No abstract

The innate immune cells underlying mucosal inflammatory responses and damage during acute HIV-1 infection remain incompletely understood. Here, we report a Vδ2 subset of gut-homing γδ T cells with significantly upregulated Δ42PD1 (a PD1 isoform) in acute (~20%) HIV-1 patients compared to chronic HIV-1 patients (~11%) and healthy controls (~2%). The frequency of Δ42PD1Vδ2 cells correlates positively with plasma levels of pro-inflammatory cytokines and fatty-acid-binding protein before detectable lipopolysaccharide in acute patients. The expression of Δ42PD1 can be induced by in vitro HIV-1 infection and is accompanied by high co-expression of gut-homing receptors CCR9/CD103. To investigate the role of Δ42PD1Vδ2 cells in vivo, they were adoptively transferred into autologous humanized mice, resulting in small intestinal inflammatory damage, probably due to the interaction of Δ42PD1 with its cognate receptor Toll-like receptor 4 (TLR4). In addition, blockade of Δ42PD1 or TLR4 successfully reduced the cytokine effect induced by Δ42PD1Vδ2 cells in vitro, as well as the mucosal pathological effect in humanized mice. Our findings have therefore uncovered a Δ42PD1-TLR4 pathway exhibited by virus-induced gut-homing Vδ2 cells that may contribute to innate immune activation and intestinal pathogenesis during acute HIV-1 infection. Δ42PD1Vδ2 cells may serve as a target for the investigation of diseases with mucosal inflammation.

Background Memory CD8 + T cell responses play an essential role in protection against persistent infection. However, HIV-1 evades vaccine-induced memory CD8 + T cell response by mechanisms that are not fully understood. Methods We analyzed the temporal dynamics of CD8 + T cell recall activity and function during EcoHIV infection in a potent PD1-based vaccine immunized immunocompetent mice. Findings Upon intraperitoneal EcoHIV infection, high levels of HIV-1 GAG-specific CD8 + T lymphocytes recall response reduced EcoHIV-infected cells significantly. However, this protective effect diminished quickly after seven days, followed by a rapid reduction of GAG-specific CD8 + T cell number and activity, and viral persistence. Mechanistically, EcoHIV activated dendritic cells (DCs) and myeloid cells. Myeloid cells were infected and rapidly expanded, exhibiting elevated PD-L1/-L2 expression and T cell suppressive function before day 7, and were resistant to CD8 + T cell-mediated apoptosis. Depletion of myeloid-derived suppressor cells (MDSCs) reduced EcoHIV infection and boosted T cell responses. Interpretation This study provides an overview of the temporal interplay of persistent virus, DCs, MDSCs and antigen-specific CD8 + T cells during acute infection. We identify MDSCs as critical gatekeepers that restrain antiviral T cell memory responses, and highlight MDSCs as an important target for developing effective vaccines against chronic human infections. Funding Hong Kong Research Grant Council (T11–709/18-N, HKU5/CRF/13G), General Research Fund (17122915 and 17114114), Hong Kong Health and Medical Research Fund (11100752, 14130582, 16150662), Grant RGC-ANR A-HKU709/14, the San-Ming Project of Medicine (SZSM201512029), University Development Fund of the University of Hong Kong and Li Ka Shing Faculty of Medicine Matching Fund to HKU AIDS Institute.

This study presents that ICVAX, a PD1-based DNA vaccine against HIV-1, could induce broad and polyfunctional T cell responses against different HIV-1 subtypes. ICVAX encodes a recombinant antigen consisting of the human soluble PD1 domain fused with two mosaic Gag-p41 antigens.

Background: The ongoing outbreak of SARS-CoV-2 Omicron BA.2 infections in Hong Kong, the world model city of universal masking, has resulted in a major public health crisis. Although the third heterologous BNT162b2 vaccination after 2-dose CoronaVac generated higher neutralizing antibody responses than the third homologous CoronaVac booster, vaccine efficacy and corelates of immune protection against the major circulating Omicron BA.2 remains to be investigated. Methods: We investigated the vaccine efficacy against the Omicron BA.2 breakthrough infection among 481 public servants who had been received with SARS-CoV-2 vaccines including two-dose BNT162b2 (2×BNT, n=169), three-dose BNT162b2 (2×BNT, n=175), two-dose CoronaVac (2×CorV, n=37), three-dose CoronaVac (3×CorV, n=68) and third-dose BNT162b2 following 2×CorV (2×CorV+1BNT, n=32). Humoral and cellular immune responses after three-dose vaccination were characterized and correlated with clinical characteristics of BA.2 infection. Results: During the BA.2 outbreak, 29.3% vaccinees were infected. Three-dose vaccination provided protection with lower incidence rates of breakthrough infections (2×BNT 49.2% vs 3×BNT 16.6%, p<0.0001; 2×CorV 48.6% vs 3×CoV 20.6%, p=0.003). The third heterologous vaccination showed the lowest incidence (2×CorV+1×BNT 6.3%). Although BA.2 conferred the highest neutralization resistance compared with variants of concern tested, the third dose vaccination-activated spike-specific memory B and Omicron cross-reactive T cell responses contributed to reduced frequencies of breakthrough infection and disease severity. Conclusions: Our results have implications to timely boost vaccination and immune responses likely required for vaccine-mediated protection against Omicron BA.2 pandemic.