Kaposi’s sarcoma-associated herpesvirus T cell responses in HIV seronegative individuals from rural Uganda

Abstract

T cell responses to Kaposi’s sarcoma-associated herpesvirus (KSHV) are likely essential in the control of KSHV infection and protection from associated disease, but remain poorly characterised. KSHV prevalence in rural Uganda is high at >90%. Here we investigate IFN- γ T cell responses to the KSHV proteome in HIV-negative individuals from a rural Ugandan population. We use an ex-vivo IFN- γ ELISpot assay with overlapping peptide pools spanning 83 KSHV open reading frames (ORF) on peripheral blood mononuclear cells (PBMC) from 116 individuals. KSHV-specific T cell IFN- γ responses are of low intensity and heterogeneous, with no evidence of immune dominance; by contrast, IFN- γ responses to Epstein–Barr virus, Cytomegalovirus and influenza peptides are frequent and intense. Individuals with KSHV DNA in PBMC have higher IFN- γ responses to ORF73 (p = 0.02) and lower responses to K8.1 (p = 0.004) when compared with those without KSHV DNA. In summary, we demonstrate low intensity, heterogeneous T cell responses to KSHV in immune-competent individuals.

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“…To be successful, a KSHV vaccine will need to generate more potent and specific neutralizing antibody and/or cell-mediated immune (CMI) responses than occurs during natural infection 59 . Measuring cellular immune responses to natural KSHV has proven challenging.…”

“…As an intracellular nuclear antigen, it is unlikely to be targeted by humoral immunity. Evidence suggests that CMI during natural infection against LANA and other antigens is heterogenous and may not limit virus replication, so CMI-based vaccine targets may have to be individually tested to determine if the enhanced immunity from vaccination provides protection 59 . Several KSHV nonstructural proteins potentially critical for viral persistence are expressed on the infected cell-extracellular surface or are secreted and that could, in theory, be neutralizing targets for vaccine-induced antibodies.…”

Immune checkpoints in T cells during oncogenic γ‐herpesvirus infections

“…Even when individuals are infected with both KSHV and EBV, KSHV‐specific T‐cell responses constitute a smaller proportion of the total peripheral blood T‐cell repertoire than those directed against EBV. 43 In addition, some of the EBV proteins are immunodominant and elicit T‐cell responses in nearly all healthy virus carriers, such as EBNA1 for CD4 + T cells and EBNA3A‐C as well as LMP2 for CD8 + T cells. 44 , 45 , 46 In contrast, KSHV‐specific T‐cell responses vary widely in their viral antigen recognition, with the most frequently recognized antigens, LANA (ORF73) and K8.1, only being recognized by T cells in less than half of healthy KSHV carriers.…”

“… 44 , 45 , 46 In contrast, KSHV‐specific T‐cell responses vary widely in their viral antigen recognition, with the most frequently recognized antigens, LANA (ORF73) and K8.1, only being recognized by T cells in less than half of healthy KSHV carriers. 43 Responses against LANA and K8.1 contain both CD4 + and CD8 + T cells. 47 , 48 , 49 , 50 , 51 Interestingly, KSHV‐specific CD4 + T cells, such as the LANA‐specific responses, were able to recognize KSHV‐infected B cells by IFN‐γ production, but not able to kill them.…”

“…In addition, some of the EBV proteins are immunodominant and elicit T‐cell responses in nearly all healthy virus carriers, such as EBNA1 for CD4 + T cells and EBNA3A‐C as well as LMP2 for CD8 + T cells 44–46 . In contrast, KSHV‐specific T‐cell responses vary widely in their viral antigen recognition, with the most frequently recognized antigens, LANA (ORF73) and K8.1, only being recognized by T cells in less than half of healthy KSHV carriers 43 . Responses against LANA and K8.1 contain both CD4 + and CD8 + T cells 47–51 .…”