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. 2020 Nov 15;205(10):2742-2749.
doi: 10.4049/jimmunol.2000489. Epub 2020 Sep 30.

The Presence of Antibody-Dependent Cell Cytotoxicity-Mediating Antibodies in Kaposi Sarcoma-Associated Herpesvirus-Seropositive Individuals Does Not Correlate with Disease Pathogenesis or Progression

Lisa K Poppe  1   2 , Charles Wood  1   2   3 , John T West  4   3
Affiliations

The Presence of Antibody-Dependent Cell Cytotoxicity-Mediating Antibodies in Kaposi Sarcoma-Associated Herpesvirus-Seropositive Individuals Does Not Correlate with Disease Pathogenesis or Progression

Lisa K Poppe et al. J Immunol. .

Abstract

Although the immune response is likely to play a pivotal role in controlling Kaposi sarcoma (KS)-associated herpesvirus (KSHV) and preventing disease development, the exact factors responsible for that control remain ill defined. T cell responses are weak and variable, and neutralizing Abs are more frequently detected in individuals with KS. This suggests a potential role for nonneutralizing Abs, which to date have been largely uninvestigated. Ab-dependent cell cytotoxicity (ADCC) is a common effector function for nonneutralizing Abs and is known to play a protective role in other herpesvirus infections; yet, ADCC has never been investigated in the context of KSHV infection. In this study, we provide, to our knowledge, the first evidence that anti-KSHV Abs are capable of mediating ADCC responses against infected human cells undergoing lytic reactivation. ADCC activity significantly higher than seronegative controls was detected in 24 of 68 KSHV-seropositive individuals tested. However, ADCC responses were not associated with KS development or progression. ADCC activity was also found to be independent of HIV status, sex, age, KSHV Ab titer, and KSHV-neutralizing activity. Nevertheless, additional investigations into effector cell function between KS and asymptomatic individuals are needed to determine whether ADCC has a role in preventing KS.

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Figures

Figure 1.
Figure 1.
Validation of a KSHV specific ADCC assay. (A) Relative fluorescent units (RFU) of supernatant from wells containing targets only (T), target and effectors (TE), targets and effectors plus KSHV seropositive plasma (KSHV+), targets and effectors plus KSHV seronegative plasma (KSHV−), and target cells plus detergent (Max) for BC3 cell stimulated with PMA (black bars) or unstimulated (gray bars). (B) Percent ADCC was calculated as (Experimental-TE)/(Max-T)*100. (C) ADCC activity for 12 KSHV seronegative individuals. (D) ADCC activity at varying dilutions of KSHV seropositive and seronegative plasma. All data shown is the mean and standard deviation from the centroid three of five experimental replicates. Significant differences denoted: **** p<0.0001
Figure 2.
Figure 2.
ADCC activity against BC3 and BJAB cells. ADCC activity of KSHV seronegative plasma 10 KSHV seropositive plasma samples against lytically reactivated and unstimulated BC3 cells (A) and BJAB cells (B). Samples with ADCC activity significantly different than their respective seronegative control are indicated with asterisks: * p<0.05; **p<0.01; ***p<0.001; ****p<0.0001
Figure 3.
Figure 3.
ADCC activity of KSHV seropositive individuals. 68 KSHV seropositive individuals were screened for ADCC activity against lytically reactivated (A) or unstimulated (B) BC3 cells. Gray bars represent KSHV seronegative controls. Data shown is the mean of 3 independent experiments, with the exception of seronegative controls (n=22 in panel A; n=14 in panel B). Each individual value is indicated with a black dot. Samples with activity significantly different (p<0.05, One-way ANOVA with Dunnett’s post-test) from KSHV seronegative controls are highlighted green if the activity is greater than controls and red if the activity is less than controls.
Figure 4.
Figure 4.
ADCC responses were not found to correlate with any measured variables. ADCC activity was not found to differ by (A) KS status, p=0.9062; (B) HIV status, p=0.9468; (C) sex, p=0.3325. (D) Age, Pearson r=−0.08475, p=0.4920; (E) KSHV Titer, Spearman r = −0.03576, p=0.8312; and (F) KSHV neutralizing activity Pearson r =0.05536, p=0.7180 were not associated with ADCC activity. Each dot represents the mean ADCC from three independent experiments.
Figure 5.
Figure 5.
ADCC activity among pre- and post-treatment KS patients. 10 KS patients were tested for ADCC activity against lytically reactivated (A) and unstimulated (B) BC3 cells. Data shown is the mean and standard deviation from 3 independent experiments. Patients are coded by response status at follow up time point. Individuals with a reduced number and/or size of lesions at follow up are represented by green circles, those with no change after treatment are shown in blue triangles, and patients presenting new lesions are depicted with red squares. There was no change in ADCC pre- and post-treatment for the group as a whole, and the magnitude of response or change in response was not found to associate with treatment outcome.
Figure 6.
Figure 6.
Variation in ADCC activity over time. The longitudinal ADCC activity profiles for 10 individuals are shown. ADCC activity is on the y-axis, while follow-up time point (in months) in on the x-axis. The enrollment sample is represented as time point 0. Each point represents the mean and standard deviation of 3 independent experiments. Time points are without a dot when no sample was available for testing.
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