Primary HIV-1 Strains Use Nef To Downmodulate HLA-E Surface Expression

doi:10.1128/JVI.00719-19

. 2019 Sep 30;93(20):e00719-19.

doi: 10.1128/JVI.00719-19. Print 2019 Oct 15.

Primary HIV-1 Strains Use Nef To Downmodulate HLA-E Surface Expression

Thomas van Stigt Thans^#¹, Janet I Akko^#^{1

2}, Annika Niehrs^{1

2}, Wilfredo F Garcia-Beltran³, Laura Richert^{1

4}, Christina M Stürzel⁵, Christopher T Ford¹, Hui Li⁶, Christina Ochsenbauer⁷, John C Kappes⁷, Beatrice H Hahn⁶, Frank Kirchhoff⁵, Glòria Martrus¹, Daniel Sauter⁵, Marcus Altfeld^{1

2

8}, Angelique Hölzemer^{9

2

10}

Affiliations

¹ Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
² German Center for Infection Research (DZIF), Site Hamburg-Lübeck-Borstel-Riems, Germany.
³ Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA.
⁴ Université Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, Inria SISTM, Bordeaux, France.
⁵ Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
⁶ Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁷ Department of Medicine, Division of Hematology and Oncology, and CFAR, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁸ Institute for Immunology, University Medical Center Eppendorf, Hamburg, Germany.
⁹ Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany angelique.hoelzemer@leibniz-hpi.de.
¹⁰ First Department of Internal Medicine, University Medical Center Eppendorf, Hamburg, Germany.

^# Contributed equally.

PMID: 31375574
PMCID: PMC6798123
DOI: 10.1128/JVI.00719-19

Primary HIV-1 Strains Use Nef To Downmodulate HLA-E Surface Expression

Thomas van Stigt Thans et al. J Virol. 2019.

. 2019 Sep 30;93(20):e00719-19.

doi: 10.1128/JVI.00719-19. Print 2019 Oct 15.

Authors

Affiliations

¹ Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
² German Center for Infection Research (DZIF), Site Hamburg-Lübeck-Borstel-Riems, Germany.
³ Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA.
⁴ Université Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, Inria SISTM, Bordeaux, France.
⁵ Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.
⁶ Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁷ Department of Medicine, Division of Hematology and Oncology, and CFAR, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁸ Institute for Immunology, University Medical Center Eppendorf, Hamburg, Germany.
⁹ Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany angelique.hoelzemer@leibniz-hpi.de.
¹⁰ First Department of Internal Medicine, University Medical Center Eppendorf, Hamburg, Germany.

^# Contributed equally.

PMID: 31375574
PMCID: PMC6798123
DOI: 10.1128/JVI.00719-19

Abstract

Human immunodeficiency virus type 1 (HIV-1) has evolved elaborate ways to evade immune cell recognition, including downregulation of classical HLA class I (HLA-I) from the surfaces of infected cells. Recent evidence identified HLA-E, a nonclassical HLA-I, as an important part of the antiviral immune response to HIV-1. Changes in HLA-E surface levels and peptide presentation can prompt both CD8⁺ T-cell and natural killer (NK) cell responses to viral infections. Previous studies reported unchanged or increased HLA-E levels on HIV-1-infected cells. Here, we examined HLA-E surface levels following infection of CD4⁺ T cells with primary HIV-1 strains and observed that a subset downregulated HLA-E. Two primary strains of HIV-1 that induced the strongest reduction in surface HLA-E expression were chosen for further testing. Expression of single Nef or Vpu proteins in a T-cell line, as well as tail swap experiments exchanging the cytoplasmic tail of HLA-A2 with that of HLA-E, demonstrated that Nef modulated HLA-E surface levels and targeted the cytoplasmic tail of HLA-E. Furthermore, infection of primary CD4⁺ T cells with HIV-1 mutants showed that a lack of functional Nef (and Vpu to some extent) impaired HLA-E downmodulation. Taken together, the results of this study demonstrate for the first time that HIV-1 can downregulate HLA-E surface levels on infected primary CD4⁺ T cells, potentially rendering them less vulnerable to CD8⁺ T-cell recognition but at increased risk of NKG2A⁺ NK cell killing.IMPORTANCE For almost two decades, it was thought that HIV-1 selectively downregulated the highly expressed HLA-I molecules HLA-A and HLA-B from the cell surface in order to evade cytotoxic-T-cell recognition, while leaving HLA-C and HLA-E molecules unaltered. It was stipulated that HIV-1 infection thereby maintained inhibition of NK cells via inhibitory receptors that bind HLA-C and HLA-E. This concept was recently revised when a study showed that primary HIV-1 strains reduce HLA-C surface levels, whereas the cell line-adapted HIV-1 strain NL4-3 lacks this ability. Here, we demonstrate that infection with distinct primary HIV-1 strains results in significant downregulation of surface HLA-E levels. Given the increasing evidence for HLA-E as an important modulator of CD8⁺ T-cell and NKG2A⁺ NK cell functions, this finding has substantial implications for future immunomodulatory approaches aimed at harnessing cytotoxic cellular immunity against HIV.

Keywords: HIV-1; HLA-E; Nef.

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Figures

**FIG 1**
Infection with HIV-1 differentially modulates HLA-E surface levels on primary T cells. (A) Gating strategy for flow cytometric analyses of HLA-E staining on HIV-1-infected primary isolated CD4⁺ T cells. Lymphocytes were first defined by forward scatter area (FSC-A) and side scatter area (SSC-A) characteristics. After doublet exclusion using forward scatter width (FSC-W) and side scatter width (SSC-W), viable cells were identified as negative for Zombie NIR staining (viability dye) and positive for CD3. Subsequently, CD4 was plotted against HIV-1 p24 to gate on two subsets: HIV-1-infected cells, defined as p24⁺ CD4^dim, and HIV-1-uninfected bystander cells, defined as p24⁻ CD4⁺ subset of the same well. The gate for the p24⁻ CD4⁺ subset was set on the no-virus control (not shown). The histograms display the fluorescence intensities of HLA-E surface staining (clone 3D12) on HIV-1-infected cells (red) and uninfected bystander cells (black). Histograms of the respective isotype control stainings (dotted red line, HIV-1-infected cells; shaded gray histogram, HIV-1-uninfected cells) are overlaid. Staining was performed with antibody panel A (Table 2). (B) (Top row) Representative dot plots of primary CD4⁺ T cells infected with several HIV-1 strains ranging from no (left) to the highest (right) extent of HLA-E downregulation. HLA-E surface staining is plotted against HIV-1 p24 intracellular staining. (Bottom row) Histograms displaying fluorescence intensities of HLA-E surface staining following gating on HIV-1-infected cells (red) or on HIV-1-uninfected cells (black) with the respective isotype controls as indicated on the right. The gating strategy was the same as for panel A; the HIV-1 strains correspond to those in the top row. (C) Each pair of connected dots displays the median fluorescence intensity (MFI) of HLA-E (red) or isotype control (gray) on HIV-1-uninfected bystander cells (filled dots) and HIV-1-infected CD4⁺ T cells (empty dots) from the same donor. HIV-1 strains are indicated below the x axis, as well as the no-virus control. Differences in HLA-E MFIs on HIV-1-infected and -uninfected CD4⁺ T cells were analyzed using Wilcoxon signed rank test for paired data; significant P values (<0.05) are marked with asterisks. FDR-adjusted P values are as follows: for SF162, LAI, SF2, and CH293, P > 0.1; for NL4-3, CH107, CH164, and CH185, *P =* 0.059; for CH236, CH077, and CH198, *P =* 0.037. (D) HIV-1 cell line-adapted strains and HIV-1 primary strains (x axis) are ordered from weakest (SF162 and CH293, respectively) to strongest (NL4-3 and CH198, respectively) median relative change (percent) in HLA-E MFI (y axis). The relative change (percent) in HLA-E MFI was calculated as follows: (MFI infected − MFI uninfected)/MFI uninfected × 100. The data are represented as box-and-whisker plots indicating IQRs and medians. In total, six to nine healthy donors were tested; samples with <150 infected CD4⁺ T cells were excluded, resulting in varying numbers of donors per viral strain (n = 6 to 9).

**FIG 2**
Nef proteins of HIV-1 CH077 and CH198 are sufficient to reduce HLA-E surface expression in Jurkat cells. (A) Flow plots displaying tetherin (top) and HLA-E (bottom) plotted against eGFP expression on *vpu*-eGFP-transduced Jurkat cells (orange). Untransduced Jurkat cells are overlaid in black to distinguish eGFP⁺ populations. (B) (Left) Graph displaying MFIs of tetherin staining on Jurkat cells. The dot-line graphs connect *vpu*-transduced (eGFP⁺, open orange dots) and eGFP⁻ cells of the same sample (filled orange dots) for all three constructs and the vector control (eGFP alone) as indicated on the x axis. (Right) Graph displaying HLA-E MFIs on *vpu*-eGFP⁺ (empty orange dots) and *vpu*-eGFP⁻ (filled orange dots) Jurkat cells from the same sample. The isotype control for HLA-E staining is depicted in gray. (C) n-fold change in HLA-E MFI following transduction with *vpu*-eGFP, calculated as the HLA-E MFI on *vpu*-eGFP⁺ divided by the HLA-E MFI on *vpu*-eGFP⁻ cells. The dotted line indicates the median n-fold change of the eGFP vector control. Differences were analyzed using Friedman test, and only significant FDR-adjusted P values are depicted. The data are derived from two independent experiments (once with three technical replicates and once with four technical replicates [n = 7]). (D) Flow plots depicting HLA-I (top) and HLA-E (bottom) surface levels plotted against mCherry (x axis) on *nef*-mCherry-transduced Jurkat cells (blue) and the untransduced parental cell line (black). (E) (Left) Graph displaying MFIs of HLA-I staining on Jurkat cells. The lines connect *nef*-transduced (mCherry⁺, empty blue dots) with mCherry⁻ cells from the same sample (filled blue dots) for all three constructs and the vector control. (Right) Graph displaying HLA-E MFIs derived from *nef*-mCherry⁻ cells (filled blue dots) and *nef*-mCherry⁺ cells (empty blue dots) from the same well. Isotype control staining for HLA-E is shown in gray. (F) Box-and-whisker plots (medians and IQRs) representing n-fold change in HLA-E MFI calculated as HLA-E MFI *nef*-mCherry⁺ divided by HLA-E MFI *nef*-mCherry⁻. The dotted line indicates the median n-fold change of the vector control. The data are derived from five independent experiments (n = 8, once with two and once with three technical replicates). Differences were analyzed using Friedman test; all P values shown are FDR adjusted, and only significant P values are displayed (<0.05). Staining was performed using antibody panel C (Table 2). (G) Association between HLA-E surface expression and HLA-I surface levels on HIV-1-infected primary CD4⁺ T cells. Each dot represents the relative change (percent) in the HLA-E MFI (clone 3D12) on the x axis and the relative change (percent) in HLA-I surface expression (clone W6/32) on the y axis for one specific donor/virus-strain combination. The relative change (percent) in MFI was calculated as follows: (MFI infected − MFI uninfected)/MFI uninfected × 100. Color coding with the same color for the same HIV-1 strain used for infection of CD4⁺ T cells from different donors, as indicated on the right. The data are derived from the same experiments shown in Fig. 1 (n = 6 to 9).

**FIG 3**
CH077 Nef and CH198 Nef target the cytoplasmic tail of HLA-A*02:01 and HLA-E*01:03, but not that of HLA-C*04:01. (A) Histograms displaying fluorescence intensities of HLA-A2 surface staining on Jurkat cells transduced with the full HLA-A*02:01 molecule (HLA-A2; dotted blue line) or the extracellular and transmembrane domains from HLA-A*02:01 fused to the cytoplasmic domain of HLA-E*01:03 (HLA-A2:E_CYT; blue line) or to the cytoplasmic domain of HLA-C*04:01 (HLA-A2:C_CYT; dashed blue line). The HLA-A2 expression of nontransduced parental Jurkat cells is depicted as a gray-shaded histogram. (B) MFIs of HLA-A2 staining in mCherry⁻ (filled blue dots) and mCherry⁺ (empty blue dots) Jurkat HLA-A2 (left), Jurkat HLA-A2:E_CYT (middle), and Jurkat HLA-A2:C_CYT (right) cells after transduction with *nef*-mCherry constructs or an mCherry vector control. Each dot represents one individual experiment, and each line connects MFIs from mCherry⁻ and mCherry⁺ cells within the same culture. (C) n-fold changes in HLA-A2 MFIs on mCherry⁺ and mCherry⁻ cells following transduction of Nef-derived constructs as indicated on the x axes, calculated as MFI HLA-A2 mCherry⁺ divided by MFI HLA-A2 mCherry⁻. The dotted line indicates the median n-fold change of the mCherry vector control for each cell line. Differences in HLA-A2 downregulation between *nef* constructs and the empty mCherry vector control were analyzed using Friedman test. Only significant FDR-adjusted P values are displayed (P < 0.05). Staining was performed with antibody panel D (Table 2). The data are derived from six independent experiments (n = 6).

**FIG 4**
Δ*nef* mutants exhibit less reduction of HLA-E surface levels on HIV-1-infected primary T cells. (A) Dot plots of primary CD4⁺ T cells infected with the WT and *Δnef* and *Δvpu* mutants of HIV-1 NL4-3 (top), HIV-1 CH198 (middle), and HIV-1 CH077 (bottom). HLA-E surface staining (clone 3D12) is plotted against HIV-1 p24. The HLA-E MFI is displayed for HIV-1 p24-positive cells (upper right corner). (B) Gating strategy for flow cytometric analyses of isolated CD4⁺ T cells infected with Δ*nef* (top) or Δ*vpu* (bottom) mutants following doublet and dead cell exclusion. To identify the HIV-1-infected cell subset, CD4 or tetherin was plotted against HIV-1 p24 staining. HIV-1-infected T cells were defined as p24⁺ tetherin^dim for Δ*nef*-infected cells and as p24⁺ CD4^dim for Δ*vpu* virus infection. Staining was performed with antibody panel B (Table 2). (C and D) Functional loss of Nef and Vpu in HIV-1 mutants was validated by analyzing surface expression of HLA-I (C) and tetherin (D). To allow comparison of mutant viruses with the WT, CD4⁺ T cells infected with WT virus were gated as the mutant virus of interest. The dot-line graphs display the respective MFIs for HIV-1-uninfected bystander cells and HIV-1-infected CD4⁺ T cells from the same donor. Non-virus-exposed CD4⁺ T cells (w/o) are depicted in gray as a control. (E and F) MFIs of HLA-E following infection with Δ*nef* (E) or Δ*vpu* (F) mutants compared to the WT for HIV-1 NL4-3 (left), CH198 (middle), and CH077 (right). The data are represented as dot-line graphs displaying MFIs of HIV-1-uninfected, bystander, and HIV-1-infected subsets as indicated with + and − on the x axes. Non-virus-exposed CD4⁺ T cells (w/o) are depicted in gray as a control. (G) Relative change in HLA-E MFIs on the surfaces of *Δnef*-infected (blue), *Δvpu*-infected (orange), or WT-infected (black) CD4⁺ T cells. The HLA-E MFI on HIV-1-infected CD4⁺ T cells was compared to the HLA-E MFI on HIV-1-uninfected bystander CD4⁺ T cells, and the relative change (percent) was calculated as follows: (MFI infected − MFI uninfected)/MFI uninfected × 100. The box-and-whisker plots display medians and IQRs (n = 7). Differences between WT and mutant viruses were analyzed using the Wilcoxon signed rank test for paired data (two tailed). Significant FDR-adjusted P values are marked with asterisks (*, *P =* 0.037); nonsignificant values (P > 0.05) are not shown in the graph. The data are derived from *in vitro* HIV-1 infection of primary CD4⁺ T cells from seven healthy donors (n = 7). MFIs are derived from measurements at two different analyzers (LSR Fortessa and FACSAria Fusion).

**FIG 5**
Loss of Nef and Vpu in CH077 disrupts HLA-E surface downregulation in HIV-1-infected primary T cells. (A) Dot plots of primary CD4⁺ T cells infected with CH077 WT or a mutant defective in HIV-1 accessory genes *nef* and *vpu* (CH077 Δ*nef*/Δ*vpu).* HLA-E surface staining (clone 3D12) is plotted against HIV-1 p24 (clone KC57). The HLA-E MFI is displayed for the HIV-1 p24-positive cell subset (bottom right corner). (B) Relative changes (percent) in surface expression of the indicated proteins (x axis) upon infection of primary CD4⁺ T cells with CH077 WT (black dots) or the mutant virus CH077 Δ*nef* Δ*vpu* (gray dots). The MFI on HIV-1-infected CD4⁺ T cells (p24⁺ p24⁺) was compared to the MFI on HIV-1-uninfected bystander CD4⁺ T cells (p24⁻ p24⁻), and the relative change (percent) was calculated as follows: (MFI infected − MFI uninfected)/MFI uninfected × 100. The data are presented as scatter plots with IQRs and medians and derived from three independent healthy donor infections (n = 3). Staining was performed with antibody panel E (Table 2).

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[1] Fellay J, Shianna KV, Ge D, Colombo S, Ledergerber B, Weale M, Zhang K, Gumbs C, Castagna A, Cossarizza A, Cozzi-Lepri A, De Luca A, Easterbrook P, Francioli P, Mallal S, Martinez-Picado J, Miro JM, Obel N, Smith JP, Wyniger J, Descombes P, Antonarakis SE, Letvin NL, McMichael AJ, Haynes BF, Telenti A, Goldstein DB. 2007. A whole-genome association study of major determinants for host control of HIV-1. Science 317:944–947. doi:10.1126/science.1143767. - DOI - PMC - PubMed

[2] Fellay J, Shianna KV, Ge D, Colombo S, Ledergerber B, Weale M, Zhang K, Gumbs C, Castagna A, Cossarizza A, Cozzi-Lepri A, De Luca A, Easterbrook P, Francioli P, Mallal S, Martinez-Picado J, Miro JM, Obel N, Smith JP, Wyniger J, Descombes P, Antonarakis SE, Letvin NL, McMichael AJ, Haynes BF, Telenti A, Goldstein DB. 2007. A whole-genome association study of major determinants for host control of HIV-1. Science 317:944–947. doi:10.1126/science.1143767. - DOI - PMC - PubMed

[3] Kuniholm MH, Gao X, Xue X, Kovacs A, Anastos K, Marti D, Greenblatt RM, Cohen MH, Minkoff H, Gange SJ, Fazzari M, Young MA, Strickler HD, Carrington M. 2011. Human leukocyte antigen genotype and risk of HIV disease progression before and after initiation of antiretroviral therapy. J Virol 85:10826–10833. doi:10.1128/JVI.00804-11. - DOI - PMC - PubMed

[4] Kuniholm MH, Gao X, Xue X, Kovacs A, Anastos K, Marti D, Greenblatt RM, Cohen MH, Minkoff H, Gange SJ, Fazzari M, Young MA, Strickler HD, Carrington M. 2011. Human leukocyte antigen genotype and risk of HIV disease progression before and after initiation of antiretroviral therapy. J Virol 85:10826–10833. doi:10.1128/JVI.00804-11. - DOI - PMC - PubMed

[7] Magierowska M, Theodorou I, Debré P, Sanson F, Autran B, Rivière Y, Charron D, Costagliola D. 1999. Combined genotypes of CCR5, CCR2, SDF1, and HLA genes can predict the long-term nonprogressor status in human immunodeficiency virus-1-infected individuals. Blood 93:936–941. - PubMed

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Primary HIV-1 Strains Use Nef To Downmodulate HLA-E Surface Expression

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Primary HIV-1 Strains Use Nef To Downmodulate HLA-E Surface Expression

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