HIV targets CD4 T cells, which are required for the induction of high-affinity antibody responses and the formation of long-lived B cell memory. The depletion of antigen-specific CD4 T cells during HIV infection is therefore believed to impede the development of protective B cell immunity. Although several different HIVrelated B cell dysfunctions have been described, the role of CD4 T follicular helper (TFH) cells in HIV infection remains unknown. Here, we assessed HIV-specific TFH responses in the lymph nodes of treatment-naive and antiretroviral-treated HIV-infected individuals. Strikingly, both the bulk TFH and HIV-specific TFH cell populations were significantly expanded in chronic HIV infection and were highly associated with viremia. In particular, GAG-specific TFH cells were detected at significantly higher levels in the lymph nodes compared with those of GP120-specific TFH cells and showed preferential secretion of the helper cytokine IL-21. In addition, TFH cell expansion was associated with an increase of germinal center B cells and plasma cells as well as IgG1 hypersecretion. Thus, our study suggests that high levels of HIV viremia drive the expansion of TFH cells, which in turn leads to perturbations of B cell differentiation, resulting in dysregulated antibody production.

Functional defects in cytotoxic CD8؉ T cell responses arise in chronic human viral infections, but the mechanisms involved are not well understood. In mice, CD4 cell-mediated interleukin-21 (IL-21) production is necessary for the maintenance of CD8 ؉ T cell function and control of persistent viral infections. To investigate the potential role of IL-21 in a chronic human viral infection, we studied the rare subset of HIV-1 controllers, who are able to spontaneously control HIV-1 replication without treatment. HIV-specific triggering of IL-21 by CD4؉ T cells was significantly enriched in these persons (P ‫؍‬ 0.0007), while isolated loss of IL-21-secreting CD4 ؉ T cells was characteristic for subjects with persistent viremia and progressive disease. IL-21 responses were mediated by recognition of discrete epitopes largely in the Gag protein, and expansion of IL-21 cells in acute infection resulted in lower viral set points (P ‫؍‬ 0.002). Moreover, IL-21 production by CD4؉ T cells of HIV controllers enhanced perforin production by HIV-1-specific CD8 ؉ T cells from chronic progressors even in late stages of disease, and HIV-1-specific effector CD8؉ T cells showed an enhanced ability to efficiently inhibit viral replication in vitro after IL-21 binding. These data suggest that HIV-1-specific IL-21؉ CD4 ؉ T cell responses might contribute to the control of viral replication in humans and are likely to be of great importance for vaccine design. CD4ϩ T cell help is essential to generate long-lived antiviral CD8 ϩ T cell memory (17, 18). Although antigen-specific CD8 ϩ T cells can be primed in the absence of CD4 ϩ T cell help, secondary expansion upon antigen reencounter is inefficient under such circumstances (7,11,18,22). Progressive loss of CD4 ϩ T cells in human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) infections has been associated with dysfunction of virus-specific CD8 ϩ T cells and ineffective containment of these chronic viral infections. Moreover, under repetitive antigenic stimulation, virus-specific cytotoxic CD8 ϩ T cells (CTL) become increasingly impaired, exhibiting decreased effector functions and upregulation of negative immunoregulatory molecules (2, 19). This dysfunction is likewise more severe in the absence of CD4 ϩ T cell help (21). The nature of CD4 help required to control chronic human infections remains unclear. In mice, recent studies indicate that CD4 ϩ T cell production of interleukin-21 (IL-21), a common ␥-chain cytokine, is required for maintenance of CD8 ϩ T cell function in persistent but not resolving viral infections (3,4,23). During lymphocytic choriomeningitis virus (LCMV) infection, expansion of CD4 ϩ T helper cells producing IL-21 is required for sustained CD8 ϩ T cell proliferation and control of viremia. In contrast, mice lacking either IL-21 or the IL-21 receptor are more susceptible to uncontrolled chronic LCMV infection, providing evidence that this cytokine is a key regulator of viral control in a murine model of chronic viral infection.

The knowledge of the exact oxygen partial pressure in tissue is crucial for patient care and in the treatment of ischemic medical conditions. However, current methods to assess oxygen partial pressure in tissue suffer from a variety of disadvantages, including complex equipment and procedures that necessitate trained personnel. Additionally, the barrier function of the stratum corneum reduces oxygen exchange and can consequently hamper surface measurements of rapidly changing oxygen partial pressure in tissue. To overcome these challenges, a novel, easy-to-use technique to monitor the oxygen partial pressure in tissue using microneedle arrays (MNAs) has been developed. The MNAs can be made from poly(ethyl methacrylate) and poly(propyl methacrylate) and overcome the skin's barrier function to measure oxygen in the capillary bed and interstitial fluid of the skin. The MNAs' tips are embedded with an oxygen-sensitive phosphorescent metalloporphyrin, where the oxygen partial pressure inversely correlates to changes in both emission intensity and phosphorescence lifetime of the in-house developed red emitting Ptcore porphyrin. It was demonstrated that the oxygen-sensing MNAs are sufficiently robust to puncture human skin via rupture of the stratum corneum, and that the MNAs can detect changes in oxygen partial pressure in skin within the physiologically relevant range (0−160 mmHg). Additionally, the MNAs can be combined with a wearable wireless optical readout system, making these oxygensensing MNAs a novel wearable and portable method for user-friendly monitoring of oxygen partial pressure in skin.