Immune quiescence: a model of protection against HIV infection.

Aberrant immune activation is a strong correlate of HIV disease progression, but little is known about how immune activation alters susceptibility to HIV infection. Susceptibility to HIV infection varies between individuals, but the immunological determinants of HIV transmission are not well understood. Here, we present evidence from studies of HIV transmission in the context of clinical trials and HIV-exposed seronegative (HESN) cohorts that implicates elevated immune activation as a risk factor for acquiring HIV. We propose a model of protection from infection based on a phenotype of low baseline immune activation referred to as immune quiescence. Immune quiescence is evidenced by reduced expression of T cell activation markers, low levels of generalized gene transcription and low levels of proinflammatory cytokine and chemokine production in the periphery and genital mucosa of HESN. Since HIV preferentially replicates in activated CD4+ T cells, immune quiescence may protect against infection by limiting HIV target cell availability. Although the determinants of immune quiescence are unclear, several potential factors have been identified that may be involved in driving this phenotype. HESN were shown to have elevated proportions of regulatory T cells (Tregs), which are known to suppress T cell activation. Likewise, proteins involved in controlling inflammation in the genital tract have been found to be elevated in HESN. Furthermore, expression of interferon regulatory factor 1 (IRF-1) is reduced in HESN as a consequence of genetic polymorphisms and differential epigenetic regulation. Since IRF-1 is an important regulator of immune responses, it may play a role in maintaining immune quiescence. Based on this model, we propose a novel avenue for HIV prevention targeted based on reducing host mucosal immune activation.

Endothelial Cells Promote Productive HIV Infection of Resting CD4+ T Cells by an Integrin-Mediated Cell Adhesion-Dependent Mechanism.

Resting CD4+ T cells are primary targets of early HIV infection events in vivo, but do not readily support HIV replication in vitro. This barrier to infection can be overcome by exposing resting CD4+ T cells to endothelial cells (ECs). ECs line blood vessels and direct T cell trafficking into inflamed tissues. Cell trafficking pathways have been shown to have overlapping roles in facilitating HIV replication, but their relevance to EC-mediated enhancement of HIV susceptibility in resting CD4+ T cells has not previously been examined. We characterized the phenotype of primary human resting CD4+ T cells that became productively infected with HIV when cocultured with primary human blood and lymphatic ECs. The infected CD4+ T cells were primarily central memory cells enriched for high expression of the integrins LFA-1 and VLA-4. ICAM-1 and VCAM-1, the cognate ligands for LFA-1 and VLA-4, respectively, were expressed by the ECs in the coculture. Blocking LFA-1 and VLA-4 on resting CD4+ T cells inhibited infection by 65.4%-96.9%, indicating that engagement of these integrins facilitates EC-mediated enhancement of productive HIV infection in resting CD4+ T cells. The demonstration that ECs influence cellular HIV susceptibility of resting memory CD4+ T cells through cell trafficking pathways engaged during the transmigration of T cells into tissues highlights the physiological relevance of these findings for HIV acquisition and opportunities for intervention.

Expansion of cytotoxic tissue-resident CD8+ T cells and CCR6+CD161+ CD4+ T cells in the nasal mucosa following mRNA COVID-19 vaccination.

Vaccines against SARS-CoV-2 have shown high efficacy in clinical trials, yet a full immunologic characterization of these vaccines, particularly within the human upper respiratory tract, is less well known. Here, we enumerate and phenotype T cells in nasal mucosa and blood using flow cytometry before and after vaccination with the Pfizer-BioNTech COVID-19 vaccine (n = 21). Tissue-resident memory (Trm) CD8+ T cells expressing CD69+CD103+ increase in number ~12 days following the first and second doses, by 0.31 and 0.43 log10 cells per swab respectively (p = 0.058 and p = 0.009 in adjusted linear mixed models). CD69+CD103+CD8+ T cells in the blood decrease post-vaccination. Similar increases in nasal CD8+CD69+CD103- T cells are observed, particularly following the second dose. CD4+ cells co-expressing CCR6 and CD161 are also increased in abundance following both doses. Stimulation of nasal CD8+ T cells with SARS-CoV-2 spike peptides elevates expression of CD107a at 2- and 6-months (p = 0.0096) post second vaccine dose, with a subset of donors also expressing increased cytokines. These data suggest that nasal T cells may be induced and contribute to the protective immunity afforded by this vaccine.

The role of regulatory T cells in chronic and acute viral infections.

Regulatory T cells, a subset of CD4(+) T lymphocytes, play a pivotal role in the maintenance of the balance between the tissue-damaging and protective effects of the immune response. These cells have immunosuppressive function and have been intensely studied in the context of autoimmunity, cancer, allergies, asthma, and infectious diseases. Their role in chronic and persistent viral infections is well appreciated. In acute viral infections, the function of these cells is still unclear. The host and pathogen factors that control the generation and activity of regulatory T cells and the role of these cells in modulating expansion, contraction, and development of immune memory in acute respiratory virus infection need to be further elucidated.

Emerging roles of lymphatic endothelium in regulating adaptive immunity.

Emerging research on the roles of stromal cells in modulating adaptive immune responses has included a new focus on lymphatic endothelial cells (LECs). LECs are presumably the first cells that come into direct contact with peripheral antigens, cytokines, danger signals, and immune cells travelling from peripheral tissues to lymph nodes. LECs can modulate dendritic cell function, present antigens to T cells on MHC class I and MHC class II molecules, and express immunomodulatory cytokines and receptors, which suggests that their roles in adaptive immunity are far more extensive than previously realized. This Review summarizes the emergent evidence that LECs are important in maintaining peripheral tolerance, limiting and resolving effector T cell responses, and modulating leukocyte function.

HIV controllers are distinguished by chemokine expression profile and HIV-specific T-cell proliferative potential.

BACKGROUND: HIV controllers demonstrate a natural ability to control HIV replication in the absence of antiretroviral therapy. We performed a comprehensive evaluation of inflammation and T-cell activation in a demographically unique cohort of HIV controllers and noncontrollers. METHODS: Plasma concentrations of 22 cytokines and chemokines were evaluated using a multiplex bead array approach. Multicolor flow cytometry was used to measure baseline levels of T-cell activation and regulatory T cells (Tregs) and HIV-specific T-cell cytokine (interferon γ, interleukin 2) and proliferation responses. RESULTS: HIV controllers were characterized by elevated macrophage inflammatory protein 1α and low levels of interferon γ-induced protein 10, monocyte chemotactic protein 1, and Transforming growth factor beta. Activated (CD38(+) HLA DR(+)) CD4(+) and CD8(+) T cells were reduced in HIV controllers relative to noncontrollers. HIV controllers and noncontrollers had comparable proportions of Tregs within the CD4(+) T-cell compartment, but absolute Treg counts were depleted in noncontrollers. Absolute Treg counts correlated inversely with T-cell activation. Proliferative CD4(+) and CD8(+) T-cell responses directed against HIV gag epitopes were found most frequently among HIV controllers with the lowest viral loads (elite controllers) and were rarely detected among noncontrollers, supporting a relationship between HIV-specific T-cell proliferation and viral control. CONCLUSIONS: Collectively, these data suggest a model in which HIV controllers maintain low levels of viral replication through robust HIV-specific T-cell responses in an environment of low inflammation and reduced availability of activated target cells.

Reduced cellular susceptibility to in vitro HIV infection is associated with CD4+ T cell quiescence.

BACKGROUND: HIV preferentially establishes productive infection in activated CD4+ T cells. Since proportions of activated CD4+ T cells vary between individuals, this study aimed to determine if individuals with a greater proportion of activated CD4+ T cells would be more susceptible to in vitro HIV infection. METHODOLOGY/PRINCIPAL FINDINGS: Unstimulated peripheral blood mononuclear cells (PBMC) from various donors were inoculated with HIV(ML1956)in vitro. HIV replication was evaluated by HIV p24 ELISA of culture supernatants and intracellular staining for HIV p24, which was detected by flow cytometry. Baseline T cell phenotypes and infected cell phenotypes were also evaluated by flow cytometry. Ex vivo phenotyping at the time of blood draw showed that elevated T cell activation and reduced Tregs were associated with increased cellular susceptibility to in vitro infection. Furthermore, the infected CD4+ T cell population was enriched for activated cells. CONCLUSION/SIGNIFICANCE: These data suggest that CD4+ T cell quiescence provides an environment less conducive to the establishment of HIV infection by limiting the pool of activated target cells.

Bacterial vaginosis, HIV serostatus and T-cell subset distribution in a cohort of East African commercial sex workers: retrospective analysis.

OBJECTIVE: Although bacterial vaginosis is a known correlate of HIV infection, no previous studies have investigated whether women defined as HIV-exposed seronegative (HESN) are less likely to have bacterial vaginosis. Little is known about the effects of bacterial vaginosis on systemic immune activation associated with HIV+ serostatus. DESIGN: Cohort-based retrospective analysis of bacterial vaginosis in relation to HESN status, HIV+ serostatus and peripheral T-helper cells, with cross-sectional analysis of bacterial vaginosis in relation to peripheral T-regulatory cells (Tregs). METHODS: Bacterial vaginosis diagnosis by Gram stain and determination of systemic CD4(+) and CD8(+) T-helper cell frequency by flow cytometry for 3504 vaginal samples from 988 commercial sex workers over 4 years. Treg phenotyping by FoxP3 staining and multiparameter flow cytometry in peripheral blood of 97 women at a single time-point. RESULTS: No differences in bacterial vaginosis diagnosis were observed between HESN and other HIV-negative (HIV-N) controls; however, HIV+ women were more likely to be diagnosed with bacterial vaginosis compared to all HIV-negative women (HESN/HIV-N combined). HIV+ women with bacterial vaginosis had significantly higher CD4(+)/CD8(+) T-helper cell counts and a lower CD4/CD8 ratio, as well as fewer Tregs as a proportion of total T-helper cells, compared to bacterial vaginosis-negative women. The number of bacterial vaginosis diagnoses in this cohort has decreased significantly over time. CONCLUSION: Bacterial vaginosis is associated with HIV serostatus and shifts in distribution of T-cell subsets. A concomitant reduction in bacterial vaginosis and HIV infections over time suggests that the elucidation of bacterial vaginosis-HIV interactions will be critical to further understanding of HIV pathogenesis and prevention in this high-risk group.

HIV vaccine efficacy trials: A brief history, and options for going forward.

HIV vaccine research has recently produced a number of efficacy results, in addition to some promising preclinical developments. Some of these have been surprising, leading to parallel calls for a better understanding of HIV pathogenesis and immunity, while accelerating the number of candidates that can be tested empirically in clinical trials. In this review, we describe the development of three HIV vaccine efficacy trials to date, and highlight some of the possible avenues available for the field of biomedical HIV prevention to proceed.

Decreased immune activation in resistance to HIV-1 infection is associated with an elevated frequency of CD4(+)CD25(+)FOXP3(+) regulatory T cells.

Human immunodeficiency virus (HIV)-resistant commercial sex workers provide a unique opportunity to study correlates of protection associated with natural resistance to HIV infection. Emerging data from studies of these individuals and other uninfected individuals who have been exposed to HIV suggest that low levels of immune activation may contribute to protection against infection. In the present study, HIV-resistant individuals were shown to have reduced frequencies of T cells expressing the activation marker CD69. They were also found to have elevated frequencies of regulatory T (T(reg)) cells, compared with HIV-negative control individuals. By controlling levels of T cell activation, T(reg) cells may contribute to HIV resistance by minimizing the pool of cells susceptible to infection.