Despite decades of focused research, the field has yet to develop a prophylactic vaccine for HIV-1 infection. In the RV144 vaccine trial, nonneutralizing antibody responses were identified as a correlate for prevention of HIV acquisition. However, factors that predict the development of such antibodies are not fully elucidated. We sought to define the contribution of circulating T follicular helper (cTfh) subsets to the development of nonneutralizing antibodies in HIV-1 clade C infection. Study participants were recruited from an acute HIV-1 clade C infection cohort. Plasma anti-gp41, -gp120, -p24, and -p17 antibodies were screened using a customized multivariate Luminex assay. Phenotypic and functional characterizations of cTfh cells were performed using HLA class II tetramers and intracellular cytokine staining. In this study, we found that acute HIV-1 clade C infection skewed the differentiation of functional cTfh subsets toward increased Tfh1 ( = 0.02) and Tfh2 ( < 0.0001) subsets, with a concomitant decrease in overall Tfh1-17 (which shares both Tfh1 and Tfh17 properties) ( = 0.01) and Tfh17 ( < 0.0001) subsets, compared to the subsets found in HIV-negative subjects. Interestingly, the frequencies of Tfh1 cells during acute infection (5.0 to 8.0 weeks postinfection) correlated negatively with the set point viral load ( = 0.03, Spearman rho [] = -60) and were predictive of p24-specific plasma IgG titers at 1 year of infection ( = 0.003, = 0.85). Taken together, our results suggest that the circulating Tfh1 subset plays an important role in the development of anti-HIV antibody responses and contributes to HIV suppression during acute HIV-1 infection. These results have implications for vaccine studies aimed at inducing long-lasting anti-HIV antibody responses. The HIV epidemic in southern Africa accounts for almost half of the global HIV burden, with HIV-1 clade C being the predominant strain. It is therefore important to define immune correlates of clade C HIV control that might have implications for vaccine design in this region. T follicular helper (Tfh) cells are critical for the development of HIV-specific antibody responses and could play a role in viral control. Here we showed that the early induction of circulating Tfh1 cells during acute infection correlated positively with the magnitude of p24-specific IgG and was associated with a lower set point viral load. This study highlights a key Tfh cell subset that could limit HIV replication by enhancing antibody generation. This study underscores the importance of circulating Tfh cells in promoting nonneutralizing antibodies during HIV-1 infection.
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
CD8+ T-cells play an important role in HIV control. However, in human lymph nodes (LNs), only a small subset of CD8+ T-cells expresses CXCR5, the chemokine receptor required for cell migration into B cell follicles, which are major sanctuaries for HIV persistence in individuals on therapy. Here, we investigate the impact of HIV infection on follicular CD8+ T-cells (fCD8s) frequencies, trafficking pattern and CXCR5 regulation. We show that, although HIV infection results in a marginal increase of fCD8s in LN, the majority of HIV-specific CD8+ T-cells are CXCR5 negative (non-fCD8s) (p<0.003). Mechanistic investigations using ATAC-seq showed that non-fCD8s have closed chromatin at the CXCR5 transcriptional start site (TSS). DNA bisulfite sequencing identified DNA hypermethylation at the CXCR5 TSS as the most probable cause of closed chromatin. Transcriptional factor footprints analysis revealed enrichment of transforming growth factors (TGFs) at the TSS of fCD8s. In-vitro stimulation of non-fCD8s with recombinant TGF-β resulted in significant increase in CXCR5 expression (fCD8s). Thus, this study identifies TGF-β signaling as a viable strategy for increasing fCD8s frequencies in follicular areas of the LN where they are needed to eliminate HIV infected cells, with implications for HIV cure strategies.
HIV persistence in tissue sites despite ART is a major barrier to HIV cure. Detailed studies of HIV-infected cells and immune responses in native lymph node tissue environment is critical for gaining insight into immune mechanisms impacting HIV persistence and clearance in tissue sanctuary sites. We compared HIV persistence and HIV-specific T cell responses in lymph node biopsies obtained from 14 individuals who initiated therapy in Fiebig stages I/II, 5 persons treated in Fiebig stages III-V and 17 late treated individuals who initiated ART in Fiebig VI and beyond. Using multicolor immunofluorescence staining and in situ hybridization, we detect HIV RNA and/or protein in 12 of 14 Fiebig I/II treated persons on suppressive therapy for 1 to 55 months, and in late treated persons with persistent antigens. CXCR3+ T follicular helper cells harbor the greatest amounts of gag mRNA transcripts. Notably, HIV-specific CD8+ T cells responses are associated with lower HIV antigen burden, suggesting that these responses may contribute to HIV suppression in lymph nodes during therapy. These results reveal HIV persistence despite the initiation of ART in hyperacute infection and highlight the contribution of virus-specific responses to HIV suppression in tissue sanctuaries during suppressive ART.
There is an urgent need for accurate and sensitive diagnostic tools that can overcome the current challenge to distinguish individuals with latent tuberculosis infection (LTBI) from individuals with active tuberculosis (TB). Recent literature has suggested that a group of cytokines may serve as biomarkers of TB disease progression. Using a multiplex ELISA, we quantified 27 circulatory markers present within the unstimulated plasma of individuals in Durban, South Africa who were healthy (n=20), LTBI (n=13), or had active TB (n=30). RT-qPCR was performed to measure gene expression of the cytokines of interest, using RNA isolated from healthy (n=20), LTBI (n=20), or active TB (n=30). We found that at the protein level, IL-1RA, IL-6, and IP-10 were significantly more abundant in participants with active TB (p< 0.05) compared to those with LTBI individuals. IP-10 also showed the strongest association with active TB compared to healthy and LTBI at mRNA level. Our data shows that these proteins may serve as biomarkers of TB at both the protein and gene level.
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