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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., (© 2022. The Author(s).)

Background: HIV eradication efforts have been unsuccessful partly due to virus persistence in immune sanctuary sites such as germinal centres within lymph node (LN) tissues. Recent evidence suggests that LNs harbour a novel subset of regulatory T cells, termed follicular regulatory T cells (TFRs), but their role in HIV pathogenesis is not fully elucidated., Results: Paired excisional LN and peripheral blood samples obtained from 20 HIV-uninfected and 31 HIV-infected treated and 7 chronic untreated, were used to determine if and how HIV infection modulate frequencies, function and spatial localization of TFRs within LN tissues. Imaging studies showed that most TFRs are localized in extra-follicular regions. Co-culture assays showed TFRs suppression of TFH help to B cells. Importantly, epigenetic and transcriptional studies identified DPP4 and FCRL3 as novel phenotypic markers that define four functionally distinct TFR subpopulations in human LNs regardless of HIV status. Imaging studies confirmed the regulatory phenotype of DPP4 + TFRs., Conclusion: Together these studies describe TFRs dynamic changes during HIV infection and reveal previously underappreciated TFR heterogeneity within human LNs., (© 2022. The Author(s).)

Sustained viremia after acute HIV infection is associated with profound CD4 + T cell loss and exhaustion of HIV-specific CD8 + T cell responses. To determine the impact of combination antiretroviral therapy (cART) on these processes, we examined the evolution of immune responses in acutely infected individuals initiating treatment before peak viremia. Immediate treatment of Fiebig stages I and II infection led to a rapid decline in viral load and diminished magnitude of HIV-specific (tetramer + ) CD8 + T cell responses compared to untreated donors. There was a strong positive correlation between cumulative viral antigen exposure before full cART-induced suppression and immune responses measured by MHC class I tetramers, IFN-γ ELISPOT, and CD8 + T cell activation. HIV-specific CD8 + T responses of early treated individuals were characterized by increased CD127 and BCL-2 expression, greater in vitro IFN-γ secretion, and enhanced differentiation into effector memory (T em ) cells. Transcriptional analysis of tetramer + CD8 + T cells from treated persons revealed reduced expression of genes associated with activation and apoptosis, with concurrent up-regulation of prosurvival genes including BCL-2 , AXL , and SRC Early treatment also resulted in robust HIV-specific CD4 + T cell responses compared to untreated HIV-infected individuals. Our data show that limiting acute viremia results in enhanced functionality of HIV-specific CD4 + and CD8 + T cells, preserving key antiviral properties of these cells., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY).)

Some closely related human leukocyte antigen (HLA) alleles are associated with variable clinical outcomes following HIV-1 infection despite presenting the same viral epitopes. Mechanisms underlying these differences remain unclear but may be due to intrinsic characteristics of the HLA alleles or responding T cell repertoires. Here we examine CD8 + T cell responses against the immunodominant HIV-1 Gag epitope TL9 (TPQDLNTML 180-188 ) in the context of the protective allele B*81:01 and the less protective allele B*42:01. We observe a population of dual-reactive T cells that recognize TL9 presented by both B*81:01 and B*42:01 in individuals lacking one allele. The presence of dual-reactive T cells is associated with lower plasma viremia, suggesting a clinical benefit. In B*42:01 expressing individuals, the dual-reactive phenotype defines public T cell receptor (TCR) clones that recognize a wider range of TL9 escape variants, consistent with enhanced control of viral infection through containment of HIV-1 sequence adaptation.

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 ( P = 0.02) and Tfh2 ( P < 0.0001) subsets, with a concomitant decrease in overall Tfh1-17 (which shares both Tfh1 and Tfh17 properties) ( P = 0.01) and Tfh17 ( P < 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 ( P = 0.03, Spearman rho [ r ] = -60) and were predictive of p24-specific plasma IgG titers at 1 year of infection ( P = 0.003, r = 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. IMPORTANCE 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., Competing Interests: We declare no conflict of interest., (Copyright © 2018 American Society for Microbiology.)

CD8(+) T cells contribute to the control of HIV, but it is not clear whether initial immune responses modulate the viral set point. We screened high-risk uninfected women twice a week for plasma HIV RNA and identified 12 hyperacute infections. Onset of viremia elicited a massive HIV-specific CD8(+) T cell response, with limited bystander activation of non-HIV memory CD8(+) T cells. HIV-specific CD8(+) T cells secreted little interferon-γ, underwent rapid apoptosis, and failed to upregulate the interleukin-7 receptor, known to be important for T cell survival. The rapidity to peak CD8(+) T cell activation and the absolute magnitude of activation induced by the exponential rise in viremia were inversely correlated with set point viremia. These data indicate that rapid, high magnitude HIV-induced CD8(+) T cell responses are crucial for subsequent immune control of acute infection, which has important implications for HIV vaccine design., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Poliomyelitis is endemic in Northern Nigeria where there is continuous transmission of wild poliovirus 1 and 3 (WPV1 and 3) and circulating vaccine derived poliovirus 2 (cVDPV2) resulting in a high number of cases of children with acute flaccid paralysis. The seroprevalence of antibodies to polio serotypes which can be used to assess the immune status of children and the effectiveness of the vaccine against poliomyelitis is unknown, despite its endemicity in this part of the world., Objective: This study aimed to determine the seroprevalence of poliovirus antibodies in children aged 1-10 years in Zaria, Northern Nigeria., Methods: A descriptive, cross sectional, community based study was undertaken in Zaria, North Western Nigeria between 2008 and 2009. Two hundred and sixty-four (264) children aged 1-10 years were enrolled from two local government in Zaria by multistage random sampling method. Demographic data and polio immunisation history were retrieved from parents and caregivers by an interviewer administered questionnaire. Neutralising antibody titres to polioserotypes 1, 2 and 3 were assayed according to the WHO Manual for the virological investigation of polio. Antibody titres ≥ 1:8 were considered positive., Results: The mean age of the 264 children studied was 6.25 years. Fifty-five percent of the children were protected against the three polioserotypes, while 86.4%, 76.1% and 77.3% of children had neutralising antibodies to P1, P2 and P3 polioserotypes respectively. 5 (1.9%) of the children had no antibodies to all the three polioserotypes. Polio antibody seropositivity was significantly associated with higher socioeconomic status and immunisation was the single most important determinant of seropositivity to poliovirus serotypes., Conclusion: Seroprevalence to poliovirus serotypes, though higher than values found in previous studies done in Nigeria, was lower compared to findings in the developed world. The use of more immunogenic vaccines and the balanced use of OPV formulations in SIAs, with further improvements in programme quality could provide the necessary immune booster to make polio eradication in Nigeria a reality., (Copyright © 2012 Elsevier Ltd. All rights reserved.)