkrug and Warner C. Greene. 2008. Apobec3
encodes Rfv3, a gene influencing
neutralizing antibody control of retrovirus infection. Science 321(5843): 1343-46. PMID: 18772436.
24. Weimin Liu, Michael Worobey, Yingying
Li, Brandon F. Keele, Frederic Bibollet-Ruche, Yuanyuan Guo, Paul A. Goepfert, Mario
L. Santiago, Jean-Bosco N. Ndjango, Cecile Neel, Stephen L. Clifford, Crickette
Sanz, Shadrack Kamenya, Michael L. Wilson, Anne E. Pusey, Nicole Gross-Camp,
Christophe Boesch, Vince Smith, Koichiro Zamma, Michael A. Huffman, John C.
Mitani, David P. Watts, Martine Peeters, George M. Shaw, William M. Switzer,
Paul M. Sharp and Beatrice H. Hahn. 2008. Molecular
ecology and natural history of simian foamy virus infection in wild-living
4(7): e1000097. PMID:
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