Entry of human immunodeficiency virus type 1 (HIV-1) commences with binding of the envelope glycoprotein (Env) to the receptor CD4, and one of two coreceptors, CXCR4 or CCR5. Env-mediated signaling through coreceptor results in Gαq-mediated Rac activation and actin cytoskeleton rearrangements necessary for fusion. Guanine nucleotide exchange factors (GEFs) activate Rac and regulate its downstream protein effectors. In this study we show that Env-induced Rac activation is mediated by the Rac GEF Tiam-1, which associates with the adaptor protein IRSp53 to link Rac to the Wave2 complex. Rac and the tyrosine kinase Abl then activate the Wave2 complex and promote Arp2/3-dependent actin polymerization. Env-mediated cell-cell fusion, virus-cell fusion and HIV-1 infection are dependent on Tiam-1, Abl, IRSp53, Wave2, and Arp3 as shown by attenuation of fusion and infection in cells expressing siRNA targeted to these signaling components. HIV-1 Env-dependent cell-cell fusion, virus-cell fusion and infection were also inhibited by Abl kinase inhibitors, imatinib, nilotinib, and dasatinib. Treatment of cells with Abl kinase inhibitors did not affect cell viability or surface expression of CD4 and CCR5. Similar results with inhibitors and siRNAs were obtained when Env-dependent cell-cell fusion, virus-cell fusion or infection was measured, and when cell lines or primary cells were the target. Using membrane curving agents and fluorescence microscopy, we showed that inhibition of Abl kinase activity arrests fusion at the hemifusion (lipid mixing) step, suggesting a role for Abl-mediated actin remodeling in pore formation and expansion. These results suggest a potential utility of Abl kinase inhibitors to treat HIV-1 infected patients.

These data illustrate the first proof-of-concept for therapeutic and safe nanoparticle-mediated inhibition of HIV-1 infectivity. Future investigations appear warranted to explore the antiviral prophylactic potential of melittin nanoparticles to capture, disrupt and prevent initial infection with HIV-1 or potentially other enveloped viruses.

In the spring of 1999 in rural Newfoundland, abortions in goats were associated with illness in goat workers. An epidemiologic investigation and a serologic survey were conducted in April 1999 to determine the number of infections, nature of illness, and risk factors for infection. Thirty-seven percent of the outbreak cohort had antibody titers to phase II Coxiella burnetii antigen >1:64, suggesting recent infection. The predominant clinical manifestation of Q fever was an acute febrile illness. Independent risk factors for infection included contact with goat placenta, smoking tobacco, and eating cheese made from pasteurized goat milk. This outbreak raises questions about management of such outbreaks, interprovincial sale and movement of domestic ungulates, and the need for discussion between public health practitioners and the dairy industry on control of this highly infectious organism.

Adolescents and young adults, aged 13e24 years, are disproportionately affected by HIV in the United States. Youth with HIV (YHIV) face many psychosocial and structural challenges resulting in poor clinical outcomes including lower rates of medication adherence and higher rates of uncontrolled HIV. The Johns Hopkins Intensive Primary Care clinic, a longstanding HIV care program in Baltimore, Maryland, cares for 76 YHIV (aged 13e24 years). The multidisciplinary team provides accessible, evidenced-based, culturally sensitive, coordinated and comprehensive patient and family-centered HIV primary care. However, the ability to provide these intensive, in-person services was abruptly disrupted by the necessary institutional, state, and national coronavirus disease 2019 (COVID-19) mitigation strategies. As most of our YHIV are from marginalized communities (racial/ethnic, sexual, and gender minorities) with existing health and social inequities that impede successful clinical outcomes and increase HIV disparities, there was heightened concern that COVID-19 would exacerbate these inequities and amplify the known HIV disparities. We chronicle the structural and logistic approaches that our team has taken to proactively address the social determinants of health that will be negatively impacted by the COVID-19 pandemic, while supporting YHIV to maintain medication adherence and viral suppression.