AIDS and Cancer Virus Program

Biography

While a student in the laboratory of Dr. Gregory Burton, Dr. Estes studied the contributions of follicular dendritic cells and the germinal center microenvironment to HIV pathogenesis receiving his Ph.D. in Immunology and HIV Pathogenesis from Brigham Young University in 2003. Dr. Estes continued his work as postdoctoral fellow in the laboratory of Dr. Ashley Haase in the Department of Microbiology at the University of Minnesota, focusing on the in vivo immunopathogology of lentiviral infections in lymphatic tissues in both human patient cohorts and non-human primate models. Dr. Estes joined the AIDS and Cancer Virus Program in 2007 and was named the head of the Tissue Analysis Core (TAC) in 2009. Dr. Estes is a Principal Scientist/Principal Investigator and currently heads both the Retroviral Immunopathology Section and Tissue Analysis Core.

Core Description

The Tissue Analysis Core provides state-of-the art tissue analysis capabilities (i.e. immunofluorescence, immunohistochemistry, in situ hybridization, quantitative image analysis, laser capture microdissection) for AIDS & Cancer Virus Program (ACVP) directed studies and in support of intramural and extramural investigators working on collaborative studies relevant to key questions in HIV/AIDS research, with an emphasis on analysis of specimens from non-human primate (NHP) models. The Tissue Analysis Core is working with ACVP investigators and a network of collaborators to better understand HIV/SIV mucosal transmission, pathogenesis and therapeutic intervention strategies. Specifically, the Tissue Analysis Core is working with both intramural and extramural scientists to: i) Elucidate the factors surrounding mucosal transmission, establishment of infection, and progression to systemic infection using nonhuman primate models of mucosal transmission, including extensive tissue analyses (IHC and ISH, in combination with Laser Capture Microdissection and SGA viral sequencing, in collaboration with the Viral Evolution Core) to define the steps and host-virus interactions involved in the spread of virus in the first days following mucosal inoculation, to determine the tissues, cells and pathways that are involved in transmission to systemic dissemination; ii) Evaluate interventions intended to attenuate the early inflammatory response to SIV infection, to assess their impact on microbial translocation and associated immune activation; aimed at determining if adjunctive immunosuppressive therapeutic strategies can block or redirect the immunoinflammatory response, in the absence of any direct impact of viral replication during the acute phase of infection; iii) Explore the potential of antifibrotic adjunctive treatment to ameliorate the immunopathogenesis of SIV infection, including the ability to limit or reverse lymphoid tissue fibrosis when treatment is started in the setting of established infection, and the effects of antifibrotic agents in combination with antiretroviral drug treatment; and iv) Provide unique capabilities available through our Core to the research community as a whole.

Research Description for Retroviral Immunopathology Section (RIPS)

During HIV-1 mucosal transmission, the viral diversity of the infecting virus is typically reduced as the virus transverses the various host barriers in order to establish a new infection. While the stringency of the mucosal blockade is now well documented, there is a paucity of understanding on where the bottlenecks occur including the contributions of various host components in determining the nature of transmitted founder viruses. Furthermore, it is currently unknown whether cell-free virus or cell-associated virus is predominately responsible for viral transmission or if both play an important role. A detailed understanding of the biology of lentiviral transmission will likely be critical to guide the design of efficacious vaccine approaches, as strategies to interdict cell-free viral transmission at mucosal surfaces will likely be vastly different from cell-associated. What is clear is that from a large, diverse inoculum, a small founder population can be successful in establishing systemic infection.

Once HIV-1 gains a foothold and begins to replicate in lymphoid tissues, in spite of vigorous and sustained host immune responses to the virus, HIV-1 is never eliminated, and in the absence of antiretroviral therapy (ART) continues to replicate. However, the host’s continual immune responses to HIV-1 results in a chronic state of aberrant immune activation, which is a hallmark of HIV-1 infection in humans and pathogenic SIV infection in rhesus macaques (RMs), the most widely used non-human primate (NHP) model for studies of HIV transmission, infection and pathogenesis. This high state of immune activation typically begins early after the acquisition of HIV/SIV (by 14 days post infection; dpi) and remains high throughout the course of infection in the absence of ART.

This immune activation is associated with the expression of pro-inflammatory immune modulators, and elevated pro-inflammatory cytokines that results in significant and progressive lymphoid tissue fibrosis and CD4+ T cell loss. Understanding the mechanisms underlying the pathological immune activation that characterizes progressive HIV/SIV disease is an active area of research. The marked persistent pathological activation of the immune system in chronic HIV/SIV is a result of not only host responses to viral antigens, but also a result of host responses to translocated microbial products from the damaged gastrointestinal tract (GI). Damage to the integrity of the epithelial barrier of the GI tract leads to microbial translocation that disseminate systemically in SIV-infected RMs and HIV-infected humans. The mechanism responsible for the damage to the epithelial barrier of the GI tract is not completely defined, however, our studies suggest that early damage to the GI epithelial barrier ensues concomitant with high acute viral replication and host inflammatory responses. Once damage has taken place bacterial constituents that translocate from the lumen of the GI tract perpetuate a state of inflammation resulting in various degrees of colitis in SIV-infected RMs. The major research aims for the Retroviral Immunopathology Section are focused on i) understanding and further elucidating the biology, mechanisms and barriers to lentiviral mucosal transmission and viral dissemination in order to better guide preventative strategies, and ii) to understand the factors driving systemic immune activation and disease progression to guide adjunctive therapeutic intervention strategies that can be used to ameliorate immune activation and its associated pathologic consequences.

Recent Publications

1. Restricted replication of xenotropic murine leukemia virus-related virus in pigtailed macaques. Del Prete GQ, Kearney MF, Spindler J, Wiegand A, Chertova E, Roser JD, Estes JD, Hao XP, Trubey CM, Lara A, Lee K, Chaipan C, Bess JW Jr, Nagashima K, Keele BF, Macallister R, Smedley J, Pathak VK, Kewalramani VN, Coffin JM, Lifson JD. J Virol. 2012 Mar;86(6):3152-66. Epub 2012 Jan 11. PMID: 22238316
2. Pathologic lesions in chimpanzees (Pan trogylodytes schweinfurthii) from Gombe National Park, Tanzania, 2004-2010. Terio KA, Kinsel MJ, Raphael J, Mlengeya T, Lipende I, Kirchhoff CA, Gilagiza B, Wilson ML, Kamenya S, Estes JD, Keele BF, Rudicell RS, Liu W, Patton S, Collins A, Hahn BH, Travis DA, Lonsdorf EV. J Zoo Wildl Med. 2011 Dec;42(4):597-607. PMID: 22204054
3. Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson's disease. Forsyth CB, Shannon KM, Kordower JH, Voigt RM, Shaikh M, Jaglin JA, Estes JD, Dodiya HB, Keshavarzian A. PLoS One. 2011;6(12):e28032. Epub 2011 Dec 1. PMID: 22145021
4. Depletion of CD4? T cells abrogates post-peak decline of viremia in SIV-infected rhesus macaques. Ortiz AM, Klatt NR, Li B, Yi Y, Tabb B, Hao XP, Sternberg L, Lawson B, Carnathan PM, Cramer EM, Engram JC, Little DM, Ryzhova E, Gonzalez-Scarano F, Paiardini M, Ansari AA, Ratcliffe S, Else JG, Brenchley JM, Collman RG, Estes JD, Derdeyn CA, Silvestri G. J Clin Invest. 2011 Nov;121(11):4433-45. doi: 10.1172/JCI46023. Epub 2011 Oct 17. PMID: 22005304
5. Altered distribution of mucosal NK cells during HIV infection. Sips M, Sciaranghella G, Diefenbach T, Dugast AS, Berger CT, Liu Q, Kwon D, Ghebremichael M, Estes JD, Carrington M, Martin JN, Deeks SG, Hunt PW, Alter G. Mucosal Immunol. 2012 Jan;5(1):30-40. doi: 10.1038/mi.2011.40. Epub 2011 Oct 12. PMID: 21993602
6. SIV infection of rhesus macaques results in dysfunctional T- and B-cell responses to neo and recall Leishmania major vaccination. Klatt NR, Vinton CL, Lynch RM, Canary LA, Ho J, Darrah PA, Estes JD, Seder RA, Moir SL, Brenchley JM. Blood. 2011 Nov 24;118(22):5803-12. Epub 2011 Sep 29. PMID: 21960586
7. One percent tenofovir applied topically to humanized BLT mice and used according to the CAPRISA 004 experimental design demonstrates partial protection from vaginal HIV infection, validating the BLT model for evaluation of new microbicide candidates. Denton PW, Othieno F, Martinez-Torres F, Zou W, Krisko JF, Fleming E, Zein S, Powell DA, Wahl A, Kwak YT, Welch BD, Kay MS, Payne DA, Gallay P, Appella E, Estes JD, Lu M, Garcia JV. J Virol. 2011 Aug;85(15):7582-93. Epub 2011 May 18. PMID: 21593172
8. Barriers to mucosal transmission of immunodeficiency viruses. Keele BF, Estes JD. Blood. 2011 Jul 28;118(4):839-46. Epub 2011 May 9. PMID: 21555745
9. Zeng M, Smith AJ, Wietgrefe SW, Southern PJ, Schacker TW, Reilly CS, Estes JD, Burton GF, Silvestri G, Lifson JD, Carlis JV, Haase AT. Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections. J Clin Invest 121(3):998-1008, 2011. 2011 Mar 1. PMID: 21393864
10. Gordon SN, Cervasi B, Odorizzi P, Silverman R, Aberra F, Ginsberg G, Estes JD, Paiardini M, Frank I, Silvestri G: Disruption of intestinal CD4+ T cell homeostasis is a key marker of systemic CD4+ T cell activation in HIV-infected individuals. J Immunol 185(9):5169-79, 2010. Epub 2010 Oct 1. PMID: 20889546
11. Harris LD, Klatt NR, Vinton C, Briant JA, Tabb B, Ladell K, Lifson J, Estes JD, Price DA, Hirsch VM, Brenchley JM: Mechanisms underlying {gamma}-{delta} T cell subset perturbations in SIV-infected Asian rhesus macaques. Blood 116(20):4148-57, 2010. Epub 2010 Jul 26. PMID: 20660793
12. Minang JT, Trivett MT, Bolton DL, Trubey CM, Estes JD, Li Y, Smedley J, Pung R, Rosati M, Jalah R, Pavlakis GN, Felber BK, Piatak M Jr, Roederer M, Lifson JD, Ott D, Ohlen C: Distribution, persistence and efficacy of adoptively transferred central and effector memory-derived autologous SIV-specific CD8+ T cell clones in rhesus macaques during acute infection. J Immunol 184(1):315-326, 2010. Epub 2009 Nov 30. PMID: 19949091.
13. Denton PW, Krisko JF, Powell DA, Mathias M, Kwak YT, Martinez-Torres F, Zou W, Payne DA, Estes JD, Garcia JV: Systemic administration of antiretrovirals prior to exposure prevents rectal and intravenous HIV-1 transmission in humanized BLT mice. PLoS ONE 5(1):e8829, 2010. Epub 2010 Jan 21. PMID: 20098623 PMCID: PMC2809117.
14. Klatt NR, Shudo E, Ortiz AM, Engram JC, Paiardini M, Lawson B, Miller MD, Else J, Pandrea I, Estes JD, Apetrei C, Schmitz JE, Ribeiro RM, Perelson AS, Silvestri G: CD8+ lymphocytes control viral replication in SIVmac239-infected rhesus macaques without decreasing the lifespan of productively infected cells. PLoS Pathog 6(1):e1000747, 2010. Epub 2010 Jan 29. PMID: 20126441 PMCID: PMC2813271.
15. Klatt NR, Harris LD, Vinton CL, Sung H, Briant JA, Tabb B, Morcock D, McGinty JW, Lifson JD, Lafont BA, Martin MA, Levine AD, Estes JD, Brenchley JM: Compromised gastrointestinal integrity in pigtail macaques is associated with increased microbial translocation, immune activation and IL-17 production in the absence of SIV infection. Mucosal Immunol 3(4):387-398, 2010. Epub 2010 Mar 31. PMID: 20357762.
16. Harris LD, Tabb B, Sodora DL, Paiardini M, Klatt NR, Douek DC, Silvestri G, Muller-Trutwin M, Vasile-Pandrea I, Apetrei C, Hirsch V, Lifson JD, Brenchley JM, Estes JD: Downregulation of robust acute type I IFN responses distinguishes nonpathogenic SIV infection of natural hosts from pathogenic SIV infection of rhesus macaques. J Virol 84(15):7886-7891, 2010. Epub 2010 May 19. PMID: 20484518.
17. Felts RL, Narayan K, Estes JD, Shi D, Trubey CM, Fu J, Hartnell LM, Ruthel GT, Schneider DK, Nagashima K, Bess JW Jr, Bavari S, Lowekamp BC, Bliss D, Lifson JD, Subramaniam S: 3D visualization of HIV transfer at the virological synapse between dendritic cells and T-cells. PNAS 107(3):13336-13341, 2010. Epub 2010 Jul 12. PMID: 206224966.
18. Estes JD, Harris LD, Klatt NR, Tabb B, Pittaluga S, Paiardini M, Barclay GR, Smedley J, Pung R, Oliveira KM, Hirsch VM, Silvestri G, Douek DC, Miller CJ, Haase AT, Lifson J, Brenchley JM: Damaged intestinal epithelial integrity linked to microbial translocation in pathogenic simian immunodeficiency virus infections. PLoS Pathog 6(8):e1001052, 2010. Epub 2010 Aug 19. PMID: 20808901.
19. Estes JD: Role of collagen deposition in lymphatic tissues and immune reconstruction during HIV-1 and SIV infections. Current HIV/AIDS Reports 6:29-35, 2009.
20. Thacker TC, Zhou X, Estes JD, Jiang Y, Keele BF, Elton TS, Burton GF: Follicular dendritic cells and HIV-1 transcription in CD4+ T cells. J Virol 83:150-158, 2009.
21. Hatziioannou T, Ambrose Z, Chung NPY, Piatak MJr, Yuan F, Trubey CM, Coalter V, Kiser R, Schneider D, Smedley J, Pung R, Gathuka M, Estes JD, Veazey RS, KewalRamani VN, Lifson JD, Bieniasz PD: A macaque model of HIV-1 infection. PNAS 106:4425-4429, 2009.
22. Li Q, Estes JD, Schlievert PM, Duan L, Brosnahan AJ, Southern PJ, Reilly CS, Peterson ML, Schultz-Darken N, Brunner KG, Nephew KR, Pambuccian S, Lifson JD, Carlis JV, Haase, AT: Glycerol monolaurate prevents mucosal SIV transmission. Nature 458:1034-1038, 2009.
23. Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, Laxer R, Tedgard U, Cowen EW, Pham T-H, Booty M, Estes JD, Sandler NG, Plass N, Stone DL, Turner ML, Hill S, Butman JA, Turner ML, Hill S, Butman JA, Schneider R, Babyn P, El-Shanti HI, Pope E, Barron K, Bing X, Laurence A, Lee C-C R, Chapelle D, Clarke GI, Ohson K, Nicholson M, Gadina M, Yang B, Korman BD, Gregersen PK, van Hagen PM, Hak aE, Huizing M, Rahman P, Douek DC, Remmers EF, Kastner DL, Goldbach-Mansky R: An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. New England Journal of Medicine 360:2426-2437, 2009.
24. 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 460:515-519, 2009.
25. Sodora DL, Allan JS, Apetrei C, Brenchley JM, Douek DC, Else JG, Estes JD, Hahn BH, Hirsch VM, Kaur A, Kirchhoff F, Muller-Trutwin M, Pandrea IV, Schmitz JE, Silvestri G: Towards an AIDS vaccine: Lessons from natural SIV infections of African nonhuman primate hosts. Nature Med 15:861-865, 2009.

Staffing - TAC

• Leslie Johnston, Research Associate II

Staffing - RIPS

• David Morcock, Research Associate II
• Recruiting, Post-doctoral Fellow
• Xing-Pei (Harry) Hao, Dedicated PHL Support