RESUMEN
Background: Attenuated varicella zoster virus (VZV) is a promising vector for recombinant vaccines. Because human immunodeficiencyvirus (HIV) vaccines are believed to require mucosal immunogenicity, we characterized mucosal VZV-specific humoral immunity following VZVOka vaccination. Methods: Adult Kenyan VZV-seropositive women (n = 44) received a single dose of the live zoster VZVOka vaccine. The anamnestic responses to the virus were followed longitudinally in both plasma and mucosal secretions using an in-house glycoprotein enzyme-linked immunosorbent assay and safety and reactogenicity monitored. VZV seroprevalence and baseline responses to the virus were also characterized in our cohorts (n = 288). Results: Besides boosting anti-VZV antibody responses systemically, vaccination also boosted anti-VZV immunity in the cervicovaginal mucosa with a 2.9-fold rise in immunoglobulin G (P < .0001) and 1.6-fold rise in immunoglobulin A (IgA) (P = .004) from the time before immunization and 4 weeks postvaccination. Baseline analysis demonstrated high avidity antibodies at the gastrointestinal and genital mucosa of VZV-seropositive women. Measurement of VZV-specific IgA in saliva is a sensitive tool for detecting prior VZV infection. Conclusions: VZVOka vaccine was safe and immunogenic in VZV-seropositive adult Kenyan women. We provided compelling evidence of VZV ability to induce genital mucosa immunity. Clinical Trials Registration: NCT02514018.
Asunto(s)
Anticuerpos Antivirales/metabolismo , Herpesvirus Humano 3/aislamiento & purificación , Inmunidad Humoral , Membrana Mucosa/inmunología , Vagina/inmunología , Infección por el Virus de la Varicela-Zóster/prevención & control , Anticuerpos Antivirales/sangre , Femenino , Vacuna contra el Herpes Zóster/inmunología , Humanos , Kenia/epidemiología , Vacunas Atenuadas , Infección por el Virus de la Varicela-Zóster/epidemiología , Infección por el Virus de la Varicela-Zóster/inmunologíaRESUMEN
The HIV pandemic disproportionately affects women, with most infections acquired through receptive vaginal sex. Although the target cells by which HIV establishes infection in the female genital tract remain poorly defined, it is known that immune activation results in CD4(+) T cells with enhanced susceptibility, as does expression of the mucosal integrin α4ß7 and the HIV coreceptor CCR5. Blood and cervical cytobrush specimens were collected from female sex workers (FSWs) in Nairobi, Kenya. Genital infection diagnostics were performed, T cell populations were defined by multiparameter flow cytometry based on their expression of surface receptors relevant to mucosal homing and/or HIV acquisition, and cytokine production was assayed by intracellular cytokine staining. The integrin α4ß7 was expressed on 26.0% of cervical CD4(+) T cells, and these cells were more likely to express both the HIV coreceptor CCR5 (p < 0.0001) and the early activation marker CD69 (p < 0.0001) but not CXCR4 (p = 0.34). Cervical Th17 frequencies were enhanced compared with blood (7.02 versus 1.24%; p < 0.0001), and cervical IL-17A(+) CD4(+) T cells preferentially coexpressed α4ß7 and CCR5. Expression of IFN-γ and IL-22 was greater in cervical Th17 cells than in blood Th17 cells. In keeping with the hypothesis that these cells are preferential HIV targets, gp120 preferentially bound CCR5(+) cervical T cells, and cervical Th17 cells were almost completely depleted in HIV(+) FSWs compared with HIV(-) FSWs. In summary, a subset of Th17 CD4(+) T cells in the cervical mucosa coexpresses multiple HIV susceptibility markers; their dramatic depletion after HIV infection suggests that these may serve as key target cells during HIV transmission.
Asunto(s)
Cuello del Útero/inmunología , Infecciones por VIH/transmisión , Inmunidad Mucosa/inmunología , Subgrupos de Linfocitos T/inmunología , Células Th17/inmunología , Adulto , Biomarcadores/análisis , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Separación Celular , Cuello del Útero/citología , Cuello del Útero/metabolismo , Citocinas/análisis , Citocinas/biosíntesis , Citocinas/inmunología , Susceptibilidad a Enfermedades/inmunología , Femenino , Citometría de Flujo , Infecciones por VIH/inmunología , Infecciones por VIH/metabolismo , Humanos , Integrinas/análisis , Integrinas/biosíntesis , Integrinas/inmunología , Interferón gamma/análisis , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Interleucina-17/análisis , Interleucina-17/biosíntesis , Interleucina-17/inmunología , Receptores CCR5/análisis , Receptores CCR5/biosíntesis , Receptores CCR5/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/virología , Células Th17/metabolismo , Células Th17/virologíaRESUMEN
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.
Asunto(s)
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
HIV-1 is grouped phylogenetically into clades, which may impact rates of HIV-1 disease progression. Clade D infection in particular has been shown to be more pathogenic. Here we confirm in a Nairobi-based prospective female sex worker cohort (1985-2004) that Clade D (n = 54) is associated with a more rapid CD4 decline than clade A1 (n = 150, 20.6% vs 13.4% decline per year, 1.53-fold increase, p = 0.015). This was independent of "protective" HLA and country of origin (p = 0.053), which in turn were also independent predictors of the rate of CD4 decline (p = 0.026 and 0.005, respectively). These data confirm that clade D is more pathogenic than clade A1. The precise reason for this difference is currently unclear, and requires further study. This is first study to demonstrate difference in HIV-1 disease progression between clades while controlling for protective HLA alleles.
Asunto(s)
Antígenos CD4 , Infecciones por VIH , VIH-1 , Trabajadores Sexuales , Adulto , Alelos , Población Negra , Antígenos CD4/genética , Antígenos CD4/inmunología , Progresión de la Enfermedad , Evolución Molecular , Femenino , Infecciones por VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/genética , VIH-1/patogenicidad , Antígenos HLA/genética , Antígenos HLA/inmunología , Humanos , Kenia , FilogeniaRESUMEN
HIV diversity may limit the breadth of vaccine coverage due to epitope sequence differences between strains. Although amino acid substitutions within CD8(+) T cell HIV epitopes can result in complete or partial abrogation of responses, this has primarily been demonstrated in effector CD8(+) T cells. In an HIV-infected Kenyan cohort, we demonstrate that the cross-reactivity of HIV epitope variants differs dramatically between overnight IFN-gamma and longer-term proliferation assays. For most epitopes, particular variants (not the index peptide) were preferred in proliferation in the absence of corresponding overnight IFN-gamma responses and in the absence of the variant in the HIV quasispecies. Most proliferating CD8(+) T cells were polyfunctional via cytokine analyses. A trend to positive correlation was observed between proliferation (but not IFN-gamma) and CD4 counts. We present findings relevant to the assessment of HIV vaccine candidates and toward a better understanding of how viral diversity is tolerated by central and effector memory CD8(+) T cells.