Sexual Violence, Genital Cytokines, and Colposcopy Findings: A Cross-Sectional Study of Women Engaged in Sex Work in Mombasa, Kenya.

BACKGROUND: Sexual violence (SV) increases HIV susceptibility in a sustained manner. This study evaluated genital cytokines and colposcopy findings in women reporting both recent and more remote SV.Methods: A cross-sectional study of HIV-1 negative Kenyan women who engage in sex work (WESW) was performed. Cervicovaginal fluid was collected by menstrual cup and cytokines (IFNγ, TNFα, IL-1ß, IL-6, IL-10, MIP-1α, MIP-1ß and CXCL10) measured using chemiluminescence. Cervical injury was assessed by colposcopy. Associations between recent (≤30 days prior), more remote (>30 days prior) and no (reference category) SV exposure and cytokine concentrations were evaluated using linear regression. RESULTS: Among 282 participants, 25 (8.9%) reported recent SV and 123 (43.6%) reported more remote SV. Only two cytokines (IL-10 and CXCL10) were associated with the 3-category SV variable in bivariable modeling at the pre-specified cut-off (p < 0.2) and carried forward. In multivariable analyses, more remote SV (ß = 0.72, 95% CI 0.06, 1.38; p = 0.03), but not recent SV (ß = 0.20, 95%CI -0.99, 1.39; p = 0.74) was associated with cervicovaginal IL-10 compared to no SV. Recent (ß = 0.36, 95% CI -0.94, 1.67; p = 0.58) and more remote (ß = 0.51, 95% CI -0.21, 1.24; p = 0.16) SV were not associated with CXCL10 compared to no SV. Cervical epithelial friability (χ2 = 1.3, p = 0.51), erythema (χ2 = 2.9, p = 0.24), vascular disruption (χ2 = 1.4; p = 0.50), epithelial disruption (χ2 = 2.6, p = 0.27), or any colposcopy finding (χ2 = 1.2, p = 0.54) were not associated with SV category by chi-square test. CONCLUSIONS: The mechanism linking SV to sustained increases in HIV susceptibility may not be related to persistent genital inflammation or injury.

phippery: a software suite for PhIP-Seq data analysis.

SUMMARY: We present the phippery software suite for analyzing data from phage display methods that use immunoprecipitation and deep sequencing to capture antibody binding to peptides, often referred to as PhIP-Seq. It has three main components that can be used separately or in conjunction: (i) a Nextflow pipeline, phip-flow, to process raw sequencing data into a compact, multidimensional dataset format and allows for end-to-end automation of reproducible workflows. (ii) a Python API, phippery, which provides interfaces for tasks such as count normalization, enrichment calculation, multidimensional scaling, and more, and (iii) a Streamlit application, phip-viz, as an interactive interface for visualizing the data as a heatmap in a flexible manner. AVAILABILITY AND IMPLEMENTATION: All software packages are publicly available under the MIT License. The phip-flow pipeline: https://github.com/matsengrp/phip-flow. The phippery library: https://github.com/matsengrp/phippery. The phip-viz Streamlit application: https://github.com/matsengrp/phip-viz.

Epitope profiling reveals binding signatures of SARS-CoV-2 immune response in natural infection and cross-reactivity with endemic human CoVs.

A major goal of current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine efforts is to elicit antibody responses that confer protection. Mapping the epitope targets of the SARS-CoV-2 antibody response is critical for vaccine design, diagnostics, and development of therapeutics. Here, we develop a pan-coronavirus phage display library to map antibody binding sites at high resolution within the complete viral proteomes of all known human-infecting coronaviruses in patients with mild or moderate/severe coronavirus disease 2019 (COVID-19). We find that the majority of immune responses to SARS-CoV-2 are targeted to the spike protein, nucleocapsid, and ORF1ab and include sites of mutation in current variants of concern. Some epitopes are identified in the majority of samples, while others are rare, and we find variation in the number of epitopes targeted between individuals. We find low levels of SARS-CoV-2 cross-reactivity in individuals with no exposure to the virus and significant cross-reactivity with endemic human coronaviruses (CoVs) in convalescent sera from patients with COVID-19.

Associations between vaginal bacteria implicated in HIV acquisition risk and proinflammatory cytokines and chemokines.

OBJECTIVES: Recent studies have identified vaginal bacterial taxa associated with increased HIV risk. A possible mechanism to explain these results is that individual taxa differentially promote cervicovaginal inflammation. This study aimed to explore relationships between concentrations of bacteria previously linked to HIV acquisition and vaginal concentrations of proinflammatory cytokines and chemokines. METHODS: In this cross-sectional analysis, concentrations of 17 bacterial taxa and four proinflammatory cytokines (interleukin (IL)-1ß, IL-6, IL-10 and tumour necrosis factor alpha (TNFα)) and two proinflammatory chemokines (IL-8 and interferon gamma-induced protein 10) were measured in vaginal swabs collected from 80 HIV-uninfected women. Cytokine and chemokine concentrations were compared between women with bacterial concentrations above or below the lower limit of detection as determined by quantitative PCR for each taxon. Principal component analysis was used to create a summary score for closely correlated bacteria, and linear regression analysis was used to evaluate associations between this score and increasing concentrations of TNFα and IL-1ß. RESULTS: Detection of Dialister micraerophilus (p=0.01), Eggerthella sp type 1 (p=0.05) or Mycoplasma hominis (p=0.03) was associated with higher TNFα concentrations, and detection of D. micraerophilus (p<0.01), Eggerthella sp type 1 (p=0.04), M. hominis (p=0.02) or Parvimonas sp type 2 (p=0.05) was associated with significantly higher IL-1ß concentrations. Seven bacterial taxa (D. micraerophilus, Eggerthella sp type 1, Gemella asaccharolytica, Sneathia sp, Megasphaera sp, M. hominis and Parvimonas sp type 2) were found to be highly correlated by principal component analysis (eigenvalue 5.24, explaining 74.92% of variability). Linear regression analysis demonstrated associations between this principal component and concentrations of TNFα (ß=0.55, 95% CI 0.01 to 1.08; p=0.048) and IL-1ß (ß=0.96, 95% CI 0.19 to 1.74; p=0.016). CONCLUSIONS: This study provides evidence that several highly correlated vaginal bacterial taxa may influence vaginal cytokine and chemokine concentrations. These results suggest a mechanism where the presence of specific bacterial taxa could influence HIV susceptibility by increasing vaginal inflammation.

Antibody Lineages with Vaccine-Induced Antigen-Binding Hotspots Develop Broad HIV Neutralization.

The vaccine-mediated elicitation of antibodies (Abs) capable of neutralizing diverse HIV-1 strains has been a long-standing goal. To understand how broadly neutralizing antibodies (bNAbs) can be elicited, we identified, characterized, and tracked five neutralizing Ab lineages targeting the HIV-1-fusion peptide (FP) in vaccinated macaques over time. Genetic and structural analyses revealed two of these lineages to belong to a reproducible class capable of neutralizing up to 59% of 208 diverse viral strains. B cell analysis indicated each of the five lineages to have been initiated and expanded by FP-carrier priming, with envelope (Env)-trimer boosts inducing cross-reactive neutralization. These Abs had binding-energy hotspots focused on FP, whereas several FP-directed Abs induced by immunization with Env trimer-only were less FP-focused and less broadly neutralizing. Priming with a conserved subregion, such as FP, can thus induce Abs with binding-energy hotspots coincident with the target subregion and capable of broad neutralization.

Why we need good mentoring.

Cancer research relies on key values such as creativity, collaboration, research integrity and resource sharing. A positive research environment which fosters these key values is becoming a decisive factor for some funders and research institutions. To create a supportive research culture in laboratories, the training and mentoring of young scientists is important. However, the fast-paced and fierce competition for funding and jobs can present a challenge to the younger generation of scientists who depend on the guidance and mentorship of scientific leaders. The annual Nature Awards for Mentoring in Science have been created to bring attention to one of the most essential but least recognized skills in scientific leadership. Thus far, 35 scientists from across the world, who are working in a range of disciplines, have been recognized by this award for their outstanding scientific mentorship. In this Viewpoint, we have asked three recipients of this award who work in fields associated with cancer research about their views on good mentoring, and how a revised approach to mentorship can help to achieve a positive research culture and contribute to scientific discovery.

Knowns and Unknowns of Assaying Antibody-Dependent Cell-Mediated Cytotoxicity Against HIV-1.

It is now well-accepted that Fc-mediated effector functions, including antibody-dependent cellular cytotoxicity (ADCC), can contribute to vaccine-elicited protection as well as post-infection control of HIV viremia. This picture was derived using a wide array of ADCC assays, no two of which are strictly comparable, and none of which is qualified at the clinical laboratory level. An earlier comparative study of assay protocols showed that while data from different ADCC assay formats were often correlated, they remained distinct in terms of target cells and the epitopes and antigen(s) available for recognition by antibodies, the effector cells, and the readout of cytotoxicity. This initial study warrants expanded analyses of the relationships among all current assay formats to determine where they detect overlapping activities and where they do not. Here we summarize knowns and unknowns of assaying ADCC against HIV-1.

Massively Parallel Profiling of HIV-1 Resistance to the Fusion Inhibitor Enfuvirtide.

Identifying drug resistance mutations is important for the clinical use of antivirals and can help define both a drug's mechanism of action and the mechanistic basis of resistance. Resistance mutations are often identified one-at-a-time by studying viral evolution within treated patients or during viral growth in the presence of a drug in cell culture. Such approaches have previously mapped resistance to enfuvirtide, the only clinically approved HIV-1 fusion inhibitor, to enfuvirtide's binding site in the N-terminal heptad repeat (NHR) of the Envelope (Env) transmembrane domain as well as a limited number of allosteric sites. Here, we sought to better delineate the genotypic determinants of resistance throughout Env. We used deep mutational scanning to quantify the effect of all single-amino-acid mutations to the subtype A BG505 Env on resistance to enfuvirtide. We identified both previously characterized and numerous novel resistance mutations in the NHR. Additional resistance mutations clustered in other regions of Env conformational intermediates, suggesting they may act during different fusion steps by altering fusion kinetics and/or exposure of the enfuvirtide binding site. This complete map of resistance sheds light on the diverse mechanisms of enfuvirtide resistance and highlights the utility of using deep mutational scanning to comprehensively map potential drug resistance mutations.

Identification of HIV gp41-specific antibodies that mediate killing of infected cells.

Antibodies that mediate killing of HIV-infected cells through antibody-dependent cellular cytotoxicity (ADCC) have been implicated in protection from HIV infection and disease progression. Despite these observations, these types of HIV antibodies are understudied compared to neutralizing antibodies. Here we describe four monoclonal antibodies (mAbs) obtained from one individual that target the HIV transmembrane protein, gp41, and mediate ADCC activity. These four mAbs arose from independent B cell lineages suggesting that in this individual, multiple B cell responses were induced by the gp41 antigen. Competition and phage peptide display mapping experiments suggested that two of the mAbs target epitopes in the cysteine loop that are highly conserved and a common target of HIV gp41-specific antibodies. The amino acid sequences that bind these mAbs are overlapping but distinct. The two other mAbs were competed by mAbs that target the C-terminal heptad repeat (CHR) and the fusion peptide proximal region (FPPR) and appear to both target a similar unique conformational epitope. These gp41-specific mAbs mediated killing of infected cells that express high levels of Env due to either pre-treatment with interferon or deletion of vpu to increase levels of BST-2/Tetherin. They also mediate killing of target cells coated with various forms of the gp41 protein, including full-length gp41, gp41 ectodomain or a mimetic of the gp41 stump. Unlike many ADCC mAbs that target HIV gp120, these gp41-mAbs are not dependent on Env structural changes associated with membrane-bound CD4 interaction. Overall, the characterization of these four new mAbs that target gp41 and mediate ADCC provides evidence for diverse gp41 B cell lineages with overlapping but distinct epitopes within an individual. Such antibodies that can target various forms of envelope protein could represent a common response to a relatively conserved HIV epitope for a vaccine.

A virus-packageable CRISPR screen identifies host factors mediating interferon inhibition of HIV.

Interferon (IFN) inhibits HIV replication by inducing antiviral effectors. To comprehensively identify IFN-induced HIV restriction factors, we assembled a CRISPR sgRNA library of Interferon Stimulated Genes (ISGs) into a modified lentiviral vector that allows for packaging of sgRNA-encoding genomes in trans into budding HIV-1 particles. We observed that knockout of Zinc Antiviral Protein (ZAP) improved the performance of the screen due to ZAP-mediated inhibition of the vector. A small panel of IFN-induced HIV restriction factors, including MxB, IFITM1, Tetherin/BST2 and TRIM5alpha together explain the inhibitory effects of IFN on the CXCR4-tropic HIV-1 strain, HIV-1LAI, in THP-1 cells. A second screen with a CCR5-tropic primary strain, HIV-1Q23.BG505, described an overlapping, but non-identical, panel of restriction factors. Further, this screen also identifies HIV dependency factors. The ability of IFN-induced restriction factors to inhibit HIV strains to replicate in human cells suggests that these human restriction factors are incompletely antagonized. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

A Prospective Cohort Study of Fertility Desire, Unprotected Sex, and Detectable Viral Load in HIV-Positive Female Sex Workers in Mombasa, Kenya.

BACKGROUND: Little is known about fertility desire in HIV-positive female sex workers. Fertility desire could increase HIV transmission risk if it was associated with condomless sex or lower adherence to antiretroviral therapy. METHODS: A prospective cohort study was conducted among 255 HIV-positive female sex workers in Mombasa, Kenya. Using generalized estimating equations, fertility desire was evaluated as a risk factor for semen detection in vaginal secretions by prostate-specific antigen (PSA) test, a biomarker of condomless sex, detectable plasma viral load (VL), and HIV transmission potential, defined as visits with positive PSA and detectable VL. RESULTS: The effect of fertility desire on PSA detection varied significantly by nonbarrier contraception use (P-interaction < 0.01). At visits when women reported not using nonbarrier contraception, fertility desire was associated with higher risk of semen detection [82/385, 21.3% vs. 158/1007, 15.7%; adjusted relative risk (aRR) 1.58, 95% confidence interval (CI): 1.12 to 2.23]. However, when women used nonbarrier contraception, fertility desire was associated with lower risk of PSA detection (10/77, 13.0% vs. 121/536, 22.6%; aRR 0.58, 95% CI: 0.35 to 0.94). Fertility desire was not associated with detectable VL (31/219, 14.2% vs. 128/776, 16.5%; aRR 0.82, 95% CI: 0.46 to 1.45) or higher absolute risk of transmission potential (10/218, 4.6% vs. 21/769, 2.7%; adjusted risk difference = 0.011, 95% CI -0.031 to 0.050). CONCLUSIONS: Fertility desire was associated with higher risk of biological evidence of semen exposure when women were not using nonbarrier contraceptives. Low HIV transmission potential regardless of fertility desire suggests that the combination of condoms and antiretroviral therapy adherence was effective.

The Role of Immune Responses in HIV Mother-to-Child Transmission.

HIV mother-to-child transmission (MTCT) represents a success story in the HIV/AIDS field given the significant reduction in number of transmission events with the scale-up of antiretroviral treatment and other prevention methods. Nevertheless, MTCT still occurs and better understanding of the basic biology and immunology of transmission will aid in future prevention and treatment efforts. MTCT is a unique setting given that the transmission pair is known and the infant receives passively transferred HIV-specific antibodies from the mother while in utero. Thus, infant exposure to HIV occurs in the face of HIV-specific antibodies, especially during delivery and breastfeeding. This review highlights the immune correlates of protection in HIV MTCT including humoral (neutralizing antibodies, antibody-dependent cellular cytotoxicity, and binding epitopes), cellular, and innate immune factors. We further discuss the future implications of this research as it pertains to opportunities for passive and active vaccination with the ultimate goal of eliminating HIV MTCT.

Mapping mutational effects along the evolutionary landscape of HIV envelope.

The immediate evolutionary space accessible to HIV is largely determined by how single amino acid mutations affect fitness. These mutational effects can shift as the virus evolves. However, the prevalence of such shifts in mutational effects remains unclear. Here, we quantify the effects on viral growth of all amino acid mutations to two HIV envelope (Env) proteins that differ at [Formula: see text]100 residues. Most mutations similarly affect both Envs, but the amino acid preferences of a minority of sites have clearly shifted. These shifted sites usually prefer a specific amino acid in one Env, but tolerate many amino acids in the other. Surprisingly, shifts are only slightly enriched at sites that have substituted between the Envs-and many occur at residues that do not even contact substitutions. Therefore, long-range epistasis can unpredictably shift Env's mutational tolerance during HIV evolution, although the amino acid preferences of most sites are conserved between moderately diverged viral strains.

Maternal Neutralization-Resistant Virus Variants Do Not Predict Infant HIV Infection Risk.

UNLABELLED: Mother-to-child transmission (MTCT) of HIV provides a setting for studying immune correlates of protection. Neutralizing antibodies (NAbs) are suggested to contribute to a viral bottleneck during MTCT, but their role in blocking transmission is unclear, as studies comparing the NAb sensitivities of maternal viruses have yielded disparate results. We sought to determine whether transmitting mothers differ from nontransmitting mothers in the ability to neutralize individual autologous virus variants present at transmission. Ten transmitting and 10 nontransmitting HIV-infected mothers at high risk of MTCT were included in this study. Full-length HIV envelope genes (n = 100) were cloned from peripheral blood mononuclear cells obtained near transmission from transmitting mothers and at similar time points from nontransmitting mothers. Envelope clones were tested as pseudoviruses against contemporaneous, autologous maternal plasma in neutralization assays. The association between transmission and the log2 50% inhibitory concentration (IC50) for multiple virus variants per mother was estimated by using logistic regression with clustered standard errors. t tests were used to compare proportions of neutralization-resistant viruses. Overall, transmitting mothers had a median IC50 of 317 (interquartile range [IQR], 202 to 521), and nontransmitting mothers had a median IC50 of 243 (IQR, 95 to 594). Transmission risk was not significantly associated with autologous NAb activity (odds ratio, 1.25; P = 0.3). Compared to nontransmitting mothers, transmitting mothers had similar numbers of or fewer neutralization-resistant virus variants, depending on the IC50 neutralization resistance cutoff. In conclusion, HIV-infected mothers harbor mostly neutralization-sensitive viruses, although resistant variants were detected in both transmitting and nontransmitting mothers. These results suggest that MTCT during the breastfeeding period is not driven solely by the presence of maternal neutralization escape variants. IMPORTANCE: There are limited data demonstrating whether NAbs can prevent HIV transmission and infection in humans, and for this reason, NAbs have been studied in MTCT, where maternal antibodies are present at the time of transmission. Results of these studies have varied, perhaps because of differences in methods. Importantly, studies often used cultured viruses and samples from time points outside the window of transmission, which could confound findings. Here, we considered the role of maternal NAbs against individual maternal virus variants near the time of transmission. We found no evidence that NAbs are associated with protection from infection. In fact, depending on the cutoff used to define neutralization resistance, we found evidence that nontransmitting mothers have more neutralization-resistant virus variants. These results suggest that lack of virus transmission in the early breastfeeding period is not simply due to an absence of maternal neutralization escape variants and likely includes multiple factors.

HIV-specific CD4-induced Antibodies Mediate Broad and Potent Antibody-dependent Cellular Cytotoxicity Activity and Are Commonly Detected in Plasma From HIV-infected humans.

HIV-specific antibodies (Abs) can reduce viral burden by blocking new rounds of infection or by destroying infected cells via activation of effector cells through Fc­FcR interaction. This latter process, referred to as antibody-dependent cellular cytotoxicity (ADCC), has been associated with viral control and improved clinical outcome following both HIV and SIV infections. Here we describe an HIV viral-like particle (VLP)-based sorting strategy that led to identification of HIV-specificmemory B cells encoding Abs that mediate ADCC froma subtype A-infected Kenyan woman at 914 days post-infection. Using this strategy, 12 HIV-envelope-specific monoclonal antibodies (mAbs) were isolated and three mediated potent ADCC activitywhen compared to well-characterized ADCC mAbs. The ADCC-mediating Abs also mediated antibody-dependent cell-mediated virus inhibition (ADCVI), which provides a net measure of Fc receptor-triggered effects against replicating virus. Two of the three ADCC-mediating Abs targeted a CD4-induced (CD4i) epitope also bound by the mAb C11; the third antibody targeted the N-terminus of V3. Both CD4i Abs identified here demonstrated strong cross-clade breadth with activity against 10 of 11 envelopes tested, including those from clades A, B, C, A/D and C/D, whereas the V3-specific antibody showed more limited breadth. Variants of these CD4i, C11-like mAbs engineered to interrupt binding to FcγRs inhibited a measurable percentage of the donor's ADCC activity starting as early as 189 days post-infection. C11-like antibodies also accounted for between 18­78% of ADCC activity in 9 chronically infected individuals from the same cohort study. Further, the two CD4i Abs originated from unique B cells, suggesting that antibodies targeting this epitope can be commonly produced. Taken together, these data provide strong evidence that CD4i, C11-like antibodies develop within the first 6 months of infection and they can arise fromunique B-cell lineages in the same individual. Further, thesemAbsmediate potent plasma IgG-specificADCC breadth and potency and contribute to ADCC activity in other HIV-infected individuals.

HIV infection.

More than 75 million people worldwide have been infected with human immunodeficiency virus (HIV), and there are now approximately 37 million individuals living with the infection. Untreated HIV replication causes progressive CD4(+) T cell loss and a wide range of immunological abnormalities, leading to an increased risk of infectious and oncological complications. HIV infection also contributes to cardiovascular disease, bone disease, renal and hepatic dysfunction and several other common morbidities. Antiretroviral drugs are highly effective at inhibiting HIV replication, and for individuals who can access and adhere to these drugs, combination antiretroviral therapy leads to durable (and probably lifelong) suppression of viral replication. Viral suppression enables immune recovery and the near elimination of the risk for developing acquired immune deficiency syndrome (AIDS). Despite effective treatment, HIV-infected individuals have a higher than expected risk of heart, bone, liver, kidney and neurological disease. When used optimally by an infected (or by an uninfected) person, antiretroviral drugs can virtually eliminate the risk of HIV transmission. Despite major advances in prevention sciences, HIV transmission remains common in many vulnerable populations, including men who have sex with men, injection drug users and sex workers. Owing to a lack of widespread HIV testing and the costs and toxicities associated with antiretroviral drugs, the majority of the infected population is not on effective antiretroviral therapy. To reverse the pandemic, improved prevention, treatment and implementation approaches are necessary.

The role of cell-associated virus in mother-to-child HIV transmission.

Mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) continues to contribute to the global burden of disease despite great advances in antiretroviral (ARV) treatment and prophylaxis. In this review, we discuss the proposed mechanisms of MTCT, evidence for cell-free and cell-associated transmission in different routes of MTCT, and the impact of ARVs on virus levels and transmission. Many population-based studies support a role for cell-associated virus in transmission and in vitro studies also provide some support for this mode of transmission. However, animal model studies provide proof-of-principle that cell-free virus can establish infection in infants, and studies of ARVs in HIV-infected pregnant women show a strong correlation with reduction in cell-free virus levels and protection. ARV treatment in MTCT potentially provides opportunities to better define the infectious form of virus, but these studies will require better tools to measure the infectious cell reservoir.

Elevation of soluble intercellular adhesion molecule-1 levels, but not angiopoietin 2, in the plasma of human immunodeficiency virus-infected African women with clinical Kaposi sarcoma.

Circulating levels of endothelial activation biomarkers are elevated in during infection with human immunodeficiency virus 1 (HIV-1) and may also be increased in Kaposi sarcoma (KS). We compared 23 HIV-1-seropositive women with clinically diagnosed KS with 46 randomly selected controls matched for visit year, CD4 count, and antiretroviral therapy status. Conditional logistic regression was used to identify differences between cases and controls. The odds of clinical KS increased with increasing plasma viral load and with intercellular adhesion molecule 1 (ICAM-1) levels above or equal to the median. There was a borderline association between increasing plasma angiopoietin 2 levels and KS. In multivariable modeling including plasma viral load, angiopoietin 2, and ICAM-1, plasma ICAM-1 levels above or equal to the median remained associated with clinical KS (odds ratio = 14.2, 95% confidence interval = 2.3-87.7). Circulating ICAM-1 levels should be evaluated as a potential biomarker for disease progression and treatment response among HIV-infected KS patients.

Systemic cytokine levels show limited correlation with risk of HIV-1 acquisition.

It has been hypothesized that immune activation and inflammation may increase HIV-1 susceptibility, and that cytokines may be useful biomarkers for risk. Within a prospective cohort, we conducted a nested case-control analysis of plasma cytokine levels among women who acquired HIV-1 <3 months after sampling, compared with 3 different control groups. We observed associations between lower interleukin (IL)-6 and IL-10 and higher IL-7 levels with HIV-1 acquisition, however, these associations were inconsistent when comparing with different control groups. Inconsistent results within our study and among previous studies suggest that reproducible findings are needed before cytokines are useful biomarkers for HIV-1 susceptibility.

Quotidian changes of genital tract cytokines in human immunodeficiency virus-1-infected women during the menstrual cycle.

The role of hormonal changes throughout the menstrual cycle on genital tract inflammation during chronic human immunodeficiency virus (HIV) infection is not well defined, but it has implications for HIV prevention. We assessed daily levels of 26 vaginal cytokines and chemokines from 15 women infected with HIV-1. Taking into account coexisting sexually transmitted infections, behavioral factors, and menstruation, this study illustrates cyclic patterns of granulocyte macrophage colony-stimulating factor, interferon-α2, interleukin (IL)-6, IL-10, macrophage inflammatory protein (MIP)-1α, MIP-1ß, and tumor necrosis factor (TNF)-α. Progesterone was associated with levels of granulocyte colony-stimulating factor, IL-1α, and monocyte chemoattractant protein-1. Interferon-α2, IL-6, MIP-1α, MIP-1ß, and TNF-α levels predicted HIV shedding, but these associations were heavily influenced by the menstrual cycle.