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 (r2 = 0.18, p = 0.02). Semen bacterial load was also directly linked to the semen HIV VL (r2 = 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.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To evaluate if systemic murine malarial infection enhances HIV susceptibility through parasite-induced mucosal immune alterations at sites of HIV sexual exposure.
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.
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.
P. chabaudi malaria increased expression of mucosal homing integrin α4β7 on blood CD4 and CD8 T cells, and these α4β7 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.
Systemic murine malarial infection induced substantial upregulation of the mucosal homing integrin α4β7 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.
Background. Chronic coinfection with herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus (HIV) has been associated with an increased HIV viral load and more rapid disease ...progression, perhaps related to HSV-2-associated alterations in host immunity. Methods. Studies were nested within (1) a cross-sectional study of men coinfected with HIV and HSV-2 and (2) women not infected with HIV, both before and after HSV-2 acquisition. HSV-2 infection status was determined by ELISA. HIV-specific CD8+ T cell epitopes were mapped, and proliferation of HIV-specific cells was also assessed. Systemic inflammatory and regulatory T cell populations were assayed by flow cytometry. Results. The breadth of both the HIV-specific CD8+ T cell interferon-γ and proliferative responses was reduced in participants coinfected with HIV and HSV-2, independent of the HIV plasma viral load and CD4+ T cell count, and the magnitude of the responses was also reduced. HSV-2 infection in this group was associated with increased T cell CD38 expression but not with differences in the proportion of CD4+ FoxP3+ regulatory T cells. However, in women not infected with HIV, acquisition of HSV-2 was associated with an increase in the proportion of regulatory T cells. Conclusions. HSV-2 coinfection was associated with reduced HIV-specific T cell responses and systemic inflammation. The immune effects of HSV-2 may underlie the negative impact that this coinfection has on the clinical course of HIV infection.
Problem
Semen is the primary medium for sexual transmission of HIV‐1 and contains high concentrations of TGF‐β1, but its role in regulating HIV‐mediated immune activation is unclear.
Method of Study
...TGF‐β1 and sCD14 were compared in blood plasma (BP) and seminal plasma (SP) from HIV‐uninfected and infected, antiretroviral therapy (ART)‐naive and ART‐treated men and in THP‐1 cells following exposure to HIV‐1. The relationship between TGF‐β1 and sCD14 was determined by Spearman correlation.
Results
Active and latent forms of TGF‐β1 were compartmentalized between BP and SP. Highest active TGF‐β1 levels were present in SP of ART‐naïve chronic‐infected men and decreased following ART treatment. Latent TGF‐β1 was upregulated in BP following HIV infection, and highest levels were observed in BP of acute‐infected men. Similar expression trends were observed between latent TGF‐β1 and sCD14 in BP. A significant negative correlation was observed between active TGF‐β1, sCD14, and semen viral load in ART‐naive men.
Conclusion
TGF‐β1 is compartmentalized between blood and semen, possibly co‐expressed with sCD14 by activated monocytes/macrophages in BP as a result of HIV infection. Conversion of latent TGF‐β1 into its active form could contribute to regulation of viral load and immune activation in the male genital tract, but depends on the stage of infection.
Problem Semen is the primary medium for sexual transmission of HIV-1 and contains high concentrations of TGF-beta1, but its role in regulating HIV-mediated immune activation is unclear. Method of ...Study TGF-beta1 and sCD14 were compared in blood plasma (BP) and seminal plasma (SP) from HIV-uninfected and infected, antiretroviral therapy (ART)-naive and ART-treated men and in THP-1 cells following exposure to HIV-1. The relationship between TGF-beta1 and sCD14 was determined by Spearman correlation. Results Active and latent forms of TGF-beta1 were compartmentalized between BP and SP. Highest active TGF-beta1 levels were present in SP of ART-naïve chronic-infected men and decreased following ART treatment. Latent TGF-beta1 was upregulated in BP following HIV infection, and highest levels were observed in BP of acute-infected men. Similar expression trends were observed between latent TGF-beta1 and sCD14 in BP. A significant negative correlation was observed between active TGF-beta1, sCD14, and semen viral load in ART-naive men. Conclusion TGF-beta1 is compartmentalized between blood and semen, possibly co-expressed with sCD14 by activated monocytes/macrophages in BP as a result of HIV infection. Conversion of latent TGF-beta1 into its active form could contribute to regulation of viral load and immune activation in the male genital tract, but depends on the stage of infection.
Semen is the primary medium for sexual transmission of HIV-1 and contains high concentrations of TGF- beta 1, but its role in regulating HIV-mediated immune activation is unclear. TGF- beta 1 and ...sCD14 were compared in blood plasma (BP) and seminal plasma (SP) from HIV-uninfected and infected, antiretroviral therapy (ART)-naive and ART-treated men and in THP-1 cells following exposure to HIV-1. The relationship between TGF- beta 1 and sCD14 was determined by Spearman correlation. Active and latent forms of TGF- beta 1 were compartmentalized between BP and SP. Highest active TGF- beta 1 levels were present in SP of ART-naive chronic-infected men and decreased following ART treatment. Latent TGF- beta 1 was upregulated in BP following HIV infection, and highest levels were observed in BP of acute-infected men. Similar expression trends were observed between latent TGF- beta 1 and sCD14 in BP. A significant negative correlation was observed between active TGF- beta 1, sCD14, and semen viral load in ART-naive men. TGF- beta 1 is compartmentalized between blood and semen, possibly co-expressed with sCD14 by activated monocytes/macrophages in BP as a result of HIV infection. Conversion of latent TGF- beta 1 into its active form could contribute to regulation of viral load and immune activation in the male genital tract, but depends on the stage of infection.
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.
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.
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.
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.
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