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. 2020 Feb 26;12(3):256.
doi: 10.3390/v12030256.

The Kaposi's Sarcoma-Associated Herpesvirus (KSHV) gH/gL Complex Is the Predominant Neutralizing Antigenic Determinant in KSHV-Infected Individuals

Yasaman Mortazavi  1 , Salum J Lidenge  1   2   3 , Tara Tran  1 , John T West  1 , Charles Wood  1 , For Yue Tso  1
Affiliations

The Kaposi's Sarcoma-Associated Herpesvirus (KSHV) gH/gL Complex Is the Predominant Neutralizing Antigenic Determinant in KSHV-Infected Individuals

Yasaman Mortazavi et al. Viruses. .

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS), one of the most prevalent cancers of people living with HIV/AIDS in sub-Saharan Africa. The seroprevalence for KSHV is high in the region, and no prophylactic vaccine against the virus is available. In this study, we characterized the antigenic targets of KSHV-specific neutralizing antibodies (nAbs) in asymptomatic KSHV-infected individuals and KS patients with high nAbs titers. We quantified the extent to which various KSHV envelope glycoproteins (gB, ORF28, ORF68, gH, gL, gM, gN and gpK8.1) adsorbed/removed KSHV-specific nAbs from the plasma of infected individuals. Our study revealed that plasma from a majority of KSHV neutralizers recognizes multiple viral glycoproteins. Moreover, the breadth of nAbs responses against these viral glycoproteins varies among endemic KS, epidemic KS and asymptomatic KSHV-infected individuals. Importantly, among the KSHV glycoproteins, the gH/gL complex, but neither gH nor gL alone, showed the highest adsorption of KSHV-specific nAbs. This activity was detected in 80% of the KSHV-infected individuals regardless of their KS status. The findings suggest that the gH/gL complex is the predominant antigenic determinant of KSHV-specific nAbs. Therefore, gH/gL is a potential target for development of KSHV prophylactic vaccines.

Keywords: KS; KSHV; gH; gL; glycoproteins; neutralizing antibodies.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Kaposi’s sarcoma-associated herpesvirus (KSHV) envelope glycoprotein constructs and their expression in 293T cells by immunoblot. (A) Schematic representation of pcDNA3.1 mammalian expression vector encoding KSHV glycoproteins fused with 3xFLAG at the C-terminus of each glycoprotein (not drawn to scale). (B) KSHV glycoproteins expression was demonstrated in the whole-cell lyses of transfected 293T cells by immunoblot against the 3xFLAG tag.
Figure 2
Figure 2
KSHV envelope glycoproteins expression in 293T cells by immunohistochemistry IHC and immunofluorescence assay (IFA). (A) KSHV glycoproteins expression was confirmed in 293T cells at 72 h post-transfection by IHC against the 3xFLAG tag. Positive cells are stained brown. (B) The cell surface expression of KSHV glycoproteins was confirmed by IFA on nonpermeabilized 293T cells at 72 h post-transfection with pooled plasma from all study participants. Positive cells are indicated by white arrows. Pictures were taken at 20X magnification.
Figure 3
Figure 3
Antigenic determinant of KSHV-specific neutralizing antibodies (nAbs) in the plasma of KSHV-infected individuals. Heat-inactivated plasma of the study participants was absorbed with KSHV glycoproteins-expressing 293T cells, and neutralization assays were carried out as described in material and methods. The relative percentage of nAbs absorbed is shown for (A) epidemic KS (EpKS) cases, (B) endemic KS (EnKS) cases and (C) non-KS (asymptomatic KSHV-infected ) cases.
Figure 4
Figure 4
Comparison of nAbs responses among various KSHV envelope glycoproteins. The gH/gL complex-specific nAbs response was compared with other KSHV glycoproteins among all the participants using the Mann–Whitney test (*** p < 0.001, **** p < 0.0001).
Figure 5
Figure 5
Comparison of nAbs responses to each KSHV glycoprotein in the EnKS, EpKS and non-KS groups. The nAbs responses against each KSHV glycoproteins were compared between the EnKS, EpKS and non-KS individuals using the Mann–Whitney test.
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