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Clinical Trial
. 2020 Jul 1;94(14):e02128-19.
doi: 10.1128/JVI.02128-19. Print 2020 Jul 1.

Delayed Expression of PD-1 and TIGIT on HIV-Specific CD8 T Cells in Untreated HLA-B*57:01 Individuals Followed from Early Infection

Lydia Scharf  1 , Johanna Tauriainen  1 , Marcus Buggert  2   3 , Wendy Hartogensis  4 , David J Nolan  5   6 , Steven G Deeks  4 , Marco Salemi  5 , Frederick M Hecht  4 , Annika C Karlsson  7
Affiliations
Clinical Trial

Delayed Expression of PD-1 and TIGIT on HIV-Specific CD8 T Cells in Untreated HLA-B*57:01 Individuals Followed from Early Infection

Lydia Scharf et al. J Virol. .

Abstract

While the relationship of protective human leukocyte antigen (HLA) class I alleles and HIV progression is well defined, the interaction of HLA-mediated protection and CD8 T-cell exhaustion is less well characterized. To gain insight into the influence of HLA-B*57:01 on the deterioration of CD8 T-cell responses during HIV infection in the absence of antiretroviral treatment, we compared HLA-B*57:01-restricted HIV-specific CD8 T-cell responses to responses restricted by other HLA class I alleles longitudinally after control of peak viremia. Detailed characterization of polyfunctionality, differentiation phenotypes, transcription factor, and inhibitory receptor expression revealed progression of CD8 T-cell exhaustion over the course of the infection in both patient groups. However, early effects on the phenotype of the total CD8 T-cell population were apparent only in HLA-B*57-negative patients. The HLA-B*57:01-restricted, HIV epitope-specific CD8 T-cell responses showed beneficial functional patterns and significantly lower frequencies of inhibitory receptor expression, i.e., PD-1 and coexpression of PD-1 and TIGIT, within the first year of infection. Coexpression of PD-1 and TIGIT was correlated with clinical markers of disease progression and declining percentages of the T-bethi Eomesdim CD8 T-cell population. In accordance with clinical and immunological deterioration in the HLA-B*57:01 group, the difference in PD-1 and TIGIT receptor expression did not persist to later stages of the disease.IMPORTANCE Given the synergistic nature of TIGIT and PD-1, the coexpression of those inhibitory receptors should be considered when evaluating T-cell pathogenesis, developing immunomodulatory therapies or vaccines for HIV, and when using immunotherapy or vaccination for other causes in HIV-infected patients. HIV-mediated T-cell exhaustion influences the patient´s disease progression, immune system and subsequently non-AIDS complications, and efficacy of vaccinations against other pathogens. Consequently, the possibilities of interfering with exhaustion are numerous. Expanding the use of immunomodulatory therapies to include HIV treatment depends on information about possible targets and their role in the deterioration of the immune system. Furthermore, the rise of immunotherapies against cancer and elevated cancer incidence in HIV-infected patients together increase the need for detailed knowledge of T-cell exhaustion and possible interactions. A broader approach to counteract immune exhaustion to alleviate complications and improve efficacy of other vaccines also promises to increase patients' health and quality of life.

Keywords: CD4; CD8-positive T lymphocytes; HIV Gag; HIV-1; PD-1; T-cell immunoreceptor with Ig and ITIM domain; TIGIT; cellular immunity; disease progression; evolution; human HLA-B*5701 antigen; molecular evolution; programmed cell death protein 1; viral load.

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Figures

FIG 1
FIG 1
Clinical presentation and viral dynamics. (A and B) HLA-B*57:01-positive and HLA-B*57-negative patients were monitored for up to 7 years after HIV infection while they remained mainly untreated. Linear regression of CD4 T-cell counts (A) and plasma viral loads (B) of HLA-B*57:01-positive (solid turquoise lines) and HLA-B*57-negative (dashed orange lines) patients were plotted throughout the study time. Data acquired during temporary treatment intervals were excluded from the analysis.
FIG 2
FIG 2
Analysis of viral evolution and functionality of HIV epitope-specific CD8 T-cell responses. (A) Longitudinal HIV p24 intrahost diversity and divergence in all 12 subjects. The six HLA-B*57:01 subjects (P1 to P6) are indicated in black, and the non-HLA-B*57 control subjects (P7 to P12) are indicated in orange. Diversity and divergence are indicated in nucleotide substitutions per site. (B) Median nucleotide substitution rate and 95% highest posterior density (HPD) intervals of HIV gag p24 in 12 longitudinally sampled patients. Substitution rates for six HLA-B*57:01 subjects (P1 to P6) and six non-HLA-B*57 control subjects (P7 to P12) are given in nucleotide substitutions/site/year along the x axis and were estimated by Bayesian inference, assuming either a strict or relaxed molecular clock depending on the best-fitting model of each subject.
FIG 3
FIG 3
Example for gating strategy to analyze differentiation phenotypes of CD8 T cells.
FIG 4
FIG 4
Differentiation phenotypes and inhibitory receptor expression of CD8 T cells. (A) Differentiation phenotypes of CD8 T cells from HLA-B*57:01-positive (black filled circles) and HLA-B*57-negative (empty circles) patients in early chronic infection (8 to 26 wpi), as well as HIV-negative control subjects (gray circles). P values are the result of Mann-Whitney tests. (B) The TEMRA subset initially differing between the patient groups in panel A was followed longitudinally throughout the study period. (C) Inhibitory receptor expression on memory CD8 T cells from HLA-B*57-negative and HLA-B*57:01-positive individuals in early chronic infection, as well as HIV-negative control subjects (gray circles). (D) CD160 expression was followed throughout the study period and analyzed for correlation with duration of HIV infection. Spearman´s rank correlation coefficient and P value are indicated for the study group with a significant correlation.
FIG 5
FIG 5
Total CD8 T-cell characterization in late chronic infection. (A) Differentiation phenotypes of CD8 T cells from HLA-B*57:01-positive (black filled circles) and HLA-B*57-negative (empty circles) patients in late chronic infection (155 to 309 wpi). (B) Frequency of inhibitory receptor expression on memory CD8 T cells in late chronic infection. (C) Frequencies of PD-1 and TIGIT expression by memory CD8 T cells were followed over the study period. Spearman´s rank correlation coefficient and P value are indicated for the patient group with significant correlation.
FIG 6
FIG 6
Functional features and transcription factor profile of HIV epitope-specific CD8 T-cell responses. (A) Effector molecule expression of HIV epitope-specific HLA-restricted CD8 T-cell responses. Per sample, the properties of the strongest autologous HIV Gag-specific CD8 T-cell responses as detected by the production of gamma interferon (IFN-γ), IL-2, tumor necrosis factor (TNF), and/or CD107a were identified and used in the comparison. Epitopes are defined in Table 3. Data from early chronic infection are depicted with HLA-B*57:01-restricted responses as turquoise filled circles, and responses restricted by other HLA class I alleles are depicted as orange filled circles. The plot shows individual values and the median. (B and C) The frequencies of effector molecule expression among responding cells were followed longitudinally. Depicted are functions showing significant correlation with the duration of HIV infection (significance was determined using a mixed-effects model; P value and study group are indicated in the panels). (D and E) Polyfunctionalities were compared between HLA-B*57:01-restricted responses and responses restricted by other HLA alleles. The simultaneous expression of CD107a, granzyme A (GrzA), GrzB, perforin, IFN-γ, IL-2, and TNF on a single-cell level was used for the Student´s t test provided in the SPICE software. Expression patterns that differed between the groups during early or late chronic infection are depicted. P, Significantly more frequent population in the HLA-B*57:01-restricted responses; N, significantly more frequent population in the responses restricted by other alleles. (F and G) Functional combinations from panels D and E with significant longitudinal changes are shown. The 10−3 values are arbitrary in order to visualize the absence of the indicated functional combination among the respective HIV-specific responses on a logarithmic axis. Analysis was done with original values and the Mann-Whitney test (rank test), rendering the absolute value inconsequential. The significance of correlation with duration of infection and differences between groups were determined using a mixed-effects model; P value and study group are indicated in the panels.
FIG 7
FIG 7
Inhibitory receptor expression of epitope-specific CD8 T cells. (A) Expression of the inhibitory receptors 2B4, CD160, KLRG-1, PD-1, and TIGIT on HIV epitope-specific CD8 T cells. HLA-B*57:01-restricted responses are depicted as turquoise filled circles; responses restricted by other HLA class I alleles are depicted as orange filled circles. The plot shows individual values and the median; P values are the result of the Mann-Whitney test. (B) Combinations of inhibitory receptors on the single-cell level were compared using a permutation test. Frequencies of individual expression patterns were grouped by the number of simultaneously expressed inhibitory receptors on a single-cell level and visualized with no inhibitor (yellow) to up to 5 inhibitors (black). (C) Examples of PD-1 and TIGIT expression of HIV epitope-specific responses. Contour plots in the background depict memory CD8 T cells; overlaid dot plots are HIV epitope-specific CD8 T-cell responses. TIGIT expression is depicted along the x axis, and PD-1 expression is depicted along the y axis. (D) PD-1/TIGIT coexpression of HIV epitope-specific CD8 T cells in early chronic infection. (E to I) Frequency of PD-1/TIGIT coexpression plotted against duration of viral infection (E), viral load (F), CD4 count (G), CD4% (H), and CD4/CD8 ratio (I). The significance of correlations and the difference between groups were determined using a mixed-effects model; P value and study group are indicated in the panels.
FIG 8
FIG 8
Inhibitory receptor expression and transcriptional profile of HIV epitope-specific CD8 T cells in late chronic infection and longitudinally. (A) Frequency of inhibitory receptor expression in late chronic infection. (B) Frequencies of inhibitory receptor-expressing cells were followed longitudinally. Spearman´s rank correlation coefficient, P value, and patient group are indicated for significant correlations. (C) Frequency of combined TIGIT and PD-1 expression in late chronic infection. (D) Transcriptional profiles of HIV epitope-specific CD8 T cells in late chronic infection.
FIG 9
FIG 9
Transcriptional profile of HIV epitope-specific CD8 T cells. (A) Frequency of T-betdim Eomeshi, T-bethi Eomesdim, and T-bet− Eomes− cell populations among HIV epitope-specific CD8 T cells during early chronic infection. (B) Proportions of cells with the analyzed transcription factor profiles were followed longitudinally. Significant correlations with duration of infection were determined using a mixed-effects model; P value and study group are indicated in the panels.
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