HIV-1 replication is concentrated within CD4+ T cells in B-cell follicles of secondary lymphoid tissues during asymptomatic disease. Limited data suggest that a subset of T follicular helper cells (TFH) within germinal centers (GC) is highly permissive to HIV-1. Whether GC TFH are the major HIV-1 virus-producing cells in vivo has not been established. Here, we investigated TFH permissivity to HIV-1 ex vivo by spinoculating and culturing tonsil cells with HIV-1 GFP reporter viruses. Using flow cytometry, higher percentages of GC TFH (CXCR5highPD-1high) and CXCR5+PD-1low cells were GFP+ than non-GC TFH (CXCR5+PD-1intermediate) or extrafollicular (CXCR5-) cells. When sorted prior to spinoculation, however, GC TFH were substantially more permissive than CXCR5+PD-1low or extrafollicular cells, suggesting that many GC TFH transition to a CXCR5+PD-1low phenotype during productive infection. In situ hybridization on inguinal lymph node sections from untreated HIV-1-infected individuals without AIDS revealed higher frequencies of HIV-1 RNA+ cells in GC than non-GC regions of follicle or extrafollicular regions. Superinfection of HIV-1-infected individuals’ lymph node cells with GFP reporter virus confirmed the permissivity of follicular cells ex vivo. Lymph node immunostaining revealed 96% of CXCR5+CD4+ cells were located in follicles. Within sorted lymph node cells from four HIV-infected individuals, CXCR5+ subsets harbored 11- to 66-fold more HIV-1 RNA than CXCR5-subsets, as determined by RT PCR. Thus, GC TFH are highly permissive to HIV-1, but downregulate PD-1 and to a lesser extent CXCR5 during HIV-1 replication. These data further implicate GC TFH as the major HIV-1-producing cells in chronic asymptomatic HIV-1 infection.

Rifampin has been used for the treatment of bacterial infections for many years. Clinically, rifampin has been found to possess immunomodulatory effects. However, the molecular target responsible for the immunosuppressive effects of rifampin is not known. Herein, we show that rifampin binds to myeloid differentiation protein 2 (MD-2), the key coreceptor for innate immune TLR4. Rifampin blocked TLR4 signaling induced by LPS, including NF-κB activation and the overproduction of proinflammatory mediators nitric oxide, interleukin 1β, and tumor necrosis factor α in mouse microglia BV-2 cells and macrophage RAW 264.7 cells. Rifampin's inhibition of TLR4 signaling was also observed in immunocompetent rat primary macrophage, microglia, and astrocytes. Further, we show that rifampin (75 or 100 mg/kg b.i.d. for 3 d, intraperitoneal) suppressed allodynia induced by chronic constriction injury of the sciatic nerve and suppressed nerve injury-induced activation of microglia. Our findings indicate that MD-2 is a important target of rifampin in its inhibition of innate immune function and contributes to its clinically observed immune-suppressive effect. The results also suggest that rifampin may be repositioned as an agent for the treatment of neuropathic pain.

Previous studies on sex-differentiated mate preferences have focused on univariate analyses. However, because mate selection is inherently multidimensional, a multivariate analysis more appropriately measures sex differences in mate preferences. We used the Mahalanobis distance (D) and logistic regression to investigate sex differences in mate preferences with data secured from participants residing in 37 cultures (n = 10,153). Sex differences are large in multivariate terms, yielding an overall D = 2.41, corresponding to overlap between the sexes of just 22.8%. Moreover, knowledge of mate preferences alone affords correct classification of sex with 92.2% accuracy. Finally, pattern-wise sex differences are negatively correlated with gender equality across cultures but are nonetheless cross-culturally robust. Discussion focuses on implications in evaluating the importance and magnitude of sex differences in mate preferences.

Individual differences in attachment bonds may influence the performance of mate retention behaviors. Because anxiously attached individuals are hypervigilant to partner rejection cues, we hypothesize that individuals higher in anxious attachment will perform more frequent mate retention behaviors. Because avoidantly attached individuals evade intimacy with their partners, we hypothesize that individuals higher in avoidant attachment will perform less frequent mate retention behaviors. Participants (N = 469) in a romantic relationship completed measures of romantic attachment and mate retention behaviors. The results provide support for the study hypotheses but also reveal that avoidantly attached women perform more frequent mate retention behaviors that deter intrasexual rivals. We discuss limitations of this research and highlight directions for research on romantic attachment, mate retention behaviors, and infidelity.

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HIV-1 hijacks and disrupts many processes in the cells it infects in order to suppress antiviral immunity and to facilitate its replication. Resting CD4 T cells are important early targets of HIV-1 infection in which HIV-1 must overcome intrinsic barriers to viral replication. Although resting CD4 T cells are refractory to infection in vitro, local environmental factors within lymphoid and mucosal tissues such as cytokines facilitate viral replication while maintaining the resting state. These factors can be utilized in vitro to study HIV-1 replication in resting CD4 T cells. In vivo, the migration of resting naïve and central memory T cells into lymphoid tissues is dependent upon expression of CD62L (L-selectin), a receptor that is subsequently down-modulated following T cell activation. CD62L gene transcription is maintained in resting T cells by Foxo1 and KLF2, transcription factors that maintain T cell quiescence and which regulate additional cellular processes including survival, migration, and differentiation. Here we report that HIV-1 down-modulates CD62L in productively infected naïve and memory resting CD4 T cells while suppressing Foxo1 activity and the expression of KLF2 mRNA. Partial T cell activation was further evident as an increase in CD69 expression. Several other Foxo1- and KLF2-regulated mRNA were increased or decreased in productively infected CD4 T cells, including IL-7rα, Myc, CCR5, Fam65b, S1P1 (EDG1), CD52, Cyclin D2 and p21CIP1, indicating a profound reprogramming of these cells. The Foxo1 inhibitor AS1842856 accelerated de novo viral gene expression and the sequella of infection, supporting the notion that HIV-1 suppression of Foxo1 activity may be a strategy to promote replication in resting CD4 T cells. As Foxo1 is an investigative cancer therapy target, the development of Foxo1 interventions may assist the quest to specifically suppress or activate HIV-1 replication in vivo.

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An increasing number of severe infections caused by Staphylococcus aureus ST398 strains has been observed. However, it has not been elucidated whether all ST398 strains are equally virulent. We collected 13 strains from China and Canada to test in a Caenorhabditis elegans infection model and compared their whole genome sequences (WGS) to explore potential insights into their virulence. All isolates belonged to ST398-methicillin-susceptible S. aureus (MSSA) with variant spa types (t034, t571, t1451, t1250). Pulsed field gel electrophoresis (PFGE) and WGS analyses showed that the 13 isolates clustered into 3 genomic types (Types A-C). WGS and prophage phylogenetic analyses also revealed that the strains could be divided into 3 phage groups (Groups 1–3), which correlated with high-, moderate-, and low-nematocidal activities, with mean killing rates of 94, 67, and 40%, respectively. Group 1 carried ϕSa3-Group 1 (ϕSa3-G1), Group 2 carried ϕSa3-G2, and Group 3 lacked ϕSa3. Interestingly, strain GD1706 (that genetically clustered within Type C) and strain GD487 (within Type B) both carried ϕSa3-G1 like phages and killed 92% of the nematodes, similar to the Type A strains carrying ϕSa3-G1. This study demonstrated that different ST398 sub-lineages possess variable virulence capacities, depending on the presence or absence, as well as the structure of the prophage ϕSa3 that carries virulence factors.IMPORTANCESince first being reported in the early 2000s, Staphylococcus aureus ST398 has not only become recognized as a frequent colonizing strain in economically important livestock animals, but has also proven to be a concern for infection in humans and, in particular, has been linked to higher rates of severe invasive human infections. We collected ST398 strains from China and Canada to test in a worm (Caenorhabditis elegans) infection model and compared their whole genome sequences to gain insight into pathogenesis. We have shown that different ST398 sub-strains differ in their virulence potential based on the presence or absence and structure of prophage ϕSa3, which carries important virulence factors. Our observations suggest that ST398 strains are relatively heterogeneous from a clinical perspective, and more studies are needed to differentiate between virulent and non-virulent ST398 strains to determine the true global spread of relevant sub-strains.