Project Summary/Abstract – Overall – Center for Drug Use and HIV Research (CDUHR) Biomedical advances in HIV prevention and care, principally pre-exposure prophylaxis (PrEP) and treatment as prevention, led to optimistic predictions and plans to bring HIV under control by 2020. For people who use drugs (PWUD) in NYC, the US, and abroad, it is unlikely that the WHO 90-90-90 goals (90% diagnosed, 90% of diagnosed in care, and 90% of those in care virally suppressed) will be met in the near future. In the US, there have been more than a dozen additional HIV outbreaks among people who inject drugs (PWID) since the sentinel HIV outbreak in Indiana PWID in 2014. In NYC, 64% of PWUD living with HIV are viremic, and mortality rates in HIV-positive PWID in NYC are twice as high as in sexual minority men and heterosexuals living with HIV. PrEP uptake among PWUD is very low (0-3% in the US), even in the midst of outbreaks when it is needed most. After a decade of declines, new HIV diagnoses in US PWID have been increasing 4% per year since 2012. COVID-19 has increased unemployment, homelessness, and substance use across the nation, and is threatening gains that have been made toward ending HIV among PWUD. Thus, our Center for Drug Use and HIV Research has chosen the theme, “Reinvigorating HIV prevention and care for people who use drugs: Accelerating progress and sustaining gains in the midst of societal disruption.” To achieve this, we will lead the field and support our investigators to: 1) understand how large- scale societal changes may undermine HIV prevention and treatment for PWUD, 2) gain knowledge and skills to carry out studies that address the specific needs of PWUD at elevated risk of HIV infection, morbidity and mortality including PWID, sexual minority men, transgender women, and people of color who use drugs, to reduce persistent and widening disparities, and 3) engage with community members to improve the relevance and impact of the knowledge generated. We are committed to supporting new and early stage investigators (new/ESI), especially those who are underrepresented in NIH funding, to achieve their potential as productive and successful scientists. We will achieve these aims through four Cores – an Administrative Core, the Pilot Projects and Mentoring Core, and two Research Support Cores – the Infectious Disease Epidemiology and Social-Behavioral Theory Core, and the Transdisciplinary Research Methods Core. These Cores support our research base and affiliated investigators to conduct cutting-edge science and enhance synergy across investigators from multiple disciplines, thereby leading to contributions to the field that are beyond what the individual projects could have achieved. Our theme and aims build upon many years of research experience and collaboration, broad methodological and theoretical expertise and innovation, and engagement with community and public health partners locally, regionally, nationally and internationally.