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Title: The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection

Abstract

Identification of the transmitted/founder virus makes possible, for the first time, a genome-wide analysis of host immune responses against the infecting HIV-1 proteome. A complete dissection was made of the primary HIV-1–specific T cell response induced in three acutely infected patients. Cellular assays, together with new algorithms which identify sites of positive selection in the virus genome, showed that primary HIV-1–specific T cells rapidly select escape mutations concurrent with falling virus load in acute infection. Kinetic analysis and mathematical modeling of virus immune escape showed that the contribution of CD8 T cell–mediated killing of productively infected cells was earlier and much greater than previously recognized and that it contributed to the initial decline of plasma virus in acute infection. After virus escape, these first T cell responses often rapidly waned, leaving or being succeeded by T cell responses to epitopes which escaped more slowly or were invariant. These latter responses are likely to be important in maintaining the already established virus set point. In addition to mutations selected by T cells, there were other selected regions that accrued mutations more gradually but were not associated with a T cell response. These included clusters of mutations in envelope that were targetedmore » by NAbs, a few isolated sites that reverted to the consensus sequence, and bystander mutations in linkage with T cell–driven escape.« less

Authors:
 [1];  [1];  [2];  [3];  [4];  [4];  [2];  [2];  [1];  [2];  [3];  [1];  [5];  [3];  [6];  [4];  [7];  [1];  [4];  [2] more »;  [2];  [7];  [1] « less
+ Show Author Affiliations
  1. University of Oxford (United Kingdom)
  2. University of Alabama, Birmingham, AL (United States)
  3. Duke University, Durham, NC (United States)
  4. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
  5. Harvard University, Boston, MA (United States)
  6. University of North Carolina, Chapel Hill, NC (United States)
  7. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States); The Santa Fe Institute, Santa Fe, NM (United States)
Publication Date:
Research Org.:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; Center for HIV/AIDS Vaccine Immunology; National Institute for Health; Bill and Melinda Gates Foundation; Jenner Fellowship; USDOE Laboratory Directed Research and Development (LDRD) Program
OSTI Identifier:
1625194
Grant/Contract Number:  
AC52-06NA25396; A1067854-03; 37874
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Experimental Medicine
Additional Journal Information:
Journal Volume: 206; Journal Issue: 6; Journal ID: ISSN 0022-1007
Publisher:
Rockefeller University Press
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; fixed-effects likelihood; intracellular cytokine staining; neutralizing antibody; spot forming unit; single genome amplification; simian immunodeficiency virus.

Citation Formats

Goonetilleke, Nilu, Liu, Michael K. P., Salazar-Gonzalez, Jesus F., Ferrari, Guido, Giorgi, Elena, Ganusov, Vitaly V., Keele, Brandon F., Learn, Gerald H., Turnbull, Emma L., Salazar, Maria G., Weinhold, Kent J., Moore, Stephen, Letvin, Norman, Haynes, Barton F., Cohen, Myron S., Hraber, Peter, Bhattacharya, Tanmoy, Borrow, Persephone, Perelson, Alan S., Hahn, Beatrice H., Shaw, George M., Korber, Bette T., and McMichael, Andrew J. The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection. United States: N. p., 2009. Web. doi:10.1084/jem.20090365.
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Goonetilleke, Nilu, Liu, Michael K. P., Salazar-Gonzalez, Jesus F., Ferrari, Guido, Giorgi, Elena, Ganusov, Vitaly V., Keele, Brandon F., Learn, Gerald H., Turnbull, Emma L., Salazar, Maria G., Weinhold, Kent J., Moore, Stephen, Letvin, Norman, Haynes, Barton F., Cohen, Myron S., Hraber, Peter, Bhattacharya, Tanmoy, Borrow, Persephone, Perelson, Alan S., Hahn, Beatrice H., Shaw, George M., Korber, Bette T., & McMichael, Andrew J. The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection. United States. https://doi.org/10.1084/jem.20090365
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Goonetilleke, Nilu, Liu, Michael K. P., Salazar-Gonzalez, Jesus F., Ferrari, Guido, Giorgi, Elena, Ganusov, Vitaly V., Keele, Brandon F., Learn, Gerald H., Turnbull, Emma L., Salazar, Maria G., Weinhold, Kent J., Moore, Stephen, Letvin, Norman, Haynes, Barton F., Cohen, Myron S., Hraber, Peter, Bhattacharya, Tanmoy, Borrow, Persephone, Perelson, Alan S., Hahn, Beatrice H., Shaw, George M., Korber, Bette T., and McMichael, Andrew J. Mon . "The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection". United States. https://doi.org/10.1084/jem.20090365. https://www.osti.gov/servlets/purl/1625194.
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@article{osti_1625194,
title = {The first T cell response to transmitted/founder virus contributes to the control of acute viremia in HIV-1 infection},
author = {Goonetilleke, Nilu and Liu, Michael K. P. and Salazar-Gonzalez, Jesus F. and Ferrari, Guido and Giorgi, Elena and Ganusov, Vitaly V. and Keele, Brandon F. and Learn, Gerald H. and Turnbull, Emma L. and Salazar, Maria G. and Weinhold, Kent J. and Moore, Stephen and Letvin, Norman and Haynes, Barton F. and Cohen, Myron S. and Hraber, Peter and Bhattacharya, Tanmoy and Borrow, Persephone and Perelson, Alan S. and Hahn, Beatrice H. and Shaw, George M. and Korber, Bette T. and McMichael, Andrew J.},
abstractNote = {Identification of the transmitted/founder virus makes possible, for the first time, a genome-wide analysis of host immune responses against the infecting HIV-1 proteome. A complete dissection was made of the primary HIV-1–specific T cell response induced in three acutely infected patients. Cellular assays, together with new algorithms which identify sites of positive selection in the virus genome, showed that primary HIV-1–specific T cells rapidly select escape mutations concurrent with falling virus load in acute infection. Kinetic analysis and mathematical modeling of virus immune escape showed that the contribution of CD8 T cell–mediated killing of productively infected cells was earlier and much greater than previously recognized and that it contributed to the initial decline of plasma virus in acute infection. After virus escape, these first T cell responses often rapidly waned, leaving or being succeeded by T cell responses to epitopes which escaped more slowly or were invariant. These latter responses are likely to be important in maintaining the already established virus set point. In addition to mutations selected by T cells, there were other selected regions that accrued mutations more gradually but were not associated with a T cell response. These included clusters of mutations in envelope that were targeted by NAbs, a few isolated sites that reverted to the consensus sequence, and bystander mutations in linkage with T cell–driven escape.},
doi = {10.1084/jem.20090365},
journal = {Journal of Experimental Medicine},
number = 6,
volume = 206,
place = {United States},
year = {Mon Jun 01 00:00:00 EDT 2009},
month = {Mon Jun 01 00:00:00 EDT 2009}
}
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    Within-Epitope Interactions Can Bias CTL Escape Estimation in Early HIV Infection
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    Monkeying Around: Using Non-human Primate Models to Study NK Cell Biology in HIV Infections
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