In vivo migration and function of transferred hiv-1-specific cytotoxic t cells

feature-image

Play all audios:

Loading...

ABSTRACT THE PERSISTENCE OF HIV REPLICATION IN INFECTED INDIVIDUALS MAY REFLECT AN INADEQUATE HOST HIV-SPECIFIC CD8 + CYTOTOXIC T LYMPHOCYTE (CTL) RESPONSE. THE FUNCTIONAL ACTIVITY OF


HIV-SPECIFIC CTLS AND THE ABILITY OF THESE EFFECTOR CELLS TO MIGRATE _IN VIVO_ TO SITES OF INFECTION WAS DIRECTLY ASSESSED BY EXPANDING AUTOLOGOUS HIV-1 GAG-SPECIFIC CD8 + CTL CLONES _IN


VITRO_ AND ADOPTIVELY TRANSFERRING THESE CTLS TO HIV-INFECTED INDIVIDUALS. THE TRANSFERRED CTLS RETAINED LYTIC FUNCTION _IN VIVO_ , ACCUMULATED ADJACENT TO HIV-INFECTED CELLS IN LYMPH NODES


AND TRANSIENTLY REDUCED THE LEVELS OF CIRCULATING PRODUCTIVELY INFECTED CD4 + T CELLS. THESE RESULTS PROVIDE DIRECT EVIDENCE THAT HIV-SPECIFIC CTLS TARGET SITES OF HIV REPLICATION AND


MEDIATE ANTIVIRAL ACTIVITY, AND INDICATE THAT THE DEVELOPMENT OF IMMUNOTHERAPEUTIC APPROACHES TO SUSTAIN A STRONG CTL RESPONSE TO HIV MAY BE A USEFUL ADJUNCT TO TREATMENT OF HIV INFECTION.


Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Subscribe to this


journal Receive 12 print issues and online access $209.00 per year only $17.42 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now


Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer


support SIMILAR CONTENT BEING VIEWED BY OTHERS IMMUNE MOBILISING T CELL RECEPTORS REDIRECT POLYCLONAL CD8+ T CELLS IN CHRONIC HIV INFECTION TO FORM IMMUNOLOGICAL SYNAPSES Article Open access


01 November 2022 CD8 LYMPHOCYTES MITIGATE HIV-1 PERSISTENCE IN LYMPH NODE FOLLICULAR HELPER T CELLS DURING HYPERACUTE-TREATED INFECTION Article Open access 12 July 2022 DYNAMIC CD4+ T CELL


HETEROGENEITY DEFINES SUBSET-SPECIFIC SUPPRESSION AND PD-L1-BLOCKADE-DRIVEN FUNCTIONAL RESTORATION IN CHRONIC INFECTION Article 18 November 2021 REFERENCES * Ada, G.L. & Jones, P.D. The


immune response to influenza virus. _Cur. Top. Microbiol. Immunol._ 128, 1–54 (1986). Article  CAS  Google Scholar  * Cannon, M.J., Openshaw, P.J. & Askonas, B.A. Cytotoxic T cells clear


virus but augment lung pathology in mice infected with respiratory syncytial virus. _J. Exp. Med. _ 168, 1163–1168 ( 1988). Article  CAS  Google Scholar  * Byrne, J.A. & Oldstone, M.B.


Biology of cloned cytotoxic T lymphocytes specific for lymphocytic choriomeningitis virus. VI. Migration and activity _in vivo_ in acute and persistent infection. _ J. Immunol._ 136, 698–704


(1986). CAS  PubMed  Google Scholar  * Riddell, S.R. & Greenberg, P.D. Principles for adoptive T cell therapy of human viral diseases. _Annu. Rev. Immunol._ 13, 545–586 (1995). Article


  CAS  Google Scholar  * Walter, E.A. _ et al._ Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the


donor. _N. Engl. J. Med._ 333, 1038– 1044 (1995). Article  CAS  Google Scholar  * Li, C.R., Greenberg, P.D., Gilbert, M.J., Goodrich, J.M. & Riddell, S.R. Recovery of HLA-restricted


cytomegalovirus (CMV)-specific T-cell responses after allogeneic bone marrow transplant: correlation with CMV disease and effect of ganciclovir prophylaxis. _Blood_ 83, 1971–1979 (1994). CAS


  Google Scholar  * Reusser, P., Riddell, S.R., Meyers, J.D. & Greenberg, P.D. Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation:


pattern of recovery and correlation with cytomegalovirus infection and disease. _Blood_ 78, 1373– 1380 (1991). CAS  Google Scholar  * Posavad, C.M., Koelle, D.M., Shaughnessy, M.F. &


Corey, L. Severe genital herpes infections in HIV-infected individuals with impaired herpes simplex virus-specific CD8+ cytotoxic T lymphocyte responses. _ Proc. Natl. Acad. Sci. USA_ 94,


10289– 10294 (1997). Article  CAS  Google Scholar  * Heslop, H.E., Brenner, M.K. & Rooney, C.M. Donor T cells to treat EBV-associated lymphoma. _ N. Engl. J. Med._ 331, 679–680 (1994).


Article  CAS  Google Scholar  * Papadopoulos, E.B. _ et al._ Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow


transplantation. _N. Engl. J. Med._ 330, 1185– 1191 (1994). Article  CAS  Google Scholar  * Safrit, J.T. & Koup, R.A. The immunology of primary HIV infection: which immune responses


control HIV replication? _Curr. Opin. Immunol. _ 7, 456–461 ( 1995). Article  CAS  Google Scholar  * Koup, R.A. _ et al._ Temporal association of cellular immune responses with the initial


control of viremia in primary human immunodeficiency virus type 1 syndrome. _J. Virol._ 68, 4650– 4655 (1994). CAS  PubMed  PubMed Central  Google Scholar  * Borrow, P., Lewicki, H., Hahn,


B.H., Shaw, G.M. & Oldstone, M.B. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. _J.


Virol._ 68, 6103– 6110 (1994). CAS  PubMed  PubMed Central  Google Scholar  * Musey, L. _et al._ Cytotoxic T cell responses, viral load, and disease progression in early human


immunodeficiency virus type 1 infection. _N. Engl. J. Med._ 337, 1267–1274 ( 1997). Article  CAS  Google Scholar  * Cao, Y., Qin, L., Zhang, L., Safrit, J. & Ho, D.D. Virologic and


immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. _N. Engl. J. Med._ 332, 201–208 (1995). Article  CAS  Google Scholar  * Harrer, T. _ et


al._ Cytotoxic T lymphocytes in asymptomatic long-term nonprogressing HIV-1 infection. Breadth and specificity of the response and relation to _ in vivo_ viral quasispecies in a person with


prolonged infection and low viral load. _J. Immunol._ 156, 2616– 2623 (1996). CAS  PubMed  Google Scholar  * Klein, M.R. _ et al._ Kinetics of gag-specific cytotoxic T lymphocyte responses


during the clinical course of HIV-1 infection: a longitudinal analysis of rapid progressors and long-term asymptomatics. _J. Exp. Med._ 181, 1365–1372 (1995). Article  CAS  Google Scholar  *


Carmichael, A., Jin, X., Sissons, P. & Borysiewicz, L. Quantitative analysis of the human immunodeficiency virus type 1 (HIV-1) specific cytotoxic T lymphocytes (CTL) response at


different stages of HIV-1 infection: differential CTL responses to HIV-1 and Epstein-Barr virus in late disease. _ J.f Exp. Med._ 177, 249–256 (1993). Article  CAS  Google Scholar  *


Goulder, P.J. _ et al._ Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. _Nature Med._ 3, 212–217 (1997). Article  CAS  Google Scholar


  * Borrow, P. _ et al._ Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. _Nature


Med._ 3, 205– 211 (1997). Article  CAS  Google Scholar  * Phillips, R.E. _ et al._ Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. _Nature_ 354,


453–459 (1991). Article  CAS  Google Scholar  * Cheynier, R. _ et al._ HIV and T cell expansion in splenic white pulps is accompanied by infiltration of HIV-specific cytotoxic T lymphoctyes.


_Cell_ 78, 373–387 (1994). Article  CAS  Google Scholar  * Ogg, G.S. _et al._ Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. _Science_ 279, 2103– 2105


(1998). Article  CAS  Google Scholar  * Pantaleo, G. _ et al._ Accumulation of human immunodeficiency virus-specific cytotoxic T lymphocytes away from the predominant site of virus


replication during primary infection. _Eur. J. Immunol._ 27, 3166– 3173 (1997). Article  CAS  Google Scholar  * Collins, K.L., Chen, B.K., Kalams, S.A., Walker, B.D. & Baltimore, D.


HIV-1 Nef protein protects infected primary cells against killing by cytotoxic T lymphoctyes. _Nature_ 391, 397–401 (1998). Article  CAS  Google Scholar  * Zinkernagel, R.M. &


Hengartner, H. T-cell-mediated immunopathology versus direct cytolysis by virus: implications for HIV and AIDS. _Immunol. Today_ 15, 262– 268 (1994). Article  CAS  Google Scholar  * Plata,


F. _et al._ AIDS virus-specific cytotoxic T lymphocytes in lung disorders. _Nature_ 328, 348–351 (1987). Article  CAS  Google Scholar  * Jassoy, C., Johnson, R.P., Navia, B.A., Worth, J.


& Walker, B.D. Detection of a vigorous HIV-1-specific cytotoxic T lymphocyte response in the cerebrospinal fluid from infected persons with AIDS dementia complex. _J. Immunol._ 149,


3113–3119 (1992). CAS  PubMed  Google Scholar  * Heslop, H.E. _ et al._ Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified


virus-specific T lymphocytes. _Nature Med._ 2, 551–555 (1996). Article  CAS  Google Scholar  * Riddell, S.R. _ et al._ Restoration of viral immunity in immunodeficient humans by the adoptive


transfer of T cell clones. _Science_ 257 , 238–241 (1992). Article  CAS  Google Scholar  * Riddell, S.R., Gilbert, M.J. & Greenberg, P.D. CD8+ cytotoxic T cell therapy of


cytomegalovirus and HIV infection. _Curr. Opin. Immunol._ 5, 484 –491 (1993). Article  CAS  Google Scholar  * Riddell, S.R. _ et al._ T-cell mediated rejection of gene-modified HIV-specific


cytotoxic T lymphocytes in HIV-infected patients. _Nature Med._ 2, 216–223 (1996). Article  CAS  Google Scholar  * Embretson, J. _ et al._ Massive covert infection of helper T lymphocytes


and macrophages by HIV during the incubation period of AIDS. _Nature_ 362, 359–362 (1993). Article  CAS  Google Scholar  * Walker, R.E. _ et al._ Peripheral expansion of pre-existing mature


T cells is an important means of CD4+ T-cell regeneration HIV-infected adults. _Nature Med._ 4, 852–856 (1998). Article  CAS  Google Scholar  * Reddehase, M.J., Mutter, W. & Koszinowski,


U.H. _In vivo_ application of recombinant interleukin 2 in the immunotherapy of established cytomegalovirus infection. _ J. Exp. Med._ 165, 650–656 (1987). Article  CAS  Google Scholar  *


Matloubian, M., Concepcion, R.J. & Ahmed, R. CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. _J. Virol._ 68, 8056–8063 (1994). CAS 


PubMed  PubMed Central  Google Scholar  * Rosenberg, E.S., _ et al._ Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. _Science_ 278, 1447– 1450 (1997).


Article  CAS  Google Scholar  * Woffendin, C., Ranga, U., Yang, Z., Xu, L. & Nabel, G.J. Expression of a protective gene prolongs survival of T cells in human immunodeficiency


virus-infected patients. _Proc. Natl. Acad. Sci. USA_ 93, 2889–2894 (1996). Article  CAS  Google Scholar  * Nelson, B.H., Lord, J.D. & Greenberg, P.D. Cytoplasmic domains of the


interleukin-2 receptor beta and gamma chains mediate the signal for T-cell proliferation. _ Nature_ 369, 333–336 ( 1994). Article  CAS  Google Scholar  * Patterson, B.K. _ et al._ Detection


of HIV-1 DNA and messenger RNA in individual cells by PCR-driven _in situ_ hybridization and flow cytometry. _ Science_ 260, 976–979 ( 1993). Article  CAS  Google Scholar  * Patterson, B.K.,


Goolsby, C., Hodara, V., Lohman, K.L. & Wolinsky, S.M. Detection of CD4+ T cells harboring human immunodeficiency virus type 1 DNA by flow cytometry using simultaneous immunophenotyping


and PCR-driven _in situ_ hybridization: evidence of epitope masking of the CD4 cells surface molecule _in vivo_. _ J. Virol._ 69, 4316–4322 (1995). CAS  PubMed  PubMed Central  Google


Scholar  * Patterson, B.K., Mosiman, V.L., Cantarero, L., Bhattacharya, M. & Goolsby, C. Detection of HIV-RNA-positive monocytes in peripheral blood of HIV-positive patients by


simultaneous flow cytometric analysis of intracellular HIV RNA and cellular immunophenotype. _ Cytometry_ 31, 265–274 ( 1998). Article  CAS  Google Scholar  * Yang, L.P. _ et al._ Productive


infection of neonatal CD8+ T lymphocytes by HIV-1. _J. Exp. Med._ 187, 1139– 1144 (1998). Article  CAS  Google Scholar  * Brodie, S.J. _ et al._ The effects of pharmacological and


lentivirus-induced immune suppression on orbivirus pathogenesis: assessment of virus burden in blood monocytes and tissues by reverse transcription-_in situ_ PCR. _ J. Virol._ 72, 5599–5609


(1998). CAS  PubMed  PubMed Central  Google Scholar  * Brodie, S.J. _ et al._ Macrophage function in simian AIDS. Killing defects _in vivo_ are independent of macrophage infection,


associated with alterations in Th phenotype, and reversible with IFN-gamma. _J. Immunol._ 153, 5790–5801 (1994). CAS  PubMed  Google Scholar  * Brodie, S.J. _ et al._ Epizootic hemorrhagic


disease: analysis of tissues by amplification and _in situ_ hybridization reveals widespread orbivirus infection at low copy numbers. _J. Virol._ 72, 3863– 3871 (1998). CAS  PubMed  PubMed


Central  Google Scholar  * Diamond, C. _ et al._ Human herpesvirus 8 in the prostate glands of men with Kaposi's sarcoma. _J. Virol._ 72, 6223– 6227 (1998). CAS  PubMed  PubMed Central


  Google Scholar  * Brodie, S.J. _ et al._ Ovine lentivirus expression and disease. Virus replication, but not entry, is restricted to macrophages of specific tissues. _ Am. J. Pathol._ 146,


250–263 (1995). CAS  PubMed  PubMed Central  Google Scholar  * Fox, C.H. & Cottler-Fox, M. _In situ_ hybridization for detection of HIV RNA. _Curr. Protocol. Immunol._ 12.18.11–21


(1994). Download references ACKNOWLEDGEMENTS _We thank D. Spach (AIDS Clinical Trial Unit, University of Washington) for patient referral; K. Diem, M. Elliot, S. Friborg (Targeted Genetics),


C. Hoffer, D. Kelly, C. B. Joiner, J. Joyce, V. Mosiman, D. Muthui, P.M. O'Hearn, E.L. Peterson, L. Wilson (Targeted Genetics) and B. Wood for technical assistance; B. Gilman and E.


Gilman for their gift to the Program in Immunology; and Targeted Genetics for obtaining the IND for these studies, for providing the LN retroviral vector and for doing quality control


testing. This study was supported by funds from the National Institutes of Health (AI36613 and AI41535 to S.B., P30 HD28834 and AI-27757 to D.L., AI30731 to S.R., P.D.G, and L.C.) and from


the Pediatric AIDS Foundation, 77296-19—PF to D.L._ AUTHOR INFORMATION Author notes * Bruce K. Patterson, Daniel Jiyamapa and Philip D. Greenberg: Department of Obstetrics and Gynecology,


Northwestern University Medical School, Chicago, Illinois 94404, USA S.J.B. and D.A.L. contributed equally to this work. AUTHORS AND AFFILIATIONS * Department of Laboratory Medicine, Box


356527, University of Washington, Seattle, 98101, Washington, USA Scott J. Brodie & Lawrence Corey * Department of Pediatrics, Box 356527, University of Washington, Seattle, 98101,


Washington, USA Deborah A. Lewinsohn * Department of Urology, Box 356527, University of Washington, Seattle, 98101, Washington, USA John Krieger * Department of Medicine, Box 356527,


University of Washington, Seattle, 98101, Washington, USA Lawrence Corey, Philip D. Greenberg & Stanley R. Riddell * Department of Immunology, Box 356527, University of Washington,


Seattle, 98101, Washington, USA Philip D. Greenberg * Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., D3-100, Seattle, 98109, Washington , USA Deborah A. Lewinsohn, Lawrence


Corey, Philip D. Greenberg & Stanley R. Riddell Authors * Scott J. Brodie View author publications You can also search for this author inPubMed Google Scholar * Deborah A. Lewinsohn View


author publications You can also search for this author inPubMed Google Scholar * Bruce K. Patterson View author publications You can also search for this author inPubMed Google Scholar *


Daniel Jiyamapa View author publications You can also search for this author inPubMed Google Scholar * John Krieger View author publications You can also search for this author inPubMed 


Google Scholar * Lawrence Corey View author publications You can also search for this author inPubMed Google Scholar * Philip D. Greenberg View author publications You can also search for


this author inPubMed Google Scholar * Stanley R. Riddell View author publications You can also search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions


ABOUT THIS ARTICLE CITE THIS ARTICLE Brodie, S., Lewinsohn, D., Patterson, B. _et al._ _In vivo_ migration and function of transferred HIV-1-specific cytotoxic T cells. _Nat Med_ 5, 34–41


(1999). https://doi.org/10.1038/4716 Download citation * Received: 29 July 1998 * Accepted: 05 November 1998 * Issue Date: January 1999 * DOI: https://doi.org/10.1038/4716 SHARE THIS ARTICLE


Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard


Provided by the Springer Nature SharedIt content-sharing initiative