Frequencies of circulating Th1-biased T follicular helper cells in acute HIV-1 infection correlate with the development of HIV-specific antibody responses and lower set point viral load

Abstract

Word count:243) 24Despite decades of focused research, the field has yet to develop a prophylactic vaccine. In the 25 RV144 vaccine trial, non-neutralizing antibody responses were identified as a correlate for 26 prevention of HIV acquisition. However, factors that predict the development of such antibodies 27 are not fully elucidated. We sought to define the contribution of circulating T follicular helper 28 (cTfh) cell subsets to the development of non-neutralizing antibodies in HIV-1 clade C infection. 29Study participants were recruited from an acute HIV-1 clade C infection cohort. Plasma anti-30 gp41, -gp120, -p24 and -p17 antibodies were screened using a customized multivariate Luminex 31 assay. Phenotypic and functional characterization of cTfh were performed using HLA class II 32 tetramers and intracellular cytokine staining. In this study, we found that acute HIV-1 clade C 33 infection skewed differentiation of functional cTfh subsets towards increased Tfh1 (p=0.02) and 34Tfh2 (p<0.0001) subsets, with a concomitant decrease in overall Tfh1-17 (that shares both Tfh1 35 and Tfh17 properties) (p=0.01) and Tfh17 subsets (p<0.0001) compared to HIV negative 36 subjects. Interestingly, the frequencies of Tfh1 during acute infection (5.0-8.0 weeks post-37 infection) correlated negatively with set point viral load (p=0.03, r=-60) and were predictive of 38 p24-specific plasma IgG titers at one year of infection (p=0.003, r=0.85). Taken together, our 39 results suggest that circulating the Tfh1 subset plays an important role in the development of 40 anti-HIV antibody responses and contributes to HIV suppression during acute HIV-1 infection. 41 These results have implications for vaccine studies aimed at inducing long lasting anti-HIV 42 antibody responses. 43 44 45 3

Evidence of potent humoral immune activity in COVID-19-infected kidney transplant recipients

“…When we quantified peripheral blood CD4 + CXCR5 + PD‐1 + T FH by flow cytometry (gating strategy Figure S3), we did not observe significant differences between the 2 groups (Figure 4A). We also did not observe significant differences in the frequencies of CD4 + CXCR5 + PD‐1 + CCR6 − CXCR3 + T FH1 cells (implicated as crucial in antiviral antibody responses 15 ), CD4 + CXCR5 + PD‐1 + CCR6 − CXCR3 − T FH2 cells (important for maturation of B cells into IgG4‐secreting cells 16 ), nor in the CD4 + CXCR5 + PD‐1 + CCR6 + CXCR3 − T FH17 cells 17 between groups (Figure 4B‐D).…”

TFH Cells Induced by Vaccination and Following SIV Challenge Support Env-Specific Humoral Immunity in the Rectal-Genital Tract and Circulation of Female Rhesus Macaques

“…Several studies have demonstrated that cT FH cells play an important role in HIV-specific humoral immunity ( 15 , 20 , 22 , 69 ). We next investigated whether immunization elicited cT FH responses in the blood of female rhesus macaques and whether vaccine-induced cT FH responses contributed to anti-HIV humoral immunity.…”

“…In humans, circulating CCR7 + PD1 + CXCR5 + CD4 + T cells were shown to be antigen-experienced cT FH cells able to return to nondraining secondary lymphoid organs to support rapid GC formation upon antigen reencounter ( 74 ). Likewise, generation of CCR7 + PD-1 + cT FH cells, central memory cells by virtue of CCR7 expression ( 20 , 69 ), may also play a role in faster GC reactions following antigen re-exposure in immunized rhesus macaques.…”

Th2-like T Follicular Helper Cells Promote Functional Antibody Production during Plasmodium falciparum Infection

“…Further highlighting the importance of specific Th2-cTfh targeting in vaccine optimization, the co-administration of viral vectored vaccines with RTS,S skewed the cTfh cell response toward Th1-cTfh cell activation, to the detriment of functional antibody induction and vaccine efficacy. 49 In contrast, multiple studies have shown that Th1-Tfh cells are associated with antibody induction to viral infections and vaccinations, including SARS-CoV-2, 16 , 17 , 18 , 19 highlighting that distinct vaccine approaches may be required for malaria vaccines compared to viral pathogens.…”

“…For example, Th2-cTfh cells have been associated with the acquisition of broadly neutralizing antibodies against HIV, 10 while Th1-cTfh cells are linked to the induction of antibodies following viral infection and vaccination, including influenza, HIV, and severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). 16 , 17 , 18 , 19 …”