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Plasma extracellular vesicle (EV)-associated cytokines were quantified in people with HIV (PWH) with different virological control status, including elite controllers (EC) who maintain persistent control (PC) or not (TC). Cytokine signatures and pathways were determined for each group. Median EV-associated cytokine levels were higher among PWH than HIV-uninfected. EC showed the highest levels of EV-associated cytokines among PWH with PC levels higher than TC levels. IL-18 levels best distinguished PWH from uninfected controls, and EC from ART-treated, and IL-3 distinguished PC from TC. The role of EV-cytokines in intercellular communication and endogenous control of HIV expression should be investigated further.

Background. Maraviroc is the first antiretroviral (ART) drug to target a human protein, the CCR5 coreceptor; however, the mechanisms of maraviroc-associated immunomodulation in human immunodeficiency virus (HIV)– infected subjects remain to be elucidated. Regulatory T cells (Tregs) play a key role in HIV-associated immunopathology and are susceptible to maraviroc-mediated CCR5 blockade. Our aim was to evaluate the effect of maraviroc on Tregs. Methods. We compared the effect of maraviroc-containing or -sparing combination ART (cART) on Tregs in ART-naive, HIV-infected subjects. Tregs were characterized as CD4 + CD25 hi FoxP3 + on day 0, 8, and 30. Additional analysis on week 48 was performed in a subgroup of patients. The potential reduction in the frequency of Tregs among maraviroc-treated peripheral blood mononuclear cells (PBMCs) was also tested in vitro. The suppressive function of Tregs was also analyzed in maraviroc-treated Tregs. Results. We found that maraviroc significantly reduced the Treg frequency in both the short term and 1 year after treatment initiation. In vitro experiments showed a dose-dependent reduction in the Treg frequency after treatment of PBMCs with maraviroc, although their in vitro suppressive function was not altered. Conclusions. These findings partially explain maraviroc-associated immunomodulatory effects and open new therapeutic expectations for the development of Treg-depleting immunotherapies.

BACKGROUND Human immunodeficiency virus (HIV) controllers spontaneously control viremia and CD4 T-cell depletion in contrast to viremic patients. After HIV exposure, plasmacytoid dendritic cells (pDCs) produce high levels of interferon alpha (IFN-α) and express the apoptotic ligand TRAIL (tumor necrosis factor-related apoptosis inducing ligand). Simian models have shown that prolonged high levels of IFN-α production could be responsible for AIDS progression. METHODS We studied pDC activation in response to human immunodeficiency virus (HIV) using flow cytometry and 3D microscopy. RESULTS We show here that pDCs from controller patients produced higher levels of IFN-α in response to HIV than pDCs from viremic patients but similar levels to pDCs from healthy donors. Because binding of HIV to CD4 is essential for pDC activation, the low CD4 expression by pDCs from viremic patients may explain the weak IFN-α response to HIV. Three-dimensional microscopy revealed that pDCs from controllers and healthy donors expressed intracellular TRAIL that is relocalized to the membrane after HIV exposure. In contrast, pDCs from viremic patients expressed membrane TRAIL without any stimulation. CONCLUSIONS We demonstrate that, in response to HIV, pDCs from controller patients produce IFN-α, express membrane TRAIL, and induce apoptosis of T-cell lines.

1,a E. Ruiz-Mateos, 1,3,a and the HIV The single-nucleotide polymorphism (SNP) rs12979860 near the IL28B gene has been associated with the spontane- ous clearance of hepatitis C virus. We sought to determine whether this SNP could be associated with the spontaneous control of human immunodeficiency virus (HIV) infection. We studied the prevalence of the IL28B CC genotype among 53 white HIV controllers, compared with the preva- lence among 389 HIV-infected noncontrollers. We found that the IL28B CC genotype was independently associated with spontaneous HIV control (odds ratio (OR), 2.669; P = .017), as were female sex (OR, 7.077; P ≤.001) and the presence of HLA-B57 and/or B27 (OR, 3.080; P = .017). This result supports the idea that common host mecha- nisms are involved in the spontaneous control of these 2 chronic infections.

Thymic function was evaluated in 32 heavily antiretroviral-treated human immunodeficiency virus type 1 (HIV-1)-infected adults with long-term virologic treatment failure by measuring thymic volume, by determining the absolute number of naive T cell phenotypes, and by determining the number of cells carrying T cell receptor excision circles (TRECs). There was a significant inverse correlation between age and thymic volume (r = -0.415; P = .018), and there was a significant direct correlation between thymic volume and total naive T cell counts (r = 0.529; P = .002), naive CD4 + cell counts (r = 0.437; P = .012), naive CD8 + cell counts (r = 0.467; P = .007), and TREC levels (r = 0.391; P = .027). In conclusion, this study found clear evidence that the thymus of heavily antiretroviral-treated HIV-1-infected adults with long-term virologic treatment failure is actively engaged in thymopoiesis, which generates new naive T cells for the peripheral lymphocyte pool.