The progressive decline of CD8⁺ cytotoxic T cells in human immunodeficiency virus (HIV)-infected patients due to infection-triggered cell exhaustion and cell death is significantly correlated with disease severity and progression into the life-threatening acquired immunodeficiency syndrome (AIDS) stage. T cell exhaustion is a condition of cell dysfunction despite antigen engagement, characterized by augmented surface expression of immune checkpoint molecules such as programmed cell death protein 1 (PD-1), which suppress T cell receptor (TCR) signaling and negatively impact the proliferative and effector activities of T cells. T cell function is tightly modulated by cellular glucose metabolism, which produces adequate energy to support a robust reaction when battling pathogen infection. The transition of the T cells from an active to an exhausted state following pathogen persistence involves a drastic change in metabolic activity. This review highlights the interplay between immune checkpoint molecules and glucose metabolism that contributes to T cell exhaustion in the context of chronic HIV infection, which could deliver an insight into the rational design of a novel therapeutic strategy.

Helicobacter pylori colonization and persistence could precede gastric adenocarcinoma. Elucidating immune recognition strategies of H. pylori is therefore imperative to curb chronic persistence in the human host. Toll-like receptor 7 (TLR7) and TLR8 are widely known as viral single-stranded RNA (ssRNA) sensors yet less studied in the bacteria context. Here, we investigated the involvement of these receptors in the immunity to H. pylori. Human THP-1 monocytic cells were infected with H. pylori, and the expression levels of human Toll-like receptors (TLRs) were examined. The roles of TLR7 and TLR8 in response to H. pylori infection were further investigated using receptor antagonists. Among all TLR transcripts examined, TLR8 exhibited the most prominent upregulation, followed by TLR7 in the THP-1 cells infected with H. pylori J99 or SS1 strains. H. pylori infection-mediated IFN-α and IFN-β transactivation was significantly abrogated by the TLR7/8 (but not TLR7) antagonist. Additionally, TLR7/8 antagonist treatment reduced H. pylori infection-mediated phosphorylation of interferon regulatory factor 7 (IRF7). Our study suggests a novel role of TLR8 signaling in host immunity against H. pylori through sensing live bacteria to elicit the production of type I interferon.

The reemergence of the Zika virus (ZIKV) infection in recent years has posed a serious threat to global health. Despite being asymptomatic or mildly symptomatic in a majority of infected individuals, ZIKV infection can result in severe manifestations including neurological complications in adults and congenital abnormalities in newborns. In a human host, ZIKV is primarily recognized by RIG-like receptors and Toll-like receptors that elicit anti-viral immunity through the secretion of type I interferon (IFN) to limit viral survival, replication, and pathogenesis. Intriguingly, ZIKV evades its host immune system through various immune evasion strategies, including suppressing the innate immune receptors and signaling pathways, mutation of viral structural and non-structural proteins, RNA modulation, or alteration of cellular pathways. Here, we present an overview of ZIKV recognition by the host immune system and the evasion strategies employed by ZIKV. Characterization of the host–viral interaction and viral disease mechanism provide a platform for the rational design of novel prophylactic and therapeutic strategies against ZIKV infection.

Antibodies against neuraminidase (NA) are an independent correlate of protection and the antigenic relatedness between H1N1pdm and H5N1 NAs suggests that seasonal influenza infection may provide cross-reactive immunity. In this study, recent H1N1pdm infection elicited modest NA-inhibiting (NAI) antibody responses against contemporary A/Victoria/4897/2022 (H1N1pdm) but strong responses against older A/California/7/2009 (H1N1pdm). Convalescent sera exhibited significantly higher cross-reactive NAI against clade 2.3.4.4b H5N1 (A/Texas/37/2024) than non-flu A patients, whereas H3N2 infection did not elicit such cross-reactivity. NAI titers were comparable between N1-California and N1-Texas but lower against N1-Victoria, indicating greater antigenic similarity between N1-California and N1-Texas. This was supported by stronger inhibition of N1-Texas by N1-California sheep antiserum compared with N1-Victoria sheep antiserum. Surprisingly, H1N1pdm-infected patients exhibited very low NAI against clade 2.3.2.1a H5N1 (N1-Bangladesh; GMT of 171 vs GMT 1159 for N1-Texas). Mouse antisera demonstrated reduced reciprocal inhibition between N1-Texas and N1-Bangladesh, consistent with their antigenic divergence. When four residues in N1-Bangladesh were substituted with their corresponding residues in N1-Texas, N1-Bangladesh antiserum showed reduced NAI, while N1-Texas antisera showed increased inhibition compared with wild-type N1-Bangladesh. This suggests that these amino acid differences are partially responsible for their antigenic divergence. Importantly, longitudinal analysis revealed that boosted cross-reactive NAI responses waned by day 90 post-infection, highlighting their limited durability. Together, these findings demonstrate that seasonal H1N1pdm infection can transiently boost cross-reactive NAI antibodies against clade 2.3.4.4b H5N1, but antigenic divergence in clade 2.3.2.1a limits cross-reactivity. As such, the impact of pre-existing antibody during an H5N1 outbreak is dependent on the infecting clade.