Magnitude and Kinetics of CD8+ T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point

doi:10.1016/j.immuni.2015.08.012

. 2015 Sep 15;43(3):591-604.

doi: 10.1016/j.immuni.2015.08.012. Epub 2015 Sep 8.

Magnitude and Kinetics of CD8+ T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point

Zaza M Ndhlovu¹, Philomena Kamya¹, Nikoshia Mewalal², Henrik N Kløverpris³, Thandeka Nkosi², Karyn Pretorius², Faatima Laher², Funsho Ogunshola², Denis Chopera⁴, Karthik Shekhar⁵, Musie Ghebremichael⁶, Nasreen Ismail², Amber Moodley¹, Amna Malik⁷, Alasdair Leslie⁸, Philip J R Goulder⁹, Søren Buus¹⁰, Arup Chakraborty¹¹, Krista Dong⁶, Thumbi Ndung'u¹², Bruce D Walker¹³

Affiliations

¹ HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA.
² HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa.
³ KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa; Department of Immunology and Microbiology, University of Copenhagen, 2200-Copenhagen N, Denmark.
⁴ KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa.
⁵ Department of Chemical Engineering, Massachusetts Institute of Technology, 25 Ames St, Cambridge, MA 02142, USA.
⁶ Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA.
⁷ Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom.
⁸ Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa.
⁹ HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa; Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom.
¹⁰ Department of Immunology and Microbiology, University of Copenhagen, 2200-Copenhagen N, Denmark.
¹¹ Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, 25 Ames St, Cambridge, MA 02142, USA.
¹² HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa; Max Planck Institute for Infection Biology, Chariteplatz 1, 10117, Berlin, Germany.
¹³ HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: bwalker@mgh.harvard.edu.

PMID: 26362266
PMCID: PMC4575777
DOI: 10.1016/j.immuni.2015.08.012

Magnitude and Kinetics of CD8+ T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point

Zaza M Ndhlovu et al. Immunity. 2015.

. 2015 Sep 15;43(3):591-604.

doi: 10.1016/j.immuni.2015.08.012. Epub 2015 Sep 8.

Authors

Affiliations

¹ HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA.
² HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa.
³ KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa; Department of Immunology and Microbiology, University of Copenhagen, 2200-Copenhagen N, Denmark.
⁴ KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa.
⁵ Department of Chemical Engineering, Massachusetts Institute of Technology, 25 Ames St, Cambridge, MA 02142, USA.
⁶ Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA.
⁷ Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom.
⁸ Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa.
⁹ HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa; Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom.
¹⁰ Department of Immunology and Microbiology, University of Copenhagen, 2200-Copenhagen N, Denmark.
¹¹ Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, 25 Ames St, Cambridge, MA 02142, USA.
¹² HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa; Max Planck Institute for Infection Biology, Chariteplatz 1, 10117, Berlin, Germany.
¹³ HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, 4001, South Africa; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, 400 Technology Square, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: bwalker@mgh.harvard.edu.

PMID: 26362266
PMCID: PMC4575777
DOI: 10.1016/j.immuni.2015.08.012

Abstract

CD8(+) T cells contribute to the control of HIV, but it is not clear whether initial immune responses modulate the viral set point. We screened high-risk uninfected women twice a week for plasma HIV RNA and identified 12 hyperacute infections. Onset of viremia elicited a massive HIV-specific CD8(+) T cell response, with limited bystander activation of non-HIV memory CD8(+) T cells. HIV-specific CD8(+) T cells secreted little interferon-γ, underwent rapid apoptosis, and failed to upregulate the interleukin-7 receptor, known to be important for T cell survival. The rapidity to peak CD8(+) T cell activation and the absolute magnitude of activation induced by the exponential rise in viremia were inversely correlated with set point viremia. These data indicate that rapid, high magnitude HIV-induced CD8(+) T cell responses are crucial for subsequent immune control of acute infection, which has important implications for HIV vaccine design.

PubMed Disclaimer

Figures

**Figure 1. Dynamics of absolute CD4 count and plasma viral loads during hyperacute HIV infection**
Plasma HIV-1 RNA magnitude (red) and absolute CD4 counts (blue) before HIV infection and following onset of detectable plasma viremia in 12 subjects with hyperacute HIV infection that were not receiving antiretroviral treatment. See also table S1

**Figure 2. CD8⁺ T cell activation following onset of plasma viremia**
Longitudinal analysis of CD38 and HLA-DR expression on CD8⁺ cells after HIV infection. (a) Representative FACS plots gated on CD8⁺ cells expressing CD38 and HLA-DR. Days following onset of plasma viremia (DFOPV) are indicated **(b)** Longitudinal dynamics of activated (CD38⁺HLA-DR⁺) CD8⁺ cells for 11 donors in whom samples were available for analysis. **(c)** Representative relationship between HIV-induced CD8⁺ cell activation kinetics and contemporaneous viral load. **(d)** Correlation between time to peak activation and viral load setpoint. **(e)** Correlation between frequency of activated CD8⁺ cells at peak activation and viral load set point. Spearman’s rank correlation was used in (d) and (e).

**Figure 3. CD8+ T cell proliferation and apoptosis following onset of viremia**
**(a)** Representative FACS plots gated on CD8⁺ cells expressing Ki-67 and Bcl-2. (b) Summary data for the longitudinal analysis of proliferating and pro-apoptotic CD8⁺ cells for 11 donors evaluated. **(c)** Representative relationship between Ki67^negBcl-2^lowCD8⁺ T cells and contemporaneous viral load. **(d)** CD8⁺T cell co-expression of CD38, HLA-DR, Ki67 and Bcl-2. **(e)** Correlation between peak Ki67^negBcl-2^lowCD8⁺ T cells and viral load set point. Spearman’s rank correlation was used in (e).

**Figure 4. Hyperacute HIV infection induces strong CD8⁺ T cell responses with degranulation potential**
HIV-specific CD8⁺ T cell responses were measured by ICS after overnight incubation with autologous HIV-infected CD4⁺ cells. Uninfected autologous CD4⁺ cells co-cultured with CD8⁺ cells were used as a negative control. **(a)** Representative flow plots demonstrating CD107a expression on CD8⁺ cells. **(b)** Upper panel shows CD107a expression on *ex vivo* CD8+ cells from 14 DFOPV incubated for 12 hours with HIV infected autologous CD4+ T cells. The lower panel shows CD107a expression on CD8⁺ cells from 14 DFOPV incubated in IL-2 containing media for 5 days prior to co-culture with infected autologous CD4⁺ T cells. **(c)** Proportion of CD8+ cells secreting cytokines following stimulation with HIV infected autologous CD4⁺ cells. Background responses in the uninfected co-culture condition are subtracted. Statistical significance was determined using Mann-Whitney and Kruskal Wallis tests. **(d)** Comparison between proliferating CD8⁺ T cells and CD107a positive cells at peak activation time points (also see supplementary figures). Statistical significance was determined using Mann-Whitney test. See also Figure S1, S2 and S3

**Figure 5. Analysis of HIV-specific CD8⁺ T cell responses during hyperacute HIV infection using MHC class I tetramers**
PBMCs were stained with MHC class I tetramers specific for HIV and antibodies against CD38 and HLA-DR. All plots are gated on CD8⁺ T cells. Upper panels show frequencies of HIV-specific CD8⁺ T cells for each HIV tetramer tested. Blue dots depict the frequency of tetramer⁺ cells co-expressing CD38 and HLA-DR overlaid on total CD8⁺ T cells (red dots). Data for subjects 208, 079 and 093 are shown in panels (a), (b) and (c), respectively. (d) Flow plots show combined tetramer staining and cytokine secretion measured by ICS. Representative data for one of the four donors tested are shown. (e) Proportion of HIV-specific and CMV-specific tetramer⁺ cells secreting IFN-γ following optimal peptide stimulation of a peak activation sample. Statistical significance was determined using Mann-Whitney test.

**Figure 6. Assessment of bystander CD8⁺ T cell activation during hyperacute HIV infection**
Intra-donor activation (CD8⁺ CD38⁺ HLA-DR⁺ cells) profiles of HIV, CMV, EBV and influenza virus specific (tetramer⁺) CD8⁺ T cells. Data for two donors with detectable tetramer⁺ cells specific for three different pathogens are shown in panels **(a)** and **(b)**. The first columns show flow plots gated on tetramer⁺ cells, the second column shows flow plots gated on tetramer⁺ cells that are double positive for CD38 and HLA-DR (blue dots) overlaid on total CD8⁺ T cells (red dots). **(c)** Activation data for 13 HIV, 5 CMV, 3 EBV and 3 influenza specific tetramer⁺ cells are graphed. Statistical significance was determined using Kruskal Wallis test.

**Figure 7. Activation profiles of CD8⁺ T cells in hyperacute HIV infection**
**(a)** Phenotypic analysis of HIV specific tetramer⁺ CD8⁺ cells. The first flow plot is gated on tetramer⁺ cells, the second, third and fourth plots depict tetramer⁺ cells (blue dots) overlaid on total CD8+ cells. Data showing frequencies of tetramer⁺ cells that are **(b)** Ki67^high, BCL2^low and **(c)** CD127^high are graphed. Statistical significance was determined using Mann-Whitney and Kruskal Wallis tests. (d) Frequencies of dead CD8⁺ T cells (annexin-V⁺, PI⁺ CD8⁺ cells). Statistical significance was determined using Mann-Whitney test. **(e)** Frequencies of dead CD4⁺ T cells (annexin-V⁺, PI⁺ CD4⁺ cells) after overnight incubation in R10. Statistical significance was determined using Mann-Whitney test. **(f)** Flow cytometric data for two donors showing *ex vivo* expression of annexin V by HIV tetramer⁺ and CMV tetramer⁺ cells at peak activation.

See this image and copyright information in PMC

Cited by

Immunometabolism and HIV-1 pathogenesis: food for thought.
Sáez-Cirión A, Sereti I. Sáez-Cirión A, et al. Nat Rev Immunol. 2021 Jan;21(1):5-19. doi: 10.1038/s41577-020-0381-7. Epub 2020 Aug 6. Nat Rev Immunol. 2021. PMID: 32764670 Review.
Nonhuman TRIM5 Variants Enhance Recognition of HIV-1-Infected Cells by CD8+ T Cells.
Jimenez-Moyano E, Ruiz A, Kløverpris HN, Rodriguez-Plata MT, Peña R, Blondeau C, Selwood DL, Izquierdo-Useros N, Moris A, Clotet B, Goulder P, Towers GJ, Prado JG. Jimenez-Moyano E, et al. J Virol. 2016 Sep 12;90(19):8552-62. doi: 10.1128/JVI.00819-16. Print 2016 Oct 1. J Virol. 2016. PMID: 27440884 Free PMC article.
The plasma levels of soluble ST2 as a marker of gut mucosal damage in early HIV infection.
Mehraj V, Jenabian MA, Ponte R, Lebouché B, Costiniuk C, Thomas R, Baril JG, LeBlanc R, Cox J, Tremblay C, Routy JP; Montreal Primary HIV Infection, the Canadian Long-Term Non-Progressors Study Groups. Mehraj V, et al. AIDS. 2016 Jun 19;30(10):1617-27. doi: 10.1097/QAD.0000000000001105. AIDS. 2016. PMID: 27045377 Free PMC article.
Envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques.
Li H, Wang S, Kong R, Ding W, Lee FH, Parker Z, Kim E, Learn GH, Hahn P, Policicchio B, Brocca-Cofano E, Deleage C, Hao X, Chuang GY, Gorman J, Gardner M, Lewis MG, Hatziioannou T, Santra S, Apetrei C, Pandrea I, Alam SM, Liao HX, Shen X, Tomaras GD, Farzan M, Chertova E, Keele BF, Estes JD, Lifson JD, Doms RW, Montefiori DC, Haynes BF, Sodroski JG, Kwong PD, Hahn BH, Shaw GM. Li H, et al. Proc Natl Acad Sci U S A. 2016 Jun 14;113(24):E3413-22. doi: 10.1073/pnas.1606636113. Epub 2016 May 31. Proc Natl Acad Sci U S A. 2016. PMID: 27247400 Free PMC article.
CD8 T cells targeting adapted epitopes in chronic HIV infection promote dendritic cell maturation and CD4 T cell trans-infection.
Qin K, Boppana S, Du VY, Carlson JM, Yue L, Dilernia DA, Hunter E, Mailliard RB, Mallal SA, Bansal A, Goepfert PA. Qin K, et al. PLoS Pathog. 2019 Aug 9;15(8):e1007970. doi: 10.1371/journal.ppat.1007970. eCollection 2019 Aug. PLoS Pathog. 2019. PMID: 31398241 Free PMC article.

See all "Cited by" articles

References

1. Anahtar MN, Byrne EH, Doherty KE, Bowman BA, Yamamoto HS, Soumillon M, Padavattan N, Ismail N, Moodley A, Sabatini ME, et al. Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. Immunity. 2015;42:965–976. - PMC - PubMed
1. Appay V, Papagno L, Spina CA, Hansasuta P, King A, Jones L, Ogg GS, Little S, McMichael AJ, Richman DD, Rowland-Jones SL. Dynamics of T cell responses in HIV infection. J Immunol. 2002;168:3660–3666. - PubMed
1. Badovinac VP, Porter BB, Harty JT. Programmed contraction of CD8(+) T cells after infection. Nature immunology. 2002;3:619–626. - PubMed
1. Bangs SC, McMichael AJ, Xu XN. Bystander T cell activation--implications for HIV infection and other diseases. Trends Immunol. 2006;27:518–524. - PubMed
1. Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. Journal of virology. 1994;68:6103–6110. - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions

Grants and funding

P30 AI060354/AI/NIAID NIH HHS/United States

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
- scite Smart Citations
Medical
- MedlinePlus Health Information
Research Materials
- NCI CPTC Antibody Characterization Program

[1] Anahtar MN, Byrne EH, Doherty KE, Bowman BA, Yamamoto HS, Soumillon M, Padavattan N, Ismail N, Moodley A, Sabatini ME, et al. Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. Immunity. 2015;42:965–976. - PMC - PubMed

[2] Anahtar MN, Byrne EH, Doherty KE, Bowman BA, Yamamoto HS, Soumillon M, Padavattan N, Ismail N, Moodley A, Sabatini ME, et al. Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. Immunity. 2015;42:965–976. - PMC - PubMed

[3] Appay V, Papagno L, Spina CA, Hansasuta P, King A, Jones L, Ogg GS, Little S, McMichael AJ, Richman DD, Rowland-Jones SL. Dynamics of T cell responses in HIV infection. J Immunol. 2002;168:3660–3666. - PubMed

[4] Appay V, Papagno L, Spina CA, Hansasuta P, King A, Jones L, Ogg GS, Little S, McMichael AJ, Richman DD, Rowland-Jones SL. Dynamics of T cell responses in HIV infection. J Immunol. 2002;168:3660–3666. - PubMed

[5] Badovinac VP, Porter BB, Harty JT. Programmed contraction of CD8(+) T cells after infection. Nature immunology. 2002;3:619–626. - PubMed

[6] Badovinac VP, Porter BB, Harty JT. Programmed contraction of CD8(+) T cells after infection. Nature immunology. 2002;3:619–626. - PubMed

[7] Bangs SC, McMichael AJ, Xu XN. Bystander T cell activation--implications for HIV infection and other diseases. Trends Immunol. 2006;27:518–524. - PubMed

[8] Bangs SC, McMichael AJ, Xu XN. Bystander T cell activation--implications for HIV infection and other diseases. Trends Immunol. 2006;27:518–524. - PubMed

[9] Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. Journal of virology. 1994;68:6103–6110. - PMC - PubMed

[10] Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. Journal of virology. 1994;68:6103–6110. - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Magnitude and Kinetics of CD8+ T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point

Affiliations

Magnitude and Kinetics of CD8+ T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point

Authors

Affiliations

Abstract

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Abstract

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials