RESUMEN
BACKGROUND: Genital immunology is a key determinant of human immunodeficiency virus (HIV) susceptibility. Both factors are modulated by bacterial vaginosis (BV) and, to some extent, by Lactobacillus iners, the genital Lactobacillus spp. that predominates in African, Caribbean, and other Black (ACB) women. We conducted a clinical trial to assess the impact of oral metronidazole treatment on the genital immune parameters of HIV acquisition risks in Kenyan women with BV. METHODS: The primary endpoint was ex vivo cervical CD4+ T-cell HIV susceptibility after 1 month; secondary endpoints included genital cytokine/chemokine levels, cervical immune cell populations, and the composition of the cervico-vaginal microbiota by 16S ribosomal RNA gene amplicon sequencing. RESULTS: BV resolved (Nugent score ≤ 3) at 1 month in 20/45 participants, and cervical CD4+ T-cell HIV entry was moderately reduced in all participants, regardless of treatment outcome. Resolution of BV and reduced abundances of BV-associated gram-negative taxa correlated with reduced genital interleukin (IL)-1α/ß. However, BV resolution and the concomitant colonization by Lactobacillus iners substantially increased several genital chemokines associated with HIV acquisition, including interferon-γ inducible protein (IP)-10, macrophage inflammatory protein (MIP)-3α, and monokine induced by gamma interferon (MIG). In an independent cohort of ACB women, most of whom were BV-free, vaginal chemokines were again closely linked with L. iners abundance, though not other Lactobacillus spp. CONCLUSIONS: BV treatment reduced genital CD4+ T-cell HIV susceptibility and IL-1 levels, but dramatically increased the genital chemokines that may enhance HIV susceptibility; the latter effect was related to the restoration of an Lactobacillus iners-dominated microbiota. Further studies are needed before treatment of asymptomatic BV can be recommended for HIV prevention in ACB communities.
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Cuello del Útero/inmunología , Susceptibilidad a Enfermedades/virología , Metronidazol/uso terapéutico , Microbiota/efectos de los fármacos , Vagina/inmunología , Vagina/microbiología , Vaginosis Bacteriana/tratamiento farmacológico , Administración Oral , Adulto , Linfocitos T CD4-Positivos/virología , Células Cultivadas , Citocinas/inmunología , Femenino , VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Estudios Prospectivos , ARN Ribosómico 16S/genética , Factores de Riesgo , Vaginosis Bacteriana/inmunología , Adulto JovenRESUMEN
Individual susceptibility to HIV is heterogeneous, but the biological mechanisms explaining differences are incompletely understood. We hypothesized that penile inflammation may increase HIV susceptibility in men by recruiting permissive CD4 T cells, and that male circumcision may decrease HIV susceptibility in part by reducing genital inflammation. We used multi-array technology to measure levels of seven cytokines in coronal sulcus (penile) swabs collected longitudinally from initially uncircumcised men enrolled in a randomized trial of circumcision in Rakai, Uganda. Coronal sulcus cytokine levels were compared between men who acquired HIV and controls who remained seronegative. Cytokines were also compared within men before and after circumcision, and correlated with CD4 T cells subsets in foreskin tissue. HIV acquisition was associated with detectable coronal sulcus Interleukin-8 (IL-8 aOR 2.26, 95%CI 1.04-6.40) and Monokine Induced by γ-interferon (MIG aOR 2.72, 95%CI 1.15-8.06) at the visit prior to seroconversion, and the odds of seroconversion increased with detection of multiple cytokines. Coronal sulcus chemokine levels were not correlated with those in the vagina of a man's female sex partner. The detection of IL-8 in swabs was significantly reduced 6 months after circumcision (PRR 0.59, 95%CI 0.44-0.87), and continued to decline for at least two years (PRR 0.29, 95%CI 0.16-0.54). Finally, prepuce IL-8 correlated with increased HIV target cell density in foreskin tissues, including highly susceptible CD4 T cells subsets, as well as with tissue neutrophil density. Together, these data suggest that penile inflammation increases HIV susceptibility and is reduced by circumcision.
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Quimiocinas/inmunología , Circuncisión Masculina , Infecciones por VIH/epidemiología , Pene/inmunología , Adolescente , Adulto , Quimiocinas/análisis , Susceptibilidad a Enfermedades/inmunología , Susceptibilidad a Enfermedades/virología , Femenino , Prepucio/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , VIH-1 , Humanos , Inmunohistoquímica , Inflamación/inmunología , Inflamación/virología , Interleucina-8/inmunología , Mediciones Luminiscentes , Masculino , Persona de Mediana Edad , Pene/cirugía , Uganda , Adulto JovenRESUMEN
BACKGROUND: The foreskin is the site of most HIV acquisition in uncircumcised heterosexual men. Although HIV-exposed, seronegative (HESN) uncircumcised men demonstrate HIV-neutralizing IgA and increased antimicrobial peptides (AMPs) in the foreskin prepuce, no prospective studies have examined the mucosal immune correlates of HIV acquisition. METHODS: To assess the association of foreskin immune parameters with HIV acquisition, antimicrobial peptides and IgA with the capacity to neutralize a primary clade C HIV strain were quantified by blinded investigators, using sub-preputial swabs collected longitudinally during a randomized trial of male circumcision for HIV prevention in Rakai, Uganda. RESULTS: Participants were 99 men who acquired HIV (cases) and 109 randomly selected controls who remained HIV seronegative. At enrollment, 44.4% of cases vs. 69.7% of controls demonstrated IgA neutralization (adjusted ORâ=â0.31; 95% CI, 0.16-0.61). IgA neutralization was detected in 38.7% of cases and 70.7% of controls at the last seronegative case visit prior to HIV acquisition and the comparable control visit (adjusted OR 0.21; 95% CI, 0.11-0.39). Levels of the α-defensins and secretory leukocyte protease inhibitor (SLPI) were over ten-fold higher in the foreskin prepuce of cases who acquired HIV, both at enrollment (mean 4.43 vs. 3.03 and 5.98 vs. 4.61 log(n) pg/mL, Pâ=â0.005 and 0.009, respectively), and at the last seronegative visit (mean 4.81 vs. 3.15 and 6.46 vs. 5.20 log(n) pg/mL, Pâ=â0.0002 and 0.013). CONCLUSIONS: This prospective, blinded analysis is the first to assess the immune correlates of HIV acquisition in the foreskin. HIV-neutralizing IgA, previously associated with the HESN phenotype, was a biomarker of HIV protection, but other HESN associations correlated with increased HIV acquisition. This emphasizes the importance of prospective epidemiological studies or in vitro tissue studies to define the impact of mucosal parameters on HIV risk.
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Antiinfecciosos/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Prepucio/inmunología , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Inmunoglobulina A/inmunología , Adolescente , Adulto , Circuncisión Masculina , Infecciones por VIH/inmunología , VIH-1/inmunología , Heterosexualidad , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Uganda , Adulto JovenRESUMEN
Semen is a major vector for HIV transmission, but the semen HIV RNA viral load (VL) only correlates moderately with the blood VL. Viral shedding can be enhanced by genital infections and associated inflammation, but it can also occur in the absence of classical pathogens. Thus, we hypothesized that a dysregulated semen microbiome correlates with local HIV shedding. We analyzed semen samples from 49 men who have sex with men (MSM), including 22 HIV-uninfected and 27 HIV-infected men, at baseline and after starting antiretroviral therapy (ART) using 16S rRNA gene-based pyrosequencing and quantitative PCR. We studied the relationship of semen bacteria with HIV infection, semen cytokine levels, and semen VL by linear regression, non-metric multidimensional scaling, and goodness-of-fit test. Streptococcus, Corynebacterium, and Staphylococcus were common semen bacteria, irrespective of HIV status. While Ureaplasma was the more abundant Mollicutes in HIV-uninfected men, Mycoplasma dominated after HIV infection. HIV infection was associated with decreased semen microbiome diversity and richness, which were restored after six months of ART. In HIV-infected men, semen bacterial load correlated with seven pro-inflammatory semen cytokines, including IL-6 (p = 0.024), TNF-α (p = 0.009), and IL-1b (p = 0.002). IL-1b in particular was associated with semen VL (r(2)â = 0.18, p = 0.02). Semen bacterial load was also directly linked to the semen HIV VL (r(2) = 0.15, p = 0.02). HIV infection reshapes the relationship between semen bacteria and pro-inflammatory cytokines, and both are linked to semen VL, which supports a role of the semen microbiome in HIV sexual transmission.
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Bacterias , Infecciones por VIH/microbiología , VIH-1 , Microbiota , Infecciones del Sistema Genital/microbiología , Semen/microbiología , Carga Viral , Adulto , Bacterias/genética , Bacterias/aislamiento & purificación , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Infecciones del Sistema Genital/virologíaRESUMEN
Mucosal Th17 cells maintain the gut epithelial barrier and prevent invasion by luminal bacteria through a delicate balance of immunosuppressive and proinflammatory functions. HIV infection is characterized by mucosal Th17 depletion, microbial translocation, and immune activation. Therefore, we assessed the function of blood and sigmoid Th17 cells during both early and chronic HIV infection, as well as the impact of short- and long-term antiretroviral therapy. Th17 cells were defined as IL-17a(+) CD4 T cells, and their functional capacity was assessed by the coproduction of the inflammatory cytokines IL-22, TNF-α, and IFN-γ, as well as the immunoregulatory cytokine IL-10. Gut Th17 cells had a much greater capacity to produce proinflammatory cytokines than did those from the blood, but this capacity was dramatically reduced from the earliest stages of HIV infection. Immunoregulatory skewing of mucosal Th17 cell function, characterized by an increased IL-10/TNF-α ratio, was uniquely seen during early HIV infection and was independently associated with reduced systemic immune activation. Antiretroviral therapy rapidly restored mucosal Th17 cell numbers; however, normalization of mucosal Th17 function, microbial translocation, and mucosal/systemic immune activation was much delayed. These findings emphasize that strategies to preserve or to more rapidly restore mucosal Th17 function may have important therapeutic benefit.
Asunto(s)
Infecciones por VIH/inmunología , Mucosa Intestinal/inmunología , Células Th17/inmunología , Adulto , Antirretrovirales/uso terapéutico , Femenino , Citometría de Flujo , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Background: Bacterial vaginosis (BV) is a proinflammatory genital condition associated with adverse reproductive health outcomes, including increased HIV incidence. However, BV recurrence rates are high after standard antibiotic treatment. While the composition of the vaginal microbiota before BV treatment may be linked to BV recurrence, it is unclear whether the preceding genital immune milieu is predictive of treatment success. Methods: Here we assessed whether baseline vaginal soluble immune factors or the composition of the vaginal microbiota predicted treatment success 1 month after metronidazole treatment in 2 separate cohorts of women with BV, 1 in the United States and 1 in Kenya; samples within 48â hours of BV treatment were also available for the US cohort. Results: Neither soluble immune factors nor the composition of the vaginal microbiota before BV treatment was associated with treatment response in either cohort. In the US cohort, although the absolute abundances of key vaginal bacterial taxa pretreatment were not associated with treatment response, participants with sustained BV clearance had a more pronounced reduction in the absolute abundance of Gardnerella vaginalis immediately after treatment. Conclusions: Pretreatment immune and microbial parameters were not predictive of BV treatment success in these clinical cohorts.
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PROBLEM: Biological mechanisms of foreskin HIV acquisition are poorly defined. The inner foreskin is preferentially infected in explant models, so we hypothesized that this site would be enriched for HIV-susceptible CD4+ T cells and proinflammatory/chemoattractant cytokines. METHOD OF STUDY: A total of 42 HIV-uninfected Ugandan men without genital symptoms provided foreskin tissues and swabs at the time of elective penile circumcision. The immune phenotype of foreskin-derived CD4+ T cells and entry of a CCR5-tropic HIV pseudovirus was characterized, and specific cytokine levels assayed by multiplexed chemiluminescent ELISA. RESULTS: Unexpectedly, outer foreskin CD4+ T cells more frequently expressed CCR5 (median 29.2% vs 22.9%, P = 0.01) and CD69 (median 36.5% vs 15%, P < 0.01), and on a per-cell basis, HIV entry was higher. However, overall CD4+ T cell density was approximately twofold higher in the inner foreskin, and several highly susceptible T cell subsets were increased at this site, including Th17 cells (20.0% vs 14.1%, P = 0.0021). Specific pro-inflammatory cytokine levels were also higher on the inner foreskin surface (IL-17, IL-8, RANTES and IL-1ß; all P < 0.05). CONCLUSION: There was marked heterogeneity in CD4+ T cell populations and immune milieu between inner and outer foreskin tissues. Despite higher per-cell viral entry into CD4+ T cells from the outer foreskin, the higher target cell density and enriched pro-inflammatory cytokines of the inner foreskin suggest that this may be a preferential site for HIV acquisition.
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Linfocitos T CD4-Positivos/inmunología , Prepucio/inmunología , Infecciones por VIH/inmunología , Subgrupos de Linfocitos T/inmunología , Adulto , Linfocitos T CD4-Positivos/virología , Citocinas/inmunología , Susceptibilidad a Enfermedades/inmunología , Células HEK293 , Humanos , Masculino , Subgrupos de Linfocitos T/virología , Uganda , Adulto JovenRESUMEN
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-1ß (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-1ß. Whether this increase in pro-inflammatory cytokine levels decreases epithelial barrier integrity and enhances susceptibility to STIs, including HIV, merits further study.
Asunto(s)
Cuello del Útero/metabolismo , Citocinas/metabolismo , Dispositivos Intrauterinos/efectos adversos , Vagina/metabolismo , Adulto , Femenino , Humanos , Inflamación/metabolismo , Proyectos Piloto , Adulto JovenRESUMEN
OBJECTIVE: Standard antiretroviral therapy (ART) is slow to reverse gut mucosal immune defects that cause persistent inflammation and immune activation. We examined whether intensifying early-administered ART through the addition of maraviroc and raltegravir would accelerate their resolution. DESIGN: ART-naïve men with early HIV infection were randomized in a double-blind manner to receive ART (emtricitabine/tenofovir disoproxil fumarateâ+âlopinavir/ritonavir), together with either combined placebo or raltegravirâ+âmaraviroc, for 48 weeks. In a predefined substudy, paired blood and sigmoid biopsies were collected at baseline and week 48. Mucosal CD4 T-cell immune subsets (Th1, Th17, and Th22 cells), CD8 T-cell immune activation, and soluble blood markers of inflammation (IL-6, IL-17, macrophage inflammatory protein-1b, soluble CD14, and IL-10) and coagulation (D-dimer) were measured. RESULTS: A total of 22 participants were enrolled, a median of 4 months after HIV acquisition. At baseline, there was substantial systemic and mucosal immune activation, and gut CD4 T-cell numbers, Th22 cell numbers, and Th17 cell function were reduced compared with controls. Early ART restored gut Th22 numbers, improved but did not restore overall CD4 numbers, and had no impact on Th17 function. Plasma levels of soluble CD14 and D-dimer normalized, whereas other inflammatory cytokines were reduced but not normalized. ART intensification had no impact on any blood or gut immune parameters. CONCLUSION: Early HIV infection causes substantial mucosal and systemic immune activation, and gut CD4 T-cell dysfunction. One year of ART improved but did not normalize most parameters, regardless of intensification with raltegravir and maraviroc, and did not restore mucosal Th17 function.
Asunto(s)
Fármacos Anti-VIH/farmacología , Infecciones por VIH/tratamiento farmacológico , Inmunidad Mucosa/efectos de los fármacos , Inflamación/sangre , Inflamación/tratamiento farmacológico , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/inmunología , Adulto , Biomarcadores/sangre , Canadá , Ciclohexanos/farmacología , Método Doble Ciego , Quimioterapia Combinada , Productos de Degradación de Fibrina-Fibrinógeno/efectos de los fármacos , Citometría de Flujo , Infecciones por VIH/sangre , Infecciones por VIH/inmunología , Humanos , Inflamación/inmunología , Activación de Linfocitos/efectos de los fármacos , Masculino , Maraviroc , Persona de Mediana Edad , Estudios Prospectivos , Raltegravir Potásico/farmacología , Células Th17/efectos de los fármacos , Resultado del Tratamiento , Triazoles/farmacología , Adulto JovenRESUMEN
BACKGROUND: This study was done to characterize parameters associated with semen human immunodeficiency virus (HIV)-1 ribonucleic acid (RNA) viral load (VL) variability in HIV-infected, therapy-naive men. METHODS: Paired blood and semen samples were collected from 30 HIV-infected, therapy-naive men who have sex with men, and 13 participants were observed longitudinally for up to 1 year. Human immunodeficiency virus RNA, bacterial load by 16S RNA, herpesvirus (Epstein-Barr virus and cytomegalovirus [CMV]) shedding, and semen cytokines/chemokines were quantified, and semen T-cell subsets were assessed by multiparameter flow cytometry. RESULTS: Semen HIV RNA was detected at 93% of visits, with >50% of men shedding high levels of virus (defined as >5000 copies/mL). In the baseline cross-sectional analysis, an increased semen HIV VL correlated with local CMV reactivation, the semen bacterial load, and semen inflammatory cytokines, particularly interleukin (IL)-8. T cells in semen were more activated than blood, and there was an increased frequency of Th17 cells and γδ-T-cells. Subsequent prospective analysis demonstrated striking interindividual variability in HIV and CMV shedding patterns, and only semen IL-8 levels and the blood VL were independently associated with semen HIV levels. CONCLUSIONS: Several clinical and immune parameters were associated with increased HIV semen levels in antiretroviral therapy-naive men, with induction of local proinflammatory cytokines potentially acting as a common pathway.
RESUMEN
Elevated inflammatory cytokines (EMCs) at mucosal surfaces have been associated with HIV susceptibility, but the underlying mechanisms remain unclear. We characterized the soluble mucosal proteome associated with elevated cytokine expression in the female reproductive tract. A scoring system was devised based on the elevation (upper quartile) of at least three of seven inflammatory cytokines in cervicovaginal lavage. Using this score, HIV-uninfected Kenyan women were classified as either having EMC (n=28) or not (n=68). Of 455 proteins quantified in proteomic analyses, 53 were associated with EMC (5% false discovery rate threshold). EMCs were associated with proteases, cell motility, and actin cytoskeletal pathways, whereas protease inhibitor, epidermal cell differentiation, and cornified envelope pathways were decreased. Multivariate analysis identified an optimal signature of 16 proteins that distinguished the EMC group with 88% accuracy. Three proteins in this signature were neutrophil-associated proteases that correlated with many cytokines, especially GM-CSF (granulocyte-macrophage colony-stimulating factor), IL-1ß (interleukin-1ß), MIP-3α (macrophage inflammatory protein-3α), IL-17, and IL-8. Gene set enrichment analyses implicated activated immune cells; we verified experimentally that EMC women had an increased frequency of endocervical CD4(+) T cells. These data reveal strong linkages between mucosal cytokines, barrier function, proteases, and immune cell movement, and propose these as potential mechanisms that increase risk of HIV acquisition.
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Linfocitos T CD4-Positivos/inmunología , Citocinas/inmunología , Proteínas del Citoesqueleto/inmunología , Membrana Mucosa/inmunología , Péptido Hidrolasas/inmunología , Adulto , Linfocitos T CD4-Positivos/citología , Movimiento Celular/inmunología , Quimiocina CCL20/genética , Quimiocina CCL20/inmunología , Citocinas/genética , Proteínas del Citoesqueleto/genética , Susceptibilidad a Enfermedades , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Genitales Femeninos/citología , Genitales Femeninos/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Infecciones por VIH , Humanos , Interleucina-17/genética , Interleucina-17/inmunología , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Interleucina-8/genética , Interleucina-8/inmunología , Kenia , Membrana Mucosa/citología , Análisis Multivariante , Péptido Hidrolasas/genética , Proteómica , Trabajadores SexualesRESUMEN
Vaginal proinflammatory cytokine expression during herpes virus reactivation was examined in human immunodeficiency virus-infected women before and after initiation of antiretroviral therapy (ART). Vaginal swabs were screened for levels of cytokines interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor (TNF)-α, and interferon-γ. The relative risk (RR) of herpes simplex virus-2 or cytomegalovirus (CMV) shedding being associated with cytokine levels above the median were estimated. Herpes simplex virus-2 shedding was significantly associated with higher levels of IL-6 (RR = 1.4, P = .003) and TNF-α (RR = 1.3, P = .010), whereas CMV shedding was associated with higher IL-6 (RR = 1.3, P = .006) and IL-2 (RR = 1.4, P = .01). The association of viral shedding with higher IL-6 levels suggests that herpes virus reactivation may be playing a role in immune activation after ART initiation.
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A patch test (PT) may be useful in defining true abacavir hypersensitivity syndrome (AHS). Seven previously PT-positive patients remote from the original AHS were shown to have robust 24 h responses, supporting PT durability. HLA-B*5701 was present in all seven PT-positive versus one of 11 controls tolerating abacavir (P < 0.001). Five of seven PT (71%) versus one of 11 controls (9%) (P = 0.005) showed significant abacavir-specific CD8 proliferation, suggesting a direct role for HLA-B*5701-restricted CD8 cells in the pathophysiology of AHS.
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Fármacos Anti-VIH/efectos adversos , Didesoxinucleósidos/efectos adversos , Erupciones por Medicamentos/etiología , Inhibidores de la Transcriptasa Inversa/efectos adversos , Linfocitos T CD8-positivos/inmunología , Erupciones por Medicamentos/diagnóstico , Erupciones por Medicamentos/inmunología , Predisposición Genética a la Enfermedad , Antígenos HLA-B/análisis , Humanos , Pruebas del Parche/métodosRESUMEN
BACKGROUND: The hallmark of HIV infection is progressive but variable rates of systemic and mucosal CD4 depletion, leading to immunodeficiency. The impact of early HIV infection on cervical CD4 T-cell populations in humans remains poorly described. METHODS: We analyzed cytobrush-derived immune cells by flow cytometry and cytokines in cervicovaginal lavage from participants in early HIV (<6 months postinfection), chronic HIV, and HIV-uninfected controls. RESULTS: CD4:CD8 ratios declined rapidly in both the cervix and the blood following HIV infection. In contrast, absolute cervical CD4 T-cell counts in early HIV were comparable to HIV-uninfected participants, declining only in chronic infection. Early HIV infection was associated with increases in RANTES and MIP3a in cervicovaginal fluids. Concurrently, slight increases in activated cells (CD38HLA-DR) and higher levels of CTLA4 expression on Tregs in the cervix were observed. Although study groups did not differ with respect to levels of CCR5, integrin B7, or CD69, the frequencies of Th17 cells (defined as CCR6CCR10) was reduced by >10-fold in early HIV infection and Th1 cells (defined as CCR6CXCR3) were reduced by >2-fold. Although CCR6CCR10 cells did not differ in HIV receptor expression, these cells produced higher levels of interferon gamma and interleukin 17. CONCLUSIONS: These data support the model of initial CD4 T-cell depletion followed by overall T-cell influx in response to infection and concomitant increases in immune activation, inflammation, and regulatory markers. These data are among the earliest characterization of the cellular milieu in the female genital tract following male-to-female HIV transmission.
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Cuello del Útero/inmunología , Infecciones por VIH/inmunología , Células Th17/citología , Adulto , Relación CD4-CD8 , Línea Celular , Estudios de Cohortes , Femenino , VIH-1 , Humanos , Inmunofenotipificación , Receptores de Quimiocina/metabolismoRESUMEN
Semen is a major transmission vector for HIV. Virus-specific CD8 T cells are critical in HIV control, but their relationship with semen viral load is unknown. We therefore examined the association between systemic HIV-specific IFN-gamma CD8 responses and viral load in the semen and blood of HIV-infected men. No correlation was observed between viral load in either semen or blood and systemic CD8 T-cell responses. Further studies of immune correlates of semen HIV shedding are needed.
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Infecciones por VIH/transmisión , VIH-1/fisiología , Semen/virología , Linfocitos T CD8-positivos/inmunología , Femenino , Infecciones por VIH/inmunología , VIH-1/genética , Humanos , Masculino , ARN/análisis , ARN/sangre , Carga Viral , Esparcimiento de VirusRESUMEN
Elite controllers (ECs) maintain undetectable HIV viral loads without antiretroviral therapy (ART) but are at increased risk of serious non-AIDS conditions (SNA). We assessed the impact of ART in ECs on gut immune dysfunction and biomarkers predicting SNA (blood CD4/CD8 ratio, plasma IL-6, D-dimer levels). At baseline, ECs had elevated IL-6 and D-dimer levels and reduced CD4/CD8 ratio compared with HIV-uninfected controls, but no difference in microbial translocation or gut CD4 subsets. ART increased CD4/CD8 ratio but did not normalize IL-6 and D-dimer levels. EC SNA pathogenesis may be independent of gut immune dysfunction, and resolution may require prolonged ART.
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Antirretrovirales/uso terapéutico , Terapia Antirretroviral Altamente Activa/métodos , Traslocación Bacteriana , Tracto Gastrointestinal/inmunología , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Sobrevivientes de VIH a Largo Plazo , Adulto , Anciano , Biomarcadores , Relación CD4-CD8 , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Humanos , Interleucina-6/sangre , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To evaluate if systemic murine malarial infection enhances HIV susceptibility through parasite-induced mucosal immune alterations at sites of HIV sexual exposure. BACKGROUND: Malaria and HIV have a high degree of geographical overlap and interact substantially within coinfected individuals. We used a murine model to test the hypothesis that malaria might also enhance HIV susceptibility at mucosal sites of HIV sexual exposure. METHODS: Female C57/BL6 mice were infected with Plasmodium chabaudi malaria using a standardized protocol. Blood, gastrointestinal tissues, upper and lower genital tract tissues, and iliac lymph nodes were sampled 10 days postinfection, and the expression of putative HIV susceptibility and immune activation markers on T cells was assessed by flow cytometry. RESULTS: P. chabaudi malaria increased expression of mucosal homing integrin α4ß7 on blood CD4 and CD8 T cells, and these α4ß7 T cells had significantly increased co-expression of both CCR5 and CD38. In addition, malaria increased expression of the HIV co-receptor CCR5 on CD4 T cells from the genital tract and gut mucosa as well as mucosal T-cell expression of the immune activation markers CD38, Major Histocompatibility Complex -II (MHC-II) and CD69. CONCLUSIONS: Systemic murine malarial infection induced substantial upregulation of the mucosal homing integrin α4ß7 in blood as well as gut and genital mucosal T-cell immune activation and HIV co-receptor expression. Human studies are required to confirm these murine findings and to examine whether malarial infection enhances the sexual acquisition of HIV.
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Susceptibilidad a Enfermedades , Tracto Gastrointestinal/inmunología , Genitales/inmunología , Infecciones por VIH/inmunología , Inmunidad Mucosa , Malaria/inmunología , Plasmodium chabaudi/inmunología , Animales , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica , Activación de Linfocitos , Malaria/complicaciones , Ratones , Ratones Endogámicos C57BL , Receptores del VIH/biosíntesis , Linfocitos T/inmunologíaAsunto(s)
Infecciones por VIH/epidemiología , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/prevención & control , Adulto , Distribución por Edad , Anciano , Recuento de Linfocito CD4 , Cuello del Útero/patología , Cuello del Útero/virología , Coinfección/epidemiología , Coinfección/virología , ADN Viral/análisis , Femenino , Infecciones por VIH/virología , Hospitales Universitarios , Humanos , Persona de Mediana Edad , New York/epidemiología , Papillomaviridae/clasificación , Papillomaviridae/genética , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/virología , Prevalencia , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de Riesgo , Neoplasias del Cuello Uterino/complicaciones , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/virología , Vacunación/estadística & datos numéricos , Frotis Vaginal , Carga ViralRESUMEN
Semen transmission of human immunodeficiency virus (HIV) drives the global pandemic. HIV loads are generally lower in semen than in blood, but semen loads may be disproportionately high in a subgroup of men. HIV loads in semen exceeded those in blood in 9 (35%) of 26 of antiretroviral therapy-naive men, and disproportionately high shedding was strongly associated with compartmentalized semen cytomegalovirus (CMV) reactivation (odds ratio [OR], 10.5; P<.01). Overall, 17 of 26 participants were shedding CMV in semen. Semen levels of HIV and CMV were closely correlated (r=0.5; P<.01), independently of blood HIV load and CD4(+) T cell count. Prevention of CMV reactivation warrants further study as a possible strategy to reduce semen shedding of HIV.
Asunto(s)
Citomegalovirus/fisiología , Infecciones por VIH/virología , VIH-1/fisiología , Semen/virología , Activación Viral , Esparcimiento de Virus , Citomegalovirus/genética , Citomegalovirus/aislamiento & purificación , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/virología , ADN Viral/análisis , Infecciones por VIH/complicaciones , VIH-1/genética , VIH-1/aislamiento & purificación , Humanos , Masculino , ARN Viral/análisis , ARN Viral/sangreRESUMEN
Sexual contact with HIV-infected semen is a major driving force behind the global HIV pandemic. Little is known regarding the immune correlates of virus shedding in this compartment, although HIV-1-specific CD8+ T cells are present in semen. We collected blood and semen from 27 chronically HIV-infected, therapy-naive men without common sexually transmitted infections or urethral inflammation and measured HIV-1 RNA viral load and cytokine/chemokine levels in both compartments. HIV-1 RNA levels were 10-fold higher in blood than semen, but discordantly high semen shedding was associated with higher semen levels of the proinflammatory cytokines IL-6, IL-8, IL-12, and IFN-gamma. Virus-specific CD8+ T cell epitopes were mapped in blood by IFN-gamma ELISPOT, using an overlapping HIV-1 clade B peptide matrix, and blood and semen CD8+ T cell responses were then assayed ex vivo using intracellular IFN-gamma staining. HIV-specific CD8+ responses were detected in 70% of semen samples, and their frequency was similar to or higher than blood. There was no correlation between the presence of virus-specific CD8+ T cells in semen and levels of HIV-1 RNA shedding. Among participants with detectable CD8+ IFN-gamma semen responses, their relative frequency was not associated with reduced HIV-1 RNA shedding, and their absolute number was correlated with higher levels of HIV-1 RNA semen shedding (r = 0.6; p = 0.03) and of several proinflammatory cytokines. Neither the presence nor the frequency of semen HIV-specific CD8+ T cell IFN-gamma responses in semen correlated with reduced levels of HIV RNA in semen.