Inflammation, Immune Activation, Immunosenescence, and Hormonal Biomarkers in the Frailty-Related Phenotype of Men With or at Risk for HIV Infection.

Background: The extent to which inflammation, immune activation/immunosenescence, and hormonal abnormalities are driven by human immunodeficiency virus (HIV) or frailty is not clear. Methods: HIV-infected frail men (n = 155) were matched to nonfrail, HIV-infected (n = 141) and HIV-uninfected (n = 150) men by age, calendar year, and antiretroviral therapy use (HIV-infected men only). Frailty was defined by ≥3 frailty-related phenotype criteria (weight loss, exhaustion, low activity, slowness) at ≥2 visits, or at 1 visit with ≥1 criteria at ≥2 visits. The following measurements were obtained: interleukin 6, high-sensitivity C-reactive protein, soluble receptors for tumor necrosis factor α 1 and 2, the percentages of CD4+CD28-, CD8+CD28-, CD4+CD38+HLA-DR+, and CD8+CD38+HLA-DR+ T cells, dehydroepiandrosterone sulfate, free testosterone, homeostatic model assessment of insulin resistance, and insulin-like growth factor 1. Log-linear regressions were adjusted for a priori selected covariates to determine differences by frailty and HIV status. Results: In multivariate analyses adjusted for covariates, frailty was associated among HIV-infected men with higher interleukin 6 and high-sensitivity C-reactive protein and lower free testosterone and dehydroepiandrosterone levels. In contrast, HIV infection but not frailty was associated with significantly greater immune senescence (percentage of CD4+CD28- or CD8+CD28- T cells) and immune activation (percentages of CD4+CD38+HLA-DR+ and CD8+CD38+HLA-DR+ T cells). Conclusions: Frailty among HIV-infected men was associated with increased inflammation and lower hormone levels, independent of comorbid conditions. Interventions targeting these pathways should be evaluated to determine the impact on prevention or reversal of frailty among HIV-infected men.

Heterogeneity of CD4+ and CD8+ T-cell responses to cytomegalovirus in HIV-infected and HIV-uninfected men who have sex with men.

Studies of T-cell immunity to human cytomegalovirus (CMV) primarily reflect anti-CMV pp65 or immediate early antigen 1 (IE-1) activity. We assessed responses of T cells from human immunodeficiency virus (HIV)-negative and HIV-infected men to peptide pools spanning 19 CMV open reading frames selected because they previously correlated with total CMV-specific T-cell responses in healthy donors. Cells producing cytokines in response to pp65 or IE-1 together composed <12% and <40% of the total CD4(+) and CD8(+) T-cell responses to CMV, respectively. These proportions were generally similar regardless of HIV serostatus. Thus, analyses of total CMV-specific T-cell responses should extend beyond pp65 and IE-1 regardless of HIV serostatus.

The fibrinolytic system enables the onset of Plasmodium infection in the mosquito vector and the mammalian host.

Plasmodium parasites must migrate across proteinaceous matrices to infect the mosquito and vertebrate hosts. Plasmin, a mammalian serine protease, degrades extracellular matrix proteins allowing cell migration through tissues. We report that Plasmodium gametes recruit human plasminogen to their surface where it is processed into plasmin by corecruited plasminogen activators. Inhibition of plasminogen activation arrests parasite development early during sexual reproduction, before ookinete formation. We show that increased fibrinogen and fibrin in the blood bolus, which are natural substrates of plasmin, inversely correlate with parasite infectivity of the mosquito. Furthermore, we show that sporozoites, the parasite form transmitted by the mosquito to humans, also bind plasminogen and plasminogen activators on their surface, where plasminogen is activated into plasmin. Surface-bound plasmin promotes sporozoite transmission by facilitating parasite migration across the extracellular matrices of the dermis and of the liver. The fibrinolytic system is a potential target to hamper Plasmodium transmission.