First-in-human immunoPET imaging of COVID-19 convalescent patients using dynamic total-body PET and a CD8-targeted minibody.

With most of the T cells residing in the tissue, not the blood, developing noninvasive methods for in vivo quantification of their biodistribution and kinetics is important for studying their role in immune response and memory. This study presents the first use of dynamic positron emission tomography (PET) and kinetic modeling for in vivo measurement of CD8+ T cell biodistribution in humans. A 89Zr-labeled CD8-targeted minibody (89Zr-Df-Crefmirlimab) was used with total-body PET in healthy individuals (N = 3) and coronavirus disease 2019 (COVID-19) convalescent patients (N = 5). Kinetic modeling results aligned with T cell-trafficking effects expected in lymphoid organs. Tissue-to-blood ratios from the first 7 hours of imaging were higher in bone marrow of COVID-19 convalescent patients compared to controls, with an increasing trend between 2 and 6 months after infection, consistent with modeled net influx rates and peripheral blood flow cytometry analysis. These results provide a promising platform for using dynamic PET to study the total-body immune response and memory.

The Emerging Role of MAIT Cell Responses in Viral Infections.

Mucosal-associated invariant T (MAIT) cells are unconventional T cells with innate-like antimicrobial responsiveness. MAIT cells are known for MR1 (MHC class I-related protein 1)-restricted recognition of microbial riboflavin metabolites giving them the capacity to respond to a broad range of microbes. However, recent progress has shown that MAIT cells can also respond to several viral infections in humans and in mouse models, ranging from HIV-1 and hepatitis viruses to influenza virus and SARS-CoV-2, in a primarily cognate Ag-independent manner. Depending on the disease context MAIT cells can provide direct or indirect antiviral protection for the host and may help recruit other immune cells, but they may also in some circumstances amplify inflammation and aggravate immunopathology. Furthermore, chronic viral infections are associated with varying degrees of functional and numerical MAIT cell impairment, suggesting secondary consequences for host defense. In this review, we summarize recent progress and highlight outstanding questions regarding the emerging role of MAIT cells in antiviral immunity.

The Association Between Heterosexual anal Intercourse and HIV Acquisition in Three Prospective Cohorts of Women.

The extent to which receptive anal intercourse (RAI) increases the HIV acquisition risk of women compared to receptive vaginal intercourse (RVI) is poorly understood. We evaluated RAI practice over time and its association with HIV incidence during three prospective HIV cohorts of women: RV217, MTN-003 (VOICE), and HVTN 907. At baseline, 16% (RV 217), 18% (VOICE) of women reported RAI in the past 3 months and 27% (HVTN 907) in the past 6 months, with RAI declining during follow-up by around 3-fold. HIV incidence in the three cohorts was positively associated with reporting RAI at baseline, albeit not always significantly. The adjusted hazard rate ratios for potential confounders (aHR) were 1.1 (95% Confidence interval: 0.8-1.5) for VOICE and 3.3 (1.6-6.8) for RV 217, whereas the ratio of cumulative HIV incidence by RAI practice was 1.9 (0.6-6.0) for HVTN 907. For VOICE, the estimated magnitude of association increased slightly when using a time-varying RAI exposure definition (aHR = 1.2; 0.9-1.6), and for women reporting RAI at every follow-up survey (aHR = 2.0 (1.3-3.1)), though not for women reporting higher RAI frequency (> 30% acts being RAI vs. no RAI in the past 3 months; aHR = 0.7 (0.4-1.1)). Findings indicated precise estimation of the RAI/HIV association, following multiple RVI/RAI exposures, is sensitive to RAI exposure definition, which remain imperfectly measured. Information on RAI practices, RAI/RVI frequency, and condom use should be more systematically and precisely recorded and reported in studies looking at sexual behaviors and HIV seroconversions; standardized measures would aid comparability across geographies and over time.

First-in-human immunoPET imaging of COVID-19 convalescent patients using dynamic total-body PET and a CD8-targeted minibody.

With the majority of CD8+ T cells residing and functioning in tissue, not blood, developing noninvasive methods for in vivo quantification of their biodistribution and kinetics in humans offers the means for studying their key role in adaptive immune response and memory. This study is the first report on using positron emission tomography (PET) dynamic imaging and compartmental kinetic modeling for in vivo measurement of whole-body biodistribution of CD8+ T cells in human subjects. For this, a 89Zr-labeled minibody with high affinity for human CD8 (89Zr-Df-Crefmirlimab) was used with total-body PET in healthy subjects (N=3) and in COVID-19 convalescent patients (N=5). The high detection sensitivity, total-body coverage, and the use of dynamic scans enabled the study of kinetics simultaneously in spleen, bone marrow, liver, lungs, thymus, lymph nodes, and tonsils, at reduced radiation doses compared to prior studies. Analysis and modeling of the kinetics was consistent with T cell trafficking effects expected from immunobiology of lymphoid organs, suggesting early uptake in spleen and bone marrow followed by redistribution and delayed increasing uptake in lymph nodes, tonsils, and thymus. Tissue-to-blood ratios from the first 7 h of CD8-targeted imaging showed significantly higher values in the bone marrow of COVID-19 patients compared to controls, with an increasing trend between 2 and 6 months post-infection, consistent with net influx rates obtained by kinetic modeling and flow cytometry analysis of peripheral blood samples. These results provide the platform for using dynamic PET scans and kinetic modelling to study total-body immunological response and memory.

Deciphering the Role of Mucosal Immune Responses and the Cervicovaginal Microbiome in Resistance to HIV Infection in HIV-Exposed Seronegative (HESN) Women.

The female genital tract (FGT) is an important site of human immunodeficiency virus (HIV) infection. Discerning the nature of HIV-specific local immune responses is crucial for identifying correlates of protection in HIV-exposed seronegative (HESN) individuals. The present study involved a comprehensive analysis of soluble immune mediators, secretory immunoglobulins (sIg), natural killer (NK) cells, CXCR5+ CD8+ T cells, T follicular helper (Tfh) cells, and T regulatory cells (Tregs) in the vaginal mucosa as well as the nature and composition of the cervicovaginal microbiome in HESN women. We found significantly elevated antiviral cytokines, soluble immunoglobulins, and increased frequencies of activated NK cells, CXCR5+ CD8+ T cells, and Tfh cells in HESN females compared to HIV-unexposed healthy (UH) women. Analysis of the genital microbiome of HESN women revealed a greater bacterial diversity and increased abundance of Gardnerella spp. in the mucosa. The findings suggest that the female genital tract of HESN females represents a microenvironment equipped with innate immune factors, antiviral mediators, and critical T cell subsets that protect against HIV infection. IMPORTANCE The vast majority of human immunodeficiency virus (HIV) infections across the world occur via the sexual route. The genital tract mucosa is thus the primary site of HIV replication, and discerning the nature of HIV-specific immune responses in this compartment is crucial. The role of the innate immune system at the mucosal level in exposed seronegative individuals and other HIV controllers remains largely unexplored. This understanding can provide valuable insights to improve vaccine design. We investigated mucosal T follicular helper (Tfh) cells, CXCR5+ CD8+ T cells, natural killer (NK) cells subsets, soluble immune markers, and microbiome diversity in HIV-exposed seronegative (HESN) women. We found a significantly higher level of mucosal CXCR5+ CD8+ T cells, CD4+ Tfh cells, activated NK cell subsets, and antiviral immune cell mediators in HESN women. We also found a higher abundance of Gardnerella spp., microbiome dysbiosis, and decreased levels of inflammatory markers to be associated with reduced susceptibility to HIV infection. Our findings indicate that increased distribution of mucosal NK cells, CXCR5+ CD8+ T cells, Tfh cells, and soluble markers in HIV controllers with a highly diverse cervicovaginal microbiome could contribute effectively to protection against HIV infection. Overall, our findings imply that future vaccine design should emphasize inducing these highly functional cell types at the mucosal sites.

The TLR7 agonist vesatolimod induced a modest delay in viral rebound in HIV controllers after cessation of antiretroviral therapy.

Toll-like receptor 7 (TLR7) agonists, in combination with other therapies, can induce sustained control of simian-human immunodeficiency virus (SHIV) or simian immunodeficiency virus (SIV) in nonhuman primates. Here, we report the results of a randomized, double-blind, placebo-controlled phase 1b clinical trial of an oral TLR7 agonist, vesatolimod, in HIV-1-infected controllers on antiretroviral therapy (ART). We randomized participants 2:1 to receive vesatolimod (n = 17) or placebo (n = 8) once every other week for a total of 10 doses while continuing on ART. ART was then interrupted, and the time to viral rebound was analyzed using the Kaplan-Meier method. Vesatolimod was associated with induction of immune cell activation, decreases in intact proviral DNA during ART, and a modest increase in time to rebound after ART was interrupted. The delayed viral rebound was predicted by the lower intact proviral DNA at the end of vesatolimod treatment (13 days after the final dose). Inferred pathway analysis suggested increased dendritic cell and natural killer cell cross-talk and an increase in cytotoxicity potential after vesatolimod dosing. Larger clinical studies will be necessary to assess the efficacy of vesatolimod-based combination therapies aimed at long-term control of HIV infection.

Compartmentalization of cerebrospinal fluid inflammation across the spectrum of untreated HIV-1 infection, central nervous system injury and viral suppression.

OBJECTIVE: To characterize the evolution of central nervous system (CNS) inflammation in HIV-1 infection applying a panel of cerebrospinal fluid (CSF) inflammatory biomarkers to grouped subjects representing a broad spectrum of systemic HIV-1 immune suppression, CNS injury and viral control. METHODS: This is a cross-sectional analysis of archived CSF and blood samples, assessing concentrations of 10 functionally diverse soluble inflammatory biomarkers by immunoassays in 143 HIV-1-infected subjects divided into 8 groups: untreated primary HIV-1 infection (PHI); four untreated groups defined by their blood CD4+ T lymphocyte counts; untreated patients presenting with subacute HIV-associated dementia (HAD); antiretroviral-treated subjects with ≥1 years of plasma viral suppression; and untreated elite controllers. Twenty HIV-1-uninfected controls were included for comparison. Background biomarkers included blood CD4+ and CD8+ T lymphocytes, CSF and blood HIV-1 RNA, CSF white blood cell (WBC) count, CSF/blood albumin ratio, CSF neurofilament light chain (NfL), and CSF t-tau. FINDINGS: HIV-1 infection was associated with a broad compartmentalized CSF inflammatory response that developed early in its course and changed with systemic disease progression, development of neurological injury, and viral suppression. CSF inflammation in untreated individuals without overt HAD exhibited at least two overall patterns of inflammation as blood CD4+ T lymphocytes decreased: one that peaked at 200-350 blood CD4+ T cells/µL and associated with lymphocytic CSF inflammation and HIV-1 RNA concentrations; and a second that steadily increased through the full range of CD4+ T cell decline and associated with macrophage responses and increasing CNS injury. Subacute HAD was distinguished by a third inflammatory profile with increased blood-brain barrier permeability and robust combined lymphocytic and macrophage CSF inflammation. Suppression of CSF and blood HIV-1 infections by antiretroviral treatment and elite viral control were associated with reduced CSF inflammation, though not fully to levels found in HIV-1 seronegative controls.

The Role of Tissue Resident Memory CD4 T Cells in Herpes Simplex Viral and HIV Infection.

Tissue-resident memory T cells (TRM) were first described in 2009. While initially the major focus was on CD8+ TRM, there has recently been increased interest in defining the phenotype and the role of CD4+ TRM in diseases. Circulating CD4+ T cells seed CD4+ TRM, but there also appears to be an equilibrium between CD4+ TRM and blood CD4+ T cells. CD4+ TRM are more mobile than CD8+ TRM, usually localized deeper within the dermis/lamina propria and yet may exhibit synergy with CD8+ TRM in disease control. This has been demonstrated in herpes simplex infections in mice. In human recurrent herpes infections, both CD4+ and CD8+ TRM persisting between lesions may control asymptomatic shedding through interferon-gamma secretion, although this has been more clearly shown for CD8+ T cells. The exact role of the CD4+/CD8+ TRM axis in the trigeminal ganglia and/or cornea in controlling recurrent herpetic keratitis is unknown. In HIV, CD4+ TRM have now been shown to be a major target for productive and latent infection in the cervix. In HSV and HIV co-infections, CD4+ TRM persisting in the dermis support HIV replication. Further understanding of the role of CD4+ TRM and their induction by vaccines may help control sexual transmission by both viruses.

Gag p24 Is a Marker of Human Immunodeficiency Virus Expression in Tissues and Correlates With Immune Response.

We demonstrate that human immunodeficiency virus (HIV) gag p24 protein is more readily detected in gut and lymph node tissues than in blood CD4+ T cells and correlates better with CD4 count during antiretroviral therapy (ART). Gut p24 levels also measurably decline with ART in natural controllers. During ART, gut p24 expression is more strongly associated both with HIV-specific CD8+ T-cell frequency and plasma soluble CD14 levels than gut HIV RNA expression. This study supports using gag p24 as a marker of HIV expression in HIV+ tissues to study effects of viral persistence and to monitor efficacy of treatment in HIV-based clearance studies.

Reproductive tract immune cells from pregnant women or those using depot medroxyprogesterone acetate show no excess susceptibility to HIV-1: Results of an ex vivo fusion assay.

INTRODUCTION: Ex vivo fusion assays offer an efficient method for studying HIV-1 entry associated with contraceptive use and pregnancy outside of cohort studies of HIV-1 incidence. METHODS: We measured ex vivo HIV-1 fusion to cervical or endometrial immune cells from three groups of women: pregnant, non-pregnant not using hormonal or intrauterine contraception, and using depot medroxyprogesterone acetate (DMPA). RESULTS AND CONCLUSIONS: There was no excess susceptibility to HIV-1 fusion of cells from pregnant women or DMPA users compared to controls. Although the number of target cells in endometrium was higher in DMPA users compared to controls, HIV-1 fusion was lower. IMPLICATIONS: In ex vivo assays, HIV-1 showed no enhanced fusion to cervical immune cells from pregnant women or DMPA users compared to controls, and lower fusion to endometrial immune cells from DMPA users. This assay is useful for studying hormonal and contraceptive effects on HIV-1 entry into reproductive tract immune cells.

RhCMV serostatus and vaccine adjuvant impact immunogenicity of RhCMV/SIV vaccines.

Rhesus cytomegalovirus (RhCMV) strain 68-1-vectored simian immunodeficiency virus (RhCMV/SIV) vaccines are associated with complete clearance of pathogenic SIV challenge virus, non-canonical major histocompatibility complex restriction, and absent antibody responses in recipients previously infected with wild-type RhCMV. This report presents the first investigation of RhCMV/SIV vaccines in RhCMV-seronegative macaques lacking anti-vector immunity. Fifty percent of rhesus macaques (RM) vaccinated with a combined RhCMV-Gag, -Env, and -Retanef (RTN) vaccine controlled pathogenic SIV challenge despite high peak viremia. However, kinetics of viral load control by vaccinated RM were considerably delayed compared to previous reports. Impact of a TLR5 agonist (flagellin; FliC) on vaccine efficacy and immunogenicity was also examined. An altered vaccine regimen containing an SIV Gag-FliC fusion antigen instead of Gag was significantly less immunogenic and resulted in reduced protection. Notably, RhCMV-Gag and RhCMV-Env vaccines elicited anti-Gag and anti-Env antibodies in RhCMV-seronegative RM, an unexpected contrast to vaccination of RhCMV-seropositive RM. These findings confirm that RhCMV-vectored SIV vaccines significantly protect against SIV pathogenesis. However, pre-existing vector immunity and a pro-inflammatory vaccine adjuvant may influence RhCMV/SIV vaccine immunogenicity and efficacy. Future investigation of the impact of pre-existing anti-vector immune responses on protective immunity conferred by this vaccine platform is warranted.

Receptive anal sex contributes substantially to heterosexually acquired HIV infections among at-risk women in twenty US cities: Results from a modelling analysis.

PROBLEM: Receptive anal intercourse (RAI) is more efficient than receptive vaginal intercourse (RVI) at transmitting HIV, but its contribution to heterosexually acquired HIV infections among at-risk women in the USA is unclear. METHOD OF STUDY: We analysed sexual behaviour data from surveys of 9152 low-income heterosexual women living in 20 cities with high rates of HIV conducted in 2010 and 2013 as part of US National HIV Behavioral Surveillance. We estimated RAI prevalence (past-year RAI) and RAI fraction (fraction of all sex acts (RVI and RAI) at the last sexual episode that were RAI among those reporting past-year RAI) overall and by key demographic characteristics. These results and HIV incidence were used to calibrate a risk equation model to estimate the population attributable fraction of new HIV infections due to RAI (PAFRAI ) accounting for uncertainty in parameter assumptions. RESULTS: Receptive anal intercourse prevalence (overall: 32%, city range: 19%-60%) and RAI fraction (overall: 27%, city range: 18%-34%) were high overall and across cities, and positively associated with exchange sex. RAI accounted for an estimated 41% (uncertainty range: 18%-55%) of new infections overall (city range: 21%-57%). Variability in PAFRAI estimates was most influenced by uncertainty in the estimate of the per-act increased risk of RAI relative to RVI and the number of sex acts. CONCLUSION: Receptive anal intercourse may contribute disproportionately to new heterosexually acquired HIV infections among at-risk low-income women in the USA, meaning that tools to prevent HIV transmission during RAI are warranted. The number of RVI and RAI acts should also be collected to monitor heterosexually acquired HIV infections.

Parallel studies of mucosal immunity in the reproductive and gastrointestinal mucosa of HIV-infected women.

PROBLEM: The effects of HIV on the gastrointestinal tract (GIT), including CD4 depletion, epithelial disruption, and collagen deposition, are well documented and only partially reversed by combination antiretroviral therapy (cART). However, the effects of HIV on the female reproductive tract (FRT) are poorly understood, and most studies have focused on ectocervix and vagina without assessing the upper tract. Here, we investigated CD4+ T-cell frequency, phenotype, and HIV-specific T-cell responses in the endocervix and endometrium of HIV-infected women, comparing these tissues to the GIT. METHOD OF STUDY: Mucosal samples and blood were obtained from 18 women: four who were HIV-positive and not on cART for at least 3 years prior to sampling, including two natural controllers (viral load [VL] undetectable and CD4 >350); nine women on cART with low to undetectable VL; and five HIV-uninfected women. Mucosal samples included terminal ileum, sigmoid colon, endocervical cytobrush, endocervical curettage, and endometrial biopsy. T-cell frequency, phenotypes, and HIV-specific T-cell responses were analyzed by multiparameter flow cytometry. RESULTS: T-cell activation, measured by CD38/HLA-DR co-expression, remained significantly elevated in endometrium following cART, but was lower in gastrointestinal tissues. HIV-specific CD8+ T-cell responses were detected in ileum, colon, and endometrial tissues of women both on and off cART, and were of higher magnitude on those not on cART. CONCLUSION: Our findings reveal differences in CD4+ T-cell frequencies, immune activation, and HIV-specific T-cell responses between the gastrointestinal and reproductive tracts, and highlight differences between HIV controllers and women on cART.

Defining T Cell Tissue Residency in Humans: Implications for HIV Pathogenesis and Vaccine Design.

PURPOSE OF REVIEW: This review summarizes recent literature defining tissue-resident memory T cells (TRM) and discusses implications for HIV pathogenesis, vaccines, and eradication efforts. RECENT FINDINGS: Investigations using animal models and human tissues have identified a TRM transcriptional profile and elucidated signals within the tissue microenvironment leading to TRM development and maintenance. TRM are major contributors to host response in infectious diseases and cancer; in addition, TRM contribute to pathogenic inflammation in a variety of settings. Although TRM are daunting to study in HIV infection, recent work has helped define their molecular signatures and effector functions and tested strategies for their mobilization. Exclusive reliance on blood sampling to gain an understanding of host immunity overlooks the contribution of TRM, which differ in significant ways from their counterparts in circulation. It is hoped that greater understanding of these cells will lead to novel approaches to prevent and/or eradicate HIV infection.

Dynamic MAIT cell response with progressively enhanced innateness during acute HIV-1 infection.

Mucosa-associated invariant T (MAIT) cell loss in chronic HIV-1 infection is a significant insult to antimicrobial immune defenses. Here we investigate the response of MAIT cells during acute HIV-1 infection utilizing the RV217 cohort with paired longitudinal pre- and post-infection samples. MAIT cells are activated and expand in blood and mucosa coincident with peak HIV-1 viremia, in a manner associated with emerging microbial translocation. This is followed by a phase with elevated function as viral replication is controlled to a set-point level, and later by their functional decline at the onset of chronic infection. Interestingly, enhanced innate-like pathways and characteristics develop progressively in MAIT cells during infection, in parallel with TCR repertoire alterations. These findings delineate the dynamic MAIT cell response to acute HIV-1 infection, and show how the MAIT compartment initially responds and expands with enhanced function, followed by progressive reprogramming away from TCR-dependent antibacterial responses towards innate-like functionality.

Increases in HIV Incidence Following Receptive Anal Intercourse Among Women: A Systematic Review and Meta-analysis.

Receptive anal intercourse (RAI) carries a greater per-act risk of HIV acquisition than receptive vaginal intercourse (RVI) and may influence HIV epidemics driven by heterosexual sex. This systematic review explores the association between RAI and incident HIV among women, globally. We searched Embase and Medline through September 2018 for longitudinal studies reporting crude (cRR) or adjusted (aRR) relative risks of HIV acquisition by RAI practice among women. Of 27,563 articles identified, 17 eligible studies were included. We pooled independent study estimates using random-effects models. Women reporting RAI were more likely to acquire HIV than women not reporting RAI (pooled cRR = 1.56 95% CI 1.03-2.38, N = 18, I2 = 72%; pooled aRR = 2.23, 1.01-4.92, N = 5, I2 = 70%). In subgroup analyses the association was lower for women in Africa (pooled cRR = 1.16, N = 13, I2 = 21%) than outside Africa (pooled cRR = 4.10, N = 5, I2 = 79%) and for high-risk (pooled aRR = 1.69, N = 4, I2 = 63%) than general-risk women (pooled aRR = 8.50, N = 1). Interview method slightly influenced cRR estimates (p value = 0.04). In leave-one-out sensitivity analyses pooled estimates were generally robust to removing individual study estimates. Main limitations included poor exposure definition, incomplete adjustment for confounders, particularly condom use, and use of non-confidential interview methods. More and better data are needed to explain differences in risk by world region and risk population. Women require better counselling and greater choice in prevention modalities that are effective during RVI and RAI.

What Proportion of Female Sex Workers Practise anal Intercourse and How Frequently? A Systematic Review and Meta-analysis.

HIV is more efficiently acquired during receptive anal intercourse (AI) compared to vaginal intercourse (VI) and may contribute substantially to female sex workers' (FSW) high HIV burden. We aim to determine how common and frequent AI is among FSW globally. We searched PubMed, Embase and PsycINFO for studies reporting the proportion of FSW practising AI (prevalence) and/or the number of AI acts (frequency) worldwide from 01/1980 to 10/2018. We assessed the influence of participant and study characteristics on AI prevalence (e.g. continent, study year and interview method) through sub-group analysis. Of 15,830 identified studies, 131 were included. Nearly all (N = 128) reported AI prevalence and few frequency (N = 13), over various recall periods. Most studies used face-to-face interviews (N = 111). Pooled prevalences varied little by recall period (lifetime: 15.7% 95%CI 12.2-19.3%, N = 30, I2 = 99%; past month: 16.2% 95%CI 10.8-21.6%, N = 18, I2 = 99%). The pooled proportion of FSW reporting < 100% condom use tended to be non-significantly higher during AI compared to during VI (e.g. any unprotected VI: 19.1% 95%CI 1.7-36.4, N = 5 and any unprotected AI: 46.4% 95%CI 9.1-83.6, N = 5 in the past week). Across all study participants, between 2.4 and 15.9% (N = 6) of all intercourse acts (AI and VI) were anal. Neither AI prevalence nor frequency varied substantially by any participant or study characteristics. Although varied, AI among FSW is generally common, inconsistently protected with condoms and practiced sufficiently frequently to contribute substantially to HIV acquisition in this risk group. Interventions to address barriers to condom use are needed.

Effects of the levonorgestrel-containing intrauterine device, copper intrauterine device, and levonorgestrel-containing oral contraceptive on susceptibility of immune cells from cervix, endometrium and blood to HIV-1 fusion measured ex vivo.

Globally, HIV/AIDS is a leading cause of morbidity worldwide among reproductive-aged cisgender women, highlighting the importance of understanding effects of contraceptives on HIV-1 risk. Some observational studies suggest there may be an increased risk of HIV-1 acquisition among women using the long-acting injectable progestin contraceptive, depo-medroxyprogesterone acetate. The potential mechanism of this susceptibility is unclear. There are few data on the role of the upper female reproductive tract in HIV-1 transmission, and the mechanisms of HIV-1 infection are likely to differ in the upper compared to the lower reproductive tract due to differences in tissue composition and variable effects of sex steroids on mucosal immune cell distribution and activity. In this study, we measured the susceptibility of mucosal immune cells from the upper female reproductive tract to HIV-1 entry using the virion-based HIV-1 fusion assay in samples from healthy female volunteers. We studied 37 infectious molecular clones for their ability to fuse to cells from endometrial biopsies in three participants and found that subtype (B or C) and origin of the virus (transmitted founder or chronic control) had little influence on HIV-1 fusion susceptibility. We studied the effect of contraceptives on HIV-1 susceptibility of immune cells from the cervix, endometrium and peripheral blood by comparing fusion susceptibility in four groups: users of the copper intrauterine device (IUD), levonorgestrel-containing oral contraceptive, levonorgestrel-containing IUD and unexposed controls (n = 58 participants). None of the contraceptives was associated with higher rates of HIV-1 entry into female reproductive tract cells compared to control samples from the mid-luteal phase.

Mucosal Immunity in HIV/SIV Infection: T Cells, B Cells and Beyond.

As our understanding of mucosal immunity increases, it is becoming clear that the host response to HIV-1 is more complex and nuanced than originally believed. The mucosal landscape is populated with a variety of specialized cell types whose functions include combating infectious agents while preserving commensal microbiota, maintaining barrier integrity, and ensuring immune homeostasis. Advances in multiparameter flow cytometry, gene expression analysis and bioinformatics have allowed more detailed characterization of these cell types and their roles in host defense than was previously possible. This review provides an overview of existing literature on immunity to HIV-1 and SIVmac in mucosal tissues of the female reproductive tract and the gastrointestinal tract, focusing on major effector cell populations and briefly summarizing new information on tissue resident memory T cells, Treg, Th17, Th22 and innate lymphocytes (ILC), subsets that have been studied primarily in the gastrointestinal mucosa.