This report describes the first reported outbreak of human monkeypox in the Republic of Congo. Eleven confirmed and probable monkeypox cases were observed during this outbreak, all were less than 18 years old, and most resided on the grounds of the Government Hospital in Impfondo. Molecular, virologic, and serologic, and diagnostic assays were used to detect evidence of monkeypox (or orthopox) virus infection in individuals with striking dermatologic and other clinical manifestations. The majority of cases in this outbreak experienced significant, symptomatic illnesses; there was one death, possibly involving secondary complications, and one instance of profound sequelae. Up to six sequential transmissions of monkeypox virus from person to person are hypothesized to have occurred, making this the longest uninterrupted chain of human monkeypox fully documented to date. The pattern of sustained human-to-human transmission observed during this outbreak may influence our current perception of the capacity for this zoonotic virus to adapt to humans.

Memory T-cells promote allograft rejection particularly in costimulation blockade (CoB)-based immunosuppressive regimens. Here we show that the CD2-specific fusion protein alefacept (LFA3-Ig) selectively eliminates memory T-cells and when combined with a CoB-based regimen utilizing CTLA4-Ig, prevents renal allograft rejection and alloantibody formation in primates. These results support the development of an immediately translatable regimen for the prevention of allograft rejection without the use of calcineurin inhibitors, steroids, or pan-T-cell depletion.

Key Points• CMV reactivation fundamentally resets posttransplant CD8 reconstitution, resulting in massive expansion of CMVspecific CD8 Tem.• CMV reactivation is associated with defects in the underlying TCRb immune repertoire.Although cytomegalovirus (CMV) reactivation has long been implicated in posttransplant immune dysfunction, the molecular mechanisms that drive this phenomenon remain undetermined. To address this, we combined multiparameter flow cytometric analysis and T-cell subpopulation sorting with high-throughput sequencing of the T-cell repertoire, to produce a thorough evaluation of the impact of CMV reactivation on T-cell reconstitution after unrelated-donor hematopoietic stem cell transplant. We observed that CMV reactivation drove a >50-fold specific expansion of Granzyme B high / CD28 low /CD57 high /CD8 1 effector memory T cells (Tem) and resulted in a linked contraction of all naive T cells, including CD31 1 /CD4 1 putative thymic emigrants. T-cell receptor b (TCRb) deep sequencing revealed a striking contraction of CD8 1 Tem diversity due to CMV-specific clonal expansions in reactivating patients. In addition to querying the topography of the expanding CMV-specific T-cell clones, deep sequencing allowed us, for the first time, to exhaustively evaluate the underlying TCR repertoire. Our results reveal new evidence for significant defects in the underlying CD8 Tem TCR repertoire in patients who reactivate CMV, providing the first molecular evidence that, in addition to driving expansion of virus-specific cells, CMV reactivation has a detrimental impact on the integrity and heterogeneity of the rest of the T-cell repertoire. This trial was registered at www.clinicaltrials. gov as #NCT01012492. (Blood. 2015;125(25):3835-3850)

Costimulation blockade (CoB), specifically CD28/B7 inhibition with belatacept, is an emerging clinical replacement for calcineurin inhibitor-based immunosuppression in allotransplantation. However, there is accumulating evidence that belatacept incompletely controls alloreactive T cells that lose CD28 expression during terminal differentiation. We have recently shown that the CD2-specific fusion protein alefacept controls costimulation blockade-resistant allograft rejection in nonhuman primates. Here, we have investigated the relationship between human alloreactive T cells, costimulation blockade sensitivity and CD2 expression to determine whether these findings warrant potential clinical translation. Using polychromatic flow cytometry, we found that CD8+ effector memory T cells are distinctly high CD2 and low CD28 expressors. Alloresponsive CD8 + CD2 hi CD28 − T cells contained the highest proportion of cells with polyfunctional cytokine (IFNc , TNF and IL-2) and cytotoxic effector molecule (CD107a and granzyme B) expression capability. Treatment with belatacept in vitro incompletely attenuated allospecific proliferation, but alefacept inhibited belatacept-resistant proliferation. These results suggest that highly alloreactive effector T cells exert their late stage functions without reliance on ongoing CD28/B7 costimulation. Their high CD2 expression increases their susceptibility to alefacept. These studies combined with in vivo nonhuman primate data provide a rationale for translation of an immunosuppression regimen pairing alefacept and belatacept to human renal transplantation.