HIV incidence continues to be unacceptably high in Eastern and Southern Africa, with women disproportionately affected. An increased per-contact risk of HIV acquisition among African, Caribbean, and ...other Black (ACB) women has been associated with the higher prevalence of bacterial vaginosis (BV) in these communities, wherein the vaginal microbiota is predominated by diverse pro-inflammatory anaerobic bacteria. However, while the vaginal microbiota in BV-free women is typically predominated by one of several different Lactobacillus spp., the degree of HIV protection afforded by a Lactobacillus-predominant vaginal microbiota also varies considerably. Specifically, L. crispatus is associated with an immunoregulatory genital immune environment, exclusion of BV-associated bacteria, and reduced HIV risk. In contrast, less HIV protection or exclusion of BV-associated bacteria and fewer immune benefits have been associated with L. iners-which is unfortunately the most common Lactobacillus species among ACB women. These species-specific clinical differences are underpinned by substantial genomic differences between Lactobacillus species: for instance, the much smaller genome of L. iners lacks the coding sequence for D-lactic acid dehydrogenase and cannot produce the D-lactate isomer that enhances HIV trapping in mucus but encodes for epithelial cell toxins and stress resistance proteins that may enhance bacterial survival in the context of microbiota and environmental fluctuations. While more studies are needed to elucidate whether differences in HIV protection between Lactobacillus species are due to direct genital immune effects or the exclusion of proinflammatory BV-associated bacteria, the current body of work suggests that for BV treatment to succeed as an HIV prevention strategy, it may be necessary to induce a vaginal microbiota that is predominated by specific (non-iners) Lactobacillus species. Video abstract.
The penis is the primary site of HIV acquisition in heterosexual men. Elevated penile inflammatory cytokines increase sexual acquisition risk, and topically applied cytokines enhance foreskin HIV ...susceptibility in an explant model. However, the impact of penile-vaginal sex on these immune parameters is undefined. Heterosexual couples were recruited to the Sex, Couples and Science (SECS) Study, with the collection of penile swabs, semen, cervico-vaginal secretions, and blood after a period of abstinence, and repeated sampling up to 72 hours after either condomless (n = 30) or condom-protected (n = 8) penile-vaginal sex. Soluble immune parameters were quantified by multiplex immunoassay. Co-primary immune endpoints were penile levels of IL-8 and MIG, cytokines previously linked to penile HIV acquisition. One hour after sex there were dramatic increases in penile IL-8 and MIG levels, regardless of condom use, with a gradual return to baseline by 72 hours; similar patterns were observed for other chemoattractant chemokines. Penile cytokine changes were similar in circumcised and uncircumcised men, and repeated measures ANOVA and ANCOVA models demonstrated that the degree of change after condomless sex was explained by cytokine levels in their partners' cervico-vaginal secretions. This may have important implications for the biology of penile HIV acquisition.
Circumcision reduces heterosexual HIV-1 acquisition in men by at least 60%. However, the biological mechanisms by which circumcision is protective remain incompletely understood. We test the ...hypothesis that the sub-preputial microenvironment created by the foreskin drives immune activation in adjacent foreskin tissues, facilitating HIV-1 infection through a combination of epithelial barrier disruption, enhanced dendritic cell maturation, and the recruitment/activation of neutrophils and susceptible CD4 T cell subsets such as Th17 cells. Furthermore, we provide evidence that the genital microbiome may be an important driver of this immune activation. This suggests that new modalities to reduce genital immune activation and/or alter the genital microbiome, used alone or in combination with topical microbicides, may be of significant benefit to HIV prevention.
While the global incidence of human immunodeficiency virus (HIV-1) remains well above UNAIDS targets, sexual transmission HIV is surprisingly inefficient. A variety of host, viral and environmental ...factors can either increase HIV-1 shedding in the infected partner and/or increase mucosal susceptibility of the HIV-1 uninfected partner. Clinical and epidemiological studies have clearly established that
Neisseria gonorrhoeae
substantially enhances HIV-1 transmission, despite it not being an ulcerative infection. This review will consider findings from molecular, immunologic and clinical studies that have focused on each of these two human-restricted pathogens, in order to develop an integrative model that describes how gonococci can both increase mucosal shedding of HIV-1 from a co-infected person and facilitate virus establishment in a susceptible host.
Transmission models provide complementary evidence to clinical trials about the potential population-level incidence reduction attributable to ART (ART prevention impact). Different modelling ...assumptions about risk heterogeneity may influence projected ART prevention impacts. We sought to review representations of risk heterogeneity in compartmental HIV transmission models applied to project ART prevention impacts in Sub-Saharan Africa.
We systematically reviewed studies published before January 2020 that used non-linear compartmental models of sexual HIV transmission to simulate ART prevention impacts in Sub-Saharan Africa. We summarized data on model structure/assumptions (factors) related to risk and intervention heterogeneity, and explored multivariate ecological associations of ART prevention impacts with modelled factors.
Of 1384 search hits, 94 studies were included. 64 studies considered sexual activity stratification and 39 modelled at least one key population. 21 studies modelled faster/slower ART cascade transitions (HIV diagnosis, ART initiation, or cessation) by risk group, including 8 with faster and 4 with slower cascade transitions among key populations versus the wider population. In ecological analysis of 125 scenarios from 40 studies (subset without combination intervention), scenarios with risk heterogeneity that included turnover of higher risk groups were associated with smaller ART prevention benefits. Modelled differences in ART cascade across risk groups also influenced the projected ART benefits, including: ART prioritized to key populations was associated with larger ART prevention benefits. Of note, zero of these 125 scenarios considered lower ART coverage among key populations.
Among compartmental transmission models applied to project ART prevention impacts in Sub-Saharan Africa, representations of risk heterogeneity and projected impacts varied considerably. Inclusion/exclusion of risk heterogeneity with turnover, and intervention heterogeneity across risk groups could influence the projected impacts of ART scale-up. These findings highlight a need to capture risk heterogeneity with turnover and cascade heterogeneity when projecting ART prevention impacts.
•We systematically reviewed compartmental models of ART prevention impacts in SSA.•2/3 and 2/5 studies considered activity groups and any key population(s).•1/3 and 1/4 studies considered risk group turnover and ART cascade differences.•Turnover and cascade differences influenced model-projected ART prevention impacts.•No scenarios considered lower ART coverage among key populations.
BackgroundBacterial vaginosis (BV) causes genital inflammation and increases HIV risk, whereas a vaginal microbiota dominated by Lactobacillus species is associated with immune quiescence and ...relative HIV protection. BV treatment reduces genital inflammation, but it is unclear whether this reduction is driven by a decrease in BV-associated bacteria or an increase in Lactobacillus species.METHODSTo evaluate the short-term effect of standard BV treatment on genital immunology and the vaginal microbiota, vaginal swabs were collected immediately before and after metronidazole treatment for BV and analyzed with multiplex ELISA, metagenomic sequencing, and quantitative PCR.RESULTSTopical metronidazole treatment rapidly reduced vaginal levels of proinflammatory cytokines, chemokines, and soluble immune markers of epithelial barrier disruption. Although the vaginal microbiota shifted to dominance by L. iners or L. jensenii, this proportional shift was primarily driven by a 2 to 4 log10-fold reduction in BV-associated bacteria absolute abundance. BV treatment induced no change in the absolute abundance of L. crispatus or L. iners and only minor (<1 log10-fold) increases in L. gasseri and L. jensenii that were not independently associated with reduced inflammation in multivariable models.CONCLUSIONThe genital immune benefits that are associated with Lactobacillus dominance after BV treatment were not directly attributable to an absolute increase in lactobacilli, but rather to the loss of BV-associated bacteria.Trial REGISTRATIONParticipants were recruited as part of a randomized controlled trial (ClinicalTrials.gov NCT02766023) from 2016 to 2019.FUNDINGCanadian Institutes of Health Research (PJT-156123) and the National Institute of Allergy and Infectious Diseases (HHSN2722013000141 and HHSN27200007).
In a prospective study of twenty sexually transmitted infection (STI)-free women, we examined the impact of an intrauterine contraceptive device (IUCD) insertion on cervico-vaginal cytokine levels. ...Nine women chose the levonorgestrel-containing IUCD and eight chose a copper IUCD. A cervico-vaginal swab was collected for cytokine analysis pre-insertion and four weeks post-insertion. Significant increases were noted in levels of IL-1α (median 483.4 versus 316.6 pg/mL, p = 0.046), IL-1β (median 605.7 versus 147.3 pg/mL, p = 0.018), IL-6 (median 570.1 versus 157.3 pg/mL, p = 0.046), TNFα (median 1.19 versus 0.6 pg/mL, p = 0.029) and the chemokine MCP-1 (median 340.2 versus 135.2 pg/mL, p = 0.003). No significant changes were noted in the levels of GM-CSF, IL-8, MIG, MIP-3α, RANTES, IL-10, IL-17, IP-10, MIP-1β. Whether this increase in pro-inflammatory cytokine levels decreases epithelial barrier integrity and enhances susceptibility to STIs, including HIV, merits further study.
ATP-binding cassette (ABC) drug efflux transporters could contribute to low intracellular concentrations of antiretroviral drugs in HIV-1 cell reservoirs and sanctuary sites. Furthermore, the ...functional expression of these transporters could be induced in activated T-cells. Therefore, we investigated the expression of ABC drug efflux transporters in human T-cells exposed to an HIV pseudotype virus (pHIV
NL4-3
), and further examined the potential involvement of the mammalian target of rapamycin (mTOR) signaling pathway in regulating their expression following exposure to pHIV
NL4-3
. Additionally, we investigated the contribution of the drug efflux transporters to the inflammatory response following pHIV
NL4-3
-induced T-cell activation. Human peripheral blood mononuclear cells (PBMCs) were exposed to HIV-1 envelope glycoprotein gp120
IIIB
, pHIV
NL4-3
and/or mTOR inhibitors. The expression of ABC transporters, T-cell activation marker CD69, mTOR and pHIV
NL4-3
was assessed in CD4
+
T-cells by Flow cytometry. mRNA and protein levels of proinflammatory cytokines (IL6, TNFα and INFγ) were examined in PBMCs by qPCR and ELISA analyses, respectively, following exposure to pHIV
NL4-3
with or without inhibitors of mTOR or ABC transporters. The expression of ABC transporters (P-glycoprotein, breast cancer resistance protein and multi-drug resistance associated protein-1) was significantly increased in CD4
+
T-cells exposed to pHIV
NL4-3
. Treatment with mTOR inhibitors attenuated pHIV
NL4-3
-induced transporter expression, as well as mRNA and protein levels of IL6, TNFα and INFγ. Additionally, inhibition of P-gp or MRP1 activity resulted in lower concentrations of proinflammatory cytokines in supernatants of PBMC exposed to pHIV
NL4-3
. Herein we present novel data demonstrating that upregulation of ABC drug efflux transporters could involve the mTOR signaling pathway in CD4
+
T-cells exposed to an HIV pseudotype. These transporters could limit antiretroviral drug penetration in HIV target T-cells. Furthermore, ABC transporters could potentially contribute to HIV-associated proinflammatory cytokine secretion.
Both activated and resting CD4⁺ T cells in mucosal tissues play important roles in the earliest phases of infection after sexual transmission of HIV-1, a process that is inefficient. HIV-1 gp120 ...binds to integrin α₄β₇ (α₄β₇), the gut mucosal homing receptor. We find that α₄β₇high CD4⁺ T cells are more susceptible to productive infection than are α₄β₇low⁻neg CD4⁺ T cells in part because this cellular subset is enriched with metabolically active CD4⁺ T cells. α₄β₇high CD4⁺ T cells are CCR5high and CXCR4low; on these cells, α₄β₇ appears in a complex with CD4. The specific affinity of gp120 for α₄β₇ provides a mechanism for HIV-1 to target activated cells that are critical for efficient virus propagation and dissemination following sexual transmission.
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