The lack of socio-behavioral research on stress and psychosocial experiences among research participants who undergo analytical treatment interruption (ATI) in HIV cure studies underscores a critical gap in cure science. Existing literature acknowledges mixed and potentially adverse mental health impacts of ATIs among trial participants, but empirical insights before, during, and after clinical studies are scarce. We used longitudinal in-depth interviews with 11 participants in HIV cure-related research to explore their experiences with stress, coping, and psychological well-being before, during, and after an ATI. Our framework analyses of participant interviews suggest an evolving interplay between person- and environment-oriented factors that shape psychosocial well-being through multiple pathways. Key emergent themes surrounding stress, coping, and psychological adaptation before the ATI encompass the stress-protective effects of pill (in)significance, curiosity in natural immunological control, and perceived support, and trust with professional help networks comprised of providers and research staff. Themes that promoted positive secondary appraisals of stressors during ATIs involved generativity and meaning-based coping, and the stress-adaptive benefits of support-seeking and actualization. Finally, a theme exposing post-ATI stress revolved around the disappointment that participants noted feeling from needing to restart their HIV medications after the ATI and accepting the permanency of HIV and medications in their lives. Our findings emphasize the importance of building supportive and trusting relationships with research teams, and specify the stress-buffering mechanisms between emotional, informational, and appraisal support on ATI-related stress. Additionally, we outline multiple implications that advocate for the adoption of several precautionary measures in HIV cure research to mitigate psychosocial risks. By documenting the evolution of psychosocial experiences, we offer valuable insights to inform the design of future studies, ensuring their ethicality, acceptability, and inclusivity.