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4. Selection bias at the heterosexual HIV-1 transmission bottleneck

Author

Carlson, Jonathan M., Schaefer, Malinda, Monaco, Daniela C., Batorsky, Rebecca, Claiborne, Daniel T., Prince, Jessica, Deymier, Martin J., Ende, Zachary S., Klatt, Nichole R., DeZiel, Charles E., Lin, Tien-Ho, Peng, Jian, Seese, Aaron M., Shapiro, Roger, Frater, John, Ndung'u, Thumbi, Tang, Jianming, Goepfert, Paul, Gilmour, Jill, Price, Matt A., Kilembe, William, Heckerman, David, Goulder, Philip J.R., Allen, Todd M., Allen, Susan, and Hunter, Eric

Published
2014

5. Impact of pre-adapted HIV transmission

Author

Carlson, Jonathan M., Du, Victor Y., Pfeifer, Nico, Bansal, Anju, Tan, Vincent Y.F., Power, Karen, Brumme, Chanson J., Kreimer, Anat, DeZiel, Charles E., Fusi, Nicolo, Schaefer, Malinda, Brockman, Mark A., Gilmour, Jill, Price, Matt A., Kilembe, William, Haubrich, Richard, John, Mina, Mallal, Simon, Shapiro, Roger, Frater, John, Harrigan, P. Richard, Ndung'u, Thumbi, Allen, Susan, Heckerman, David, Sidney, John, Allen, Todd M., Goulder, Philip J.R., Brumme, Zabrina L., Hunter, Eric, and Goepfert, Paul A.

Subjects
T cells -- Physiological aspects -- Genetic aspects -- Research, HLA histocompatibility antigens -- Physiological aspects -- Genetic aspects -- Research, Disease transmission -- Development and progression -- Genetic aspects -- Research, Histocompatibility antigens -- Physiological aspects -- Genetic aspects -- Research, HIV infection -- Development and progression -- Genetic aspects -- Research, Biological sciences, Health
Abstract

Human leukocyte antigen class I (HLA)-restricted [CD8.sup.+] T lymphocyte (CTL) responses are crucial to HIV-1 control. Although HIV can evade these responses, the longer-term impact of viral escape mutants remains unclear, as these variants can also reduce intrinsic viral fitness. To address this, we here developed a metric to determine the degree of HIV adaptation to an HLA profile. We demonstrate that transmission of viruses that are pre-adapted to the HLA molecules expressed in the recipient is associated with impaired immunogenicity, elevated viral load and accelerated [CD4.sup.+] T cell decline. Furthermore, the extent of pre-adaptation among circulating viruses explains much of the variation in outcomes attributed to the expression of certain HLA alleles. Thus, viral pre-adaptation exploits 'holes' in the immune response. Accounting for these holes may be key for vaccine strategies seeking to elicit functional responses from viral variants, and to HIV cure strategies that require broad CTL responses to achieve successful eradication of HIV reservoirs., Immune control of HIV is epidemiologically linked to the expression of certain HLA alleles, which mediate control through the presentation of viral peptides to CTLs (1,2). The resulting suppression of [...]

Published
2016
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6. Emergence of immune escape at dominant SARS-CoV-2 killer T cell epitope

Author

Dolton, Garry, primary, Rius, Cristina, additional, Hasan, Md Samiul, additional, Wall, Aaron, additional, Szomolay, Barbara, additional, Behiry, Enas, additional, Whalley, Thomas, additional, Southgate, Joel, additional, Fuller, Anna, additional, Morin, Théo, additional, Topley, Katie, additional, Tan, Li Rong, additional, Goulder, Philip J.R., additional, Spiller, Owen B., additional, Rizkallah, Pierre J., additional, Jones, Lucy C., additional, Connor, Thomas R., additional, and Sewell, Andrew K., additional

Published
2022
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7. The antibody response to SARS-CoV-2 Beta underscores the antigenic distance to other variants

Author

Liu, Chang, primary, Zhou, Daming, additional, Nutalai, Rungtiwa, additional, Duyvesteyn, Helen M.E., additional, Tuekprakhon, Aekkachai, additional, Ginn, Helen M., additional, Dejnirattisai, Wanwisa, additional, Supasa, Piyada, additional, Mentzer, Alexander J., additional, Wang, Beibei, additional, Case, James Brett, additional, Zhao, Yuguang, additional, Skelly, Donal T., additional, Chen, Rita E., additional, Johnson, Sile Ann, additional, Ritter, Thomas G., additional, Mason, Chris, additional, Malik, Tariq, additional, Temperton, Nigel, additional, Paterson, Neil G., additional, Williams, Mark A., additional, Hall, David R., additional, Clare, Daniel K., additional, Howe, Andrew, additional, Goulder, Philip J.R., additional, Fry, Elizabeth E., additional, Diamond, Michael S., additional, Mongkolsapaya, Juthathip, additional, Ren, Jingshan, additional, Stuart, David I., additional, and Screaton, Gavin R., additional

Published
2022
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9. Magnitude and Kinetics of CD8+ T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point

Author

Ndhlovu, Zaza M., Kamya, Philomena, Mewalal, Nikoshia, Klverpris, Henrik N., Nkosi, Thandeka, Pretorius, Karyn, Laher, Faatima, Ogunshola, Funsho, Chopera, Denis, Shekhar, Karthik, Ghebremichael, Musie, Ismail, Nasreen, Moodley, Amber, Malik, Amna, Leslie, Alasdair, Goulder, Philip J.R., Buus, Sren, Chakraborty, Arup, Dong, Krista, Ndung’u, Thumbi, and Walker, Bruce D.

Published
2015
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10. The antibody response to SARS-CoV-2 Beta underscores the antigenic distance to other variants

Author

Liu, Chang, Zhou, Daming, Nutalai, Rungtiwa, Duyvesteyn, Helen M.E., Tuekprakhon, Aekkachai, Ginn, Helen M., Dejnirattisai, Wanwisa, Supasa, Piyada, Mentzer, Alexander J., Wang, Beibei, Case, James Brett, Zhao, Yuguang, Skelly, Donal T., Chen, Rita E., Johnson, Sile Ann, Ritter, Thomas G., Mason, Chris, Malik, Tariq, Temperton, Nigel, Paterson, Neil G., Williams, Mark A., Hall, David R., Clare, Daniel K., Howe, Andrew, Goulder, Philip J.R., Fry, Elizabeth E., Diamond, Michael S., Mongkolsapaya, Juthathip, Ren, Jingshan, Stuart, David I., Screaton, Gavin R., Liu, Chang, Zhou, Daming, Nutalai, Rungtiwa, Duyvesteyn, Helen M.E., Tuekprakhon, Aekkachai, Ginn, Helen M., Dejnirattisai, Wanwisa, Supasa, Piyada, Mentzer, Alexander J., Wang, Beibei, Case, James Brett, Zhao, Yuguang, Skelly, Donal T., Chen, Rita E., Johnson, Sile Ann, Ritter, Thomas G., Mason, Chris, Malik, Tariq, Temperton, Nigel, Paterson, Neil G., Williams, Mark A., Hall, David R., Clare, Daniel K., Howe, Andrew, Goulder, Philip J.R., Fry, Elizabeth E., Diamond, Michael S., Mongkolsapaya, Juthathip, Ren, Jingshan, Stuart, David I., and Screaton, Gavin R.

Abstract

Alpha-B.1.1.7, Beta-B.1.351, Gamma-P.1 and Delta-B.1.617.2 variants of SARS-CoV-2 express multiple mutations in the spike protein (S). These may alter the antigenic structure of S, causing escape from natural or vaccine-induced immunity. Beta is particularly difficult to neutralize using serum induced by early pandemic SARS-CoV-2 strains and is most antigenically separated from Delta. To understand this, we generated 674 mAbs from Beta infected individuals and performed a detailed structure-function analysis of the 27 most potent mAbs: one binding the spike N-terminal domain (NTD), the rest the receptor binding domain (RBD). Two of these RBD-binding mAbs recognise a neutralizing epitope conserved between SARS-CoV-1 and -2, whilst 18 target mutated residues in Beta: K417N, E484K, and N501Y. There is a major response to N501Y including a public IgVH4-39 sequence, with E484K and K417N also targeted. Recognition of these key residues underscores why serum from Beta cases poorly neutralizes early pandemic and Delta viruses.

Published
2021

11. HIV TRANSMISSION: Selection bias at the heterosexual HIV-1 transmission bottleneck

Author

Carlson, Jonathan M., Schaefer, Malinda, Monaco, Daniela C., Batorsky, Rebecca, Claiborne, Daniel T., Prince, Jessica, Deymier, Martin J., Ende, Zachary S., Klatt, Nichole R., DeZiel, Charles E., Lin, Tien-Ho, Peng, Jian, Seese, Aaron M., Shapiro, Roger, Frater, John, Ndungʼu, Thumbi, Tang, Jianming, Goepfert, Paul, Gilmour, Jill, Price, Matt A., Kilembe, William, Heckerman, David, Goulder, Philip J.R., Allen, Todd M., Allen, Susan, and Hunter, Eric

Published
2014
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16. Copresentation of natural HIV-1 agonist and antagonist ligands fails to induce the T cell receptor signaling cascade

Author

Purbhoo, Marco A., Sewell, Andrew K., Klenerman, Paul, Goulder, Philip J.R., Hilyard, Katherine L., Bell, John I., Jakobsen, Bent K., and Phillips, Rodney E.

Subjects
HIV (Viruses) -- Receptors, Enzyme inhibitors -- Research, Ligands -- Research, T cells -- Receptors, Science and technology
Abstract

It is not known how human immunodeficiency virus type 1 (HIV-l)-derived antagonist peptides interfere with intracellular activation of cytotoxic T lymphocytes (CTL). We identified Gag epitope variants in HIV-1-infected patients that act as antagonists of CTL responses to unmutated epitopes. We then investigated the effect that presentation of each variant has on the early events of T cell receptor (TCR) signal transduction. We found that altered peptide ligands (APL) failed to induce phosphorylation of pp36, a crucial adaptor protein involved in TCR signal transduction. We further investigated the effect that simultaneous presentation of APL and native antigen at low, physiological, peptide concentrations (1 nM) has on TCR signal transduction, and we found that the presence of APL can completely inhibit induction of the protein tyrosine phosphorylation events of the TCR signal transduction cascade.

Published
1998

17. Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection

Author

Price, David A., Goulder, Philip J.R., Klenerman, Paul, Sewell, Andrew K., Easterbrook, Philippa J., Troop, Maxine, Bangham, Charles R.M., and Phillips, Rodney E.

Subjects
HIV (Viruses) -- Genetic aspects, HIV infection -- Genetic aspects, T cells -- Physiological aspects, Science and technology
Abstract

Cytotoxic T lymphocytes (CTLs) are thought to play a crucial role in the termination of the acute primary HIV-1 syndrome, but clear evidence for this presumption has been lacking. Here we demonstrate positive selection of HIV-1 proviral sequences encoding variants within a CTL epitope in Nef, a gene product critical for vital pathogenicity, during and after seroconversion. These positively selected HIV-1 variants carried epitope sequence changes that either diminished or escaped CTL recognition. Other proviruses had mutations that abolished the Nef epitope altogether. These results provide clear evidence that CTLs exert selection pressure on the viral population in acute HIV-1 infection.

Published
1997

18. Differential Pathogen-Specific Immune Reconstitution in Antiretroviral Therapy-Treated Human Immunodeficiency Virus-Infected Children

Author

Muenchhoff, Maximilian, Adland, Emily, Roider, Julia, Kløverpris, Henrik, Leslie, Alasdair, Boehm, Stephan, Keppler, Oliver T., Ndung'u, Thumbi, Goulder, Philip J.R., Muenchhoff, Maximilian, Adland, Emily, Roider, Julia, Kløverpris, Henrik, Leslie, Alasdair, Boehm, Stephan, Keppler, Oliver T., Ndung'u, Thumbi, and Goulder, Philip J.R.

Abstract

BACKGROUND: Susceptibility to coinfections in human immunodeficiency virus (HIV)-infected patients remains increased despite antiretroviral therapy (ART). To elucidate mechanisms involved in immune reconstitution, we studied immune activation, immune exhaustion, and HIV- and copathogen-specific T-cell responses in children before and after ART. METHODS: We prospectively enrolled 25 HIV-infected children to study HIV-, cytomegalovirus (CMV)-, and tuberculosis (TB)-specific T-cell responses before and 1 year after initiation of ART using intracellular cytokine (interleukin-2, interferon-γ, tumor necrosis factor-α) staining assays after in vitro stimulation. We further measured expression of activation, immune exhaustion, and memory phenotype markers and studied proliferative responses after antigen stimulation. RESULTS: We observed differential, pathogen-specific changes after 1 year of ART in cytokine profiles of CD4 T-cell responses that were associated with shifts in memory phenotype and decreased programmed cell death 1 (PD-1) expression. The proliferative capacity of HIV- and PPD-specific responses increased after 1 year of ART. Of note, the recovery of CMV- and TB-specific responses was correlated with a decrease in PD-1 expression (r = 0.83, P = .008 and r = 0.81, P = .0007, respectively). CONCLUSIONS: Reconstitution of immune responses on ART is associated with alterations in T-cell phenotype, function, and PD-1 expression that are distinct for HIV, TB, and CMV. The PD-1 pathway represents a potential target for immunotherapy in HIV-infected patients on ART with insufficient immune reconstitution.

Published
2019

19. Plasma IL-5 but not CXCL13 correlates with neutralization breadth in HIV-infected children

Author

Roider, Julia, Zachary Porterfield, J., Ogongo, Paul, Muenchhoff, Maximilian, Adland, Emily, Groll, Andreas, Morris, Lynn, Moore, Penny L., Ndung'U, Thumbi, Kløverpris, Henrik, Goulder, Philip J.R., Leslie, Alasdair, Roider, Julia, Zachary Porterfield, J., Ogongo, Paul, Muenchhoff, Maximilian, Adland, Emily, Groll, Andreas, Morris, Lynn, Moore, Penny L., Ndung'U, Thumbi, Kløverpris, Henrik, Goulder, Philip J.R., and Leslie, Alasdair

Abstract

Children may be the optimal target for HIV vaccine development as they generate substantially more frequent and more potent broadly HIV neutralizing antibodies (bnAbs) than adults. Development of a biomarker that correlates with neutralization breadth in this group could function as a powerful tool to facilitate the development of an HIV vaccine. Previously, we observed that this preferential ability in HIV-infected children over adults to generate bnAbs is associated with an enrichment of circulating follicular helper T-cells (TFH) with an effector phenotype, and the presence of IL-21 secreting HIV-specific TFH within lymphoid tissue germinal centers (GC). In adults, bnAbs development has been linked with high plasma levels of CXCL13, a chemoattractant for CXCR5-expressing TFH cells to the lymph node GC. We sought to test this relationship in HIV-infected children, but found no association between neutralization breadth and plasma levels of CXCL13, or with the Th2 cytokines IL-4 and IL-13, or the TFH associated factor Activin A. However, we did find an unexpected association between plasma IL-5 levels and bnAb development in these children. Importantly, although CXCL13 correlated with total circulating TFH cells, it was not associated with effector TFH. Additionally, raised CXCL13 expression was associated with a lower CD4 percentage, higher viral load and a loss of immune function, implying it is associated with progressive disease rather than HIV-specific GC activity in these subjects. Taken together, our data suggests that IL-5 should be evaluated further as a candidate plasma biomarker for HIV neutralization breadth and for monitoring vaccine responses in the pediatric age group.

Published
2019

22. Functionally Inert HIV-specific Cytotoxic T Lymphocytes Do Not Play a Major Role in Chronically Infected Adults and Children

Author

Goulder, Philip J.R., Tang, Yanhua, Brander, Christian, Betts, Michael R., Altfeld, Marcus, Annamalai, Ken, Trocha, Alicja, He, Suqin, Rosenberg, Eric S., Ogg, Graham, O'Callaghan, Christopher A., Kalams, Spyros A., McKinney, Ross E., Jr., Mayer, Kenneth, Koup, Richard A., Pelton, Stephen I., Burchett, Sandra K., McIntosh, Kenneth, and Walker, Bruce D.

Published
2000

24. The great escape -- AIDS viruses and immune control

Author

Goulder, Philip J.R. and Walker, Bruce D.

Subjects
HIV (Viruses) -- Physiological aspects, Cell-mediated cytotoxicity -- Research
Abstract

The AIDS virus can outmaneuver the cytotoxic T-cell response the immune system creates to kill it. Therefore, researchers need to develop treatments that enhance the body's immune response to the virus.

Published
1999

25. Reduced Expression of Siglec-7, NKG2A, and CD57 on Terminally Differentiated CD56−CD16+ Natural Killer Cell Subset Is Associated with Natural Killer Cell Dysfunction in Chronic HIV-1 Clade C Infection

Author

Zulu, Michael Z., primary, Naidoo, Kewreshini K., additional, Mncube, Zenele, additional, Jaggernath, Manjeetha, additional, Goulder, Philip J.R., additional, Ndung'u, Thumbi, additional, Altfeld, Marcus, additional, and Thobakgale, Christina F., additional

Published
2017
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26. Phenotypic analysis of antigen-specific T lymphocytes

Author

Altman, John D., Moss, Paul A.H., Goulder, Philip J.R., Barouch, Dan H., McHeyzer-Williams, Michael G., Bell, John I., McMichael, Andrew J., and Davis, Mark M.

Subjects
T cells -- Analysis -- Physiological aspects, Immune response -- Physiological aspects -- Analysis, Antigenic determinants -- Physiological aspects -- Analysis, Science and technology, Physiological aspects, Analysis
Abstract

Identification and characterization of antigen-specific T-lymphocytes during the course of an immune response is tedious and indirect. To address this problem, the peptide-major histocompatibility complex (MHC) ligand for a given population of T-cells was multimerized to make soluble peptide-MHC tetramers. Tetramers of human lymphocyte antigen A2 that were complexed with two different human immunodeficiency virus (HIV)-derived from influenza A matrix protein bound individuals. In general, tetramer binding correlated well with cytotoxicity assays. This approach should be useful in the analysis of T cells specific for infectious agents, tumors, and autoantigens., Quantitative analyses of antigen-specific T cell populations have provided important information on the natural course of immune-responses (1-3). Currently, the standard method for deriving frequency information is limiting dilution analysis [...]

Published
1996

27. Immunodominant cytomegalovirus-specific CD8+ T-cell responses in sub-Saharan African populations

Author

Malik, Amna, Adland, Emily, Laker, Leana, Kløverpris, Henrik, Fardoos, Rabiah, Roider, Julia, Severinsen, Mai C., Chen, Fabian, Riddell, Lynn, Edwards, Anne, Buus, Søren, Jooste, Pieter, Matthews, Philippa C., Goulder, Philip J.R., Malik, Amna, Adland, Emily, Laker, Leana, Kløverpris, Henrik, Fardoos, Rabiah, Roider, Julia, Severinsen, Mai C., Chen, Fabian, Riddell, Lynn, Edwards, Anne, Buus, Søren, Jooste, Pieter, Matthews, Philippa C., and Goulder, Philip J.R.

Abstract

More than 90% of children in Africa are infected with cytomegalovirus (CMV) by the age of 12 months. However, the high-frequency, immunodominant CD8+ T-cell responses that control CMV infection have not been well studied in African populations. We therefore sought to define the immunodominant CMV-specific CD8+ T-cell responses within sub-Saharan African study subjects. Among 257 subjects, we determined the CD8+ T-cell responses to overlapping peptides spanning three of the most immunogenic CMV proteins, pp65, IE-1 and IE-2, using IFN-y ELISpot assays. A bioinformatics tool was used to predict optimal epitopes within overlapping peptides whose recognition was statistically associated with expression of particular HLA class I molecules. Using this approach, we identified 16 predicted novel CMV-specific epitopes within CMV-pp65, IE-1 and IE-2. The immunodominant pp65-specific, IE-1, IE-2 responses were all either previously well characterised or were confirmed using peptide-MHC tetramers. The novel epitopes identified included an IE-2-specific epitope restricted by HLA∗B∗44:03 that induced high-frequency CD8+ T-cell responses (mean 3.4% of CD8+ T-cells) in 95% of HLA-B∗44:03-positive subjects tested, in one individual accounting for 18.8% of all CD8+ T-cells. These predicted novel CMV-specific CD8+ T-cell epitopes identified in an African cohort will facilitate future analyses of immune responses in African populations where CMV infection is almost universal during infancy.

Published
2017

28. Saporin-conjugated tetramers identify efficacious anti-HIV CD8+ T-cell specificities

Author

Leitman, Ellen M., Palmer, Christine D., Buus, Søren, Chen, Fabian, Riddell, Lynn, Sims, Stuart, Klenerman, Paul, Sáez-Cirión, Asier, Walker, Bruce D., Hess, Paul R., Altfeld, Marcus, Matthews, Philippa C., Goulder, Philip J.R., Leitman, Ellen M., Palmer, Christine D., Buus, Søren, Chen, Fabian, Riddell, Lynn, Sims, Stuart, Klenerman, Paul, Sáez-Cirión, Asier, Walker, Bruce D., Hess, Paul R., Altfeld, Marcus, Matthews, Philippa C., and Goulder, Philip J.R.

Abstract

Antigen-specific T-cells are highly variable, spanning potent antiviral efficacy and damaging auto-reactivity. In virus infections, identifying the most efficacious responses is critical to vaccine design. However, current methods depend on indirect measures or on ex vivo expanded CTL clones. We here describe a novel application of cytotoxic saporin-conjugated tetramers to kill antigen-specific T-cells without significant off-target effects. The relative efficacy of distinct antiviral CD8+ T-cell specificity can be directly assessed via antigen-specific CD8+ T-cell depletion. The utility of these reagents is demonstrated here in identifying the CD8+ T-cell specificity most effective in preventing HIV progression in HIV-infected HLA-B*27-positive immune controllers.

Published
2017

29. HLA-B*14:02-restricted Env-specific CD8+ T-cell activity has highly potent antiviral efficacy associated with immune control of HIV infection

Author

Leitman, Ellen M., Willberg, Christian B., Tsai, Ming Han, Chen, Huabiao, Buus, Søren, Chen, Fabian, Riddell, Lynn, Haas, David, Fellay, Jacques, Goedert, James J., Piechocka-Trocha, Alicja, Walker, Bruce D., Martin, Jeffrey, Deeks, Steven, Wolinsky, Steven M., Martinson, Jeremy, Martin, Maureen, Qi, Ying, Sáez-Cirión, Asier, Yang, Otto O., Matthews, Philippa C., Carrington, Mary, Goulder, Philip J.R., Leitman, Ellen M., Willberg, Christian B., Tsai, Ming Han, Chen, Huabiao, Buus, Søren, Chen, Fabian, Riddell, Lynn, Haas, David, Fellay, Jacques, Goedert, James J., Piechocka-Trocha, Alicja, Walker, Bruce D., Martin, Jeffrey, Deeks, Steven, Wolinsky, Steven M., Martinson, Jeremy, Martin, Maureen, Qi, Ying, Sáez-Cirión, Asier, Yang, Otto O., Matthews, Philippa C., Carrington, Mary, and Goulder, Philip J.R.

Abstract

Immune control of human immunodeficiency virus type 1 (HIV) infection is typically associated with effective Gag-specific CD8+ T-cell responses. We here focus on HLA-B*14, which protects against HIV disease progression, but the immunodominant HLA-B*14-restricted anti-HIV response is Env specific (ERYLKDQQL, HLA-B*14-EL9). A subdominant HLA-B*14-restricted response targets Gag (DRYFKTLRA, HLA-B*14-DA9). Using HLA-B*14/peptide-saporin-conjugated tetramers, we show that HLA-B*14-EL9 is substantially more potent at inhibiting viral replication than HLA-B*14-DA9. HLA-B*14-EL9 also has significantly higher functional avidity (P < 0.0001) and drives stronger selection pressure on the virus than HLA-B*14-DA9. However, these differences were HLA-B*14 subtype specific, applying only to HLA-B*14:02 and not to HLA-B*14:01. Furthermore, the HLA-B*14-associated protection against HIV disease progression is significantly greater for HLA-B*14:02 than for HLA-B*14:01, consistent with the superior antiviral efficacy of the HLA-B*14-EL9 response. Thus, although Gag-specific CD8+ T-cell responses may usually have greater anti-HIV efficacy, factors independent of protein specificity, including functional avidity of individual responses, are also critically important to immune control of HIV.

Published
2017

30. Role of HIV-specific CD8+ T cells in pediatric HIV cure strategies after widespread early viral escape

Author

Leitman, Ellen M., primary, Thobakgale, Christina F., additional, Adland, Emily, additional, Ansari, M. Azim, additional, Raghwani, Jayna, additional, Prendergast, Andrew J., additional, Tudor-Williams, Gareth, additional, Kiepiela, Photini, additional, Hemelaar, Joris, additional, Brener, Jacqui, additional, Tsai, Ming-Han, additional, Mori, Masahiko, additional, Riddell, Lynn, additional, Luzzi, Graz, additional, Jooste, Pieter, additional, Ndung’u, Thumbi, additional, Walker, Bruce D., additional, Pybus, Oliver G., additional, Kellam, Paul, additional, Naranbhai, Vivek, additional, Matthews, Philippa C., additional, Gall, Astrid, additional, and Goulder, Philip J.R., additional

Published
2017
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31. PARV4 prevalence, phylogeny, immunology and coinfection with HIV, HBV and HCV in a multicentre African cohort

Author

Sharp, Colin P., primary, Gregory, William F., additional, Hattingh, Louise, additional, Malik, Amna, additional, Adland, Emily, additional, Daniels, Samantha, additional, van Zyl, Anriette, additional, Carlson, Jonathan M., additional, Wareing, Susan, additional, Ogwu, Anthony, additional, Shapiro, Roger, additional, Riddell, Lynn, additional, Chen, Fabian, additional, Ndung'u, Thumbi, additional, Goulder, Philip J.R., additional, Klenerman, Paul, additional, Simmonds, Peter, additional, Jooste, Pieter, additional, and Matthews, Philippa C., additional

Published
2017
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32. Lower Viral Loads and Slower CD4+T-Cell Count Decline in MRKAd5 HIV-1 Vaccinees Expressing Disease-Susceptible HLA-B*58:02

Author

Leitman, Ellen M., primary, Hurst, Jacob, additional, Mori, Masahiko, additional, Kublin, James, additional, Ndung'u, Thumbi, additional, Walker, Bruce D., additional, Carlson, Jonathan, additional, Gray, Glenda E., additional, Matthews, Philippa C., additional, Frahm, Nicole, additional, and Goulder, Philip J.R., additional

Published
2016
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34. Reduced Expression of Siglec-7, NKG2A, and CD57 on Terminally Differentiated CD56−CD16+ Natural Killer Cell Subset Is Associated with Natural Killer Cell Dysfunction in Chronic HIV-1 Clade C Infection.

Author

Zulu, Michael Z., Naidoo, Kewreshini K., Mncube, Zenele, Jaggernath, Manjeetha, Goulder, Philip J.R., Ndung'u, Thumbi, Altfeld, Marcus, and Thobakgale, Christina F.

Abstract

HIV-1 viremia has been shown to induce several phenotypic and functional abnormalities in natural killer (NK) cells. To assess immune defects associated with HIV viremia, we examined NK cell function, differentiation status, and phenotypic alterations based on expression of inhibitory and activating receptors on NK cells in HIV-1 subtype C chronically infected participants from Durban, South Africa. NK cell phenotypic profiles were characterized by assessing sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7), NKG2A, and NKG2C markers on frozen peripheral blood mononuclear cells from viremic, antiretroviral therapy (ART)-naive HIV-1 chronically infected participants ( n = 23), HIV-1 chronically infected participants who had been on combination antiretroviral therapy (cART) for at least 12 months ( n = 23) compared with healthy donors ( n = 23). NK cell differentiation was assessed by measurement of killer immunoglobulin receptor (KIR) and NKG2A expression; CD57 and CD107a measurements were carried out in HIV viremic and healthy donors. All phenotypic and functional assessments were analyzed by using multicolor flow cytometry. HIV-1-infected participants displayed greater frequencies of the CD56−CD16+ (CD56negative) NK cell subset compared with healthy donors ( p < .0001). Downregulation of Siglec-7 and NKG2A and upregulation of NKG2C were more pronounced in the CD56negative NK cell subset of viremic participants. The CD56negative subset demonstrated a differentiated (KIR+NKG2A−) phenotype with reduced CD57 expression and lower degranulation capacity in HIV-1-infected participants compared with healthy donors. HIV-1 infection induces the expansion of the CD56negative NK cell subset marked by altered receptor expression profiles that are indicative of impaired function and may explain the overall NK cell dysfunction observed in chronic HIV-1 infection. [ABSTRACT FROM AUTHOR]

Published
2017
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35. Nef-mediated down-regulation of CD4 and HLA class I in HIV-1 subtype C infection: Association with disease progression and influence of immune pressure

Author

Mann, Jaclyn K., primary, Chopera, Denis, additional, Omarjee, Saleha, additional, Kuang, Xiaomei T., additional, Le, Anh Q., additional, Anmole, Gursev, additional, Danroth, Ryan, additional, Mwimanzi, Philip, additional, Reddy, Tarylee, additional, Carlson, Jonathan, additional, Radebe, Mopo, additional, Goulder, Philip J.R., additional, Walker, Bruce D., additional, Abdool Karim, Salim, additional, Novitsky, Vladimir, additional, Williamson, Carolyn, additional, Brockman, Mark A., additional, Brumme, Zabrina L., additional, and Ndung’u, Thumbi, additional

Published
2014
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37. Characterization of anti-HIV-1 neutralizing and binding antibodies in chronic HIV-1 subtype C infection

Author

Archary, Derseree, primary, Rong, Rong, additional, Gordon, Michelle L., additional, Boliar, Saikat, additional, Madiga, Maphuti, additional, Gray, Elin S., additional, Dugast, Anne-Sophie, additional, Hermanus, Tandile, additional, Goulder, Philip J.R., additional, Coovadia, Hoosen M., additional, Werner, Lise, additional, Morris, Lynn, additional, Alter, Galit, additional, Derdeyn, Cynthia A., additional, and Ndung'u, Thumbi, additional

Published
2012
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38. Short Communication: CD8+ T Cell Polyfunctionality Profiles in Progressive and Nonprogressive Pediatric HIV Type 1 Infection

Author

Thobakgale, Christina F., primary, Streeck, Hendrik, additional, Mkhwanazi, Nompumelelo, additional, Mncube, Zenele, additional, Maphumulo, Lungile, additional, Chonco, Fundisiwe, additional, Prendergast, Andrew, additional, Tudor-Williams, Gareth, additional, Walker, Bruce D., additional, Goulder, Philip J.R., additional, Altfeld, Marcus, additional, and Ndung'u, Thumbi, additional

Published
2011
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40. B-cell depletion reveals a role for antibodies in the control of chronic HIV-1 infection

Author

Huang, Kuan-Hsiang G., primary, Bonsall, David, additional, Katzourakis, Aris, additional, Thomson, Emma C., additional, Fidler, Sarah J., additional, Main, Janice, additional, Muir, David, additional, Weber, Jonathan N., additional, Frater, Alexander J., additional, Phillips, Rodney E., additional, Pybus, Oliver G., additional, Goulder, Philip J.R., additional, McClure, Myra O., additional, Cooke, Graham S., additional, and Klenerman, Paul, additional

Published
2010
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42. Evolution of HLA-B*5703 HIV-1 escape mutations in HLA-B*5703–positive individuals and their transmission recipients

Author

Crawford, Hayley, primary, Lumm, Wendy, additional, Leslie, Alasdair, additional, Schaefer, Malinda, additional, Boeras, Debrah, additional, Prado, Julia G., additional, Tang, Jianming, additional, Farmer, Paul, additional, Ndung'u, Thumbi, additional, Lakhi, Shabir, additional, Gilmour, Jill, additional, Goepfert, Paul, additional, Walker, Bruce D., additional, Kaslow, Richard, additional, Mulenga, Joseph, additional, Allen, Susan, additional, Goulder, Philip J.R., additional, and Hunter, Eric, additional

Published
2009
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43. Rare HLA Drive Additional HIV Evolution Compared to More Frequent Alleles

Author

Rousseau, Christine M., primary, Lockhart, David W., additional, Listgarten, Jennifer, additional, Maley, Stephen N., additional, Kadie, Carl, additional, Learn, Gerald H., additional, Nickle, David C., additional, Heckerman, David E., additional, Deng, Wenjie, additional, Brander, Christian, additional, Ndung'u, Thumbi, additional, Coovadia, Hoosen, additional, Goulder, Philip J.R., additional, Korber, Bette T., additional, Walker, Bruce D., additional, and Mullins, James I., additional

Published
2009
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44. Transmission of HIV-1 Gag immune escape mutations is associated with reduced viral load in linked recipients

Author

Goepfert, Paul A., primary, Lumm, Wendy, additional, Farmer, Paul, additional, Matthews, Philippa, additional, Prendergast, Andrew, additional, Carlson, Jonathan M., additional, Derdeyn, Cynthia A., additional, Tang, Jianming, additional, Kaslow, Richard A., additional, Bansal, Anju, additional, Yusim, Karina, additional, Heckerman, David, additional, Mulenga, Joseph, additional, Allen, Susan, additional, Goulder, Philip J.R., additional, and Hunter, Eric, additional

Published
2008
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45. Detection of HIV Type 1 Gag-Specific CD4+T Cell Responses in Acutely Infected Infants

Author

Ramduth, Danni, primary, Thobakgale, Christina F., additional, Mkhwanazi, Nompumelelo P., additional, De Pierres, Chantal, additional, Reddy, Sharon, additional, van der Stok, Mary, additional, Mncube, Zenele, additional, Mphatswe, Wendy, additional, Blanckenberg, Natasha, additional, Cengimbo, Ayanda, additional, Prendergast, Andrew, additional, Tudor-Williams, Gareth, additional, Dong, Krista, additional, Jeena, Prakash, additional, Coovadia, Hoosen M., additional, Day, Cheryl L., additional, Kiepiela, Photini, additional, Goulder, Philip J.R., additional, and Walker, Bruce D., additional

Published
2008
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46. Immune Selection for Altered Antigen Processing Leads to Cytotoxic T Lymphocyte Escape in Chronic HIV-1 Infection

Author

Draenert, Rika, primary, Le Gall, Sylvie, additional, Pfafferott, Katja J., additional, Leslie, Alasdair J., additional, Chetty, Polan, additional, Brander, Christian, additional, Holmes, Edward C., additional, Chang, Shih-Chung, additional, Feeney, Margaret E., additional, Addo, Marylyn M., additional, Ruiz, Lidia, additional, Ramduth, Danni, additional, Jeena, Prakash, additional, Altfeld, Marcus, additional, Thomas, Stephanie, additional, Tang, Yanhua, additional, Verrill, Cori L., additional, Dixon, Catherine, additional, Prado, Julia G., additional, Kiepiela, Photini, additional, Martinez-Picado, Javier, additional, Walker, Bruce D., additional, and Goulder, Philip J.R., additional

Published
2004
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47. Role of HIV-specific CD8+ T cells in pediatric HIV cure strategies after widespread early viral escape

Author

Leitman, Ellen M., Thobakgale, Christina F., Adland, Emily, Ansari, M. Azim, Raghwani, Jayna, Prendergast, Andrew J., Tudor-Williams, Gareth, Kiepiela, Photini, Hemelaar, Joris, Brener, Jacqui, Tsai, Ming-Han, Mori, Masahiko, Riddell, Lynn, Luzzi, Graz, Jooste, Pieter, Ndung’u, Thumbi, Walker, Bruce D., Pybus, Oliver G., Kellam, Paul, Naranbhai, Vivek, Matthews, Philippa C., Gall, Astrid, and Goulder, Philip J.R.

Subjects
Article
Abstract

Recent studies have suggested greater HIV cure potential among infected children than adults. A major obstacle to HIV eradication in adults is that the viral reservoir is largely comprised of HIV-specific cytotoxic T lymphocyte (CTL) escape variants. We here evaluate the potential for CTL in HIV-infected slow-progressor children to play an effective role in “shock-and-kill” cure strategies. Two distinct subgroups of children were identified on the basis of viral load. Unexpectedly, in both groups, as in adults, HIV-specific CTL drove the selection of escape variants across a range of epitopes within the first weeks of infection. However, in HIV-infected children, but not adults, de novo autologous variant-specific CTL responses were generated, enabling the pediatric immune system to “corner” the virus. Thus, even when escape variants are selected in early infection, the capacity in children to generate variant-specific anti-HIV CTL responses maintains the potential for CTL to contribute to effective shock-and-kill cure strategies in pediatric HIV infection.

Published
2017
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48. Comparison of overlapping peptide sets for detection of antiviral CD8 and CD4 T cell responses

Author

Draenert, Rika, primary, Altfeld, Marcus, additional, Brander, Christian, additional, Basgoz, Nesli, additional, Corcoran, Colleen, additional, Wurcel, Alysse G., additional, Stone, David R., additional, Kalams, Spyros A., additional, Trocha, Alicja, additional, Addo, Marylyn M., additional, Goulder, Philip J.R., additional, and Walker, Bruce D., additional

Published
2003
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49. Mother-to-child transmission of HIV infection and CTL escape through HLA-A2-SLYNTVATL epitope sequence variation

Author

Goulder, Philip J.R, primary, Pasquier, Christophe, additional, Holmes, Eddie C, additional, Liang, Bin, additional, Tang, Yanhua, additional, Izopet, Jacques, additional, Saune, Karine, additional, Rosenberg, Eric S, additional, Burchett, Sandra K, additional, McIntosh, Kenneth, additional, Barnardo, Martin, additional, Bunce, Michael, additional, Walker, Bruce D, additional, Brander, Christian, additional, and Phillips, Rodney E, additional

Published
2001
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50. Cellular Immune Responses and Viral Diversity in Individuals Treated during Acute and Early HIV-1 Infection

Author

Altfeld, Marcus, primary, Rosenberg, Eric S., additional, Shankarappa, Raj, additional, Mukherjee, Joia S., additional, Hecht, Frederick M., additional, Eldridge, Robert L., additional, Addo, Marylyn M., additional, Poon, Samuel H., additional, Phillips, Mary N., additional, Robbins, Gregory K., additional, Sax, Paul E., additional, Boswell, Steve, additional, Kahn, James O., additional, Brander, Christian, additional, Goulder, Philip J.R., additional, Levy, Jay A., additional, Mullins, James I., additional, and Walker, Bruce D., additional

Published
2001
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