Intragenic proviral elements support transcription of defective HIV-1 proviruses.

HIV-1 establishes a persistent proviral reservoir by integrating into the genome of infected host cells. Current antiretroviral treatments do not target this persistent population of proviruses which include latently infected cells that upon treatment interruption can be reactivated to contribute to HIV-1 rebound. Deep sequencing of persistent HIV proviruses has revealed that greater than 90% of integrated HIV genomes are defective and unable to produce infectious virions. We hypothesized that intragenic elements in the HIV genome support transcription of aberrant HIV-1 RNAs from defective proviruses that lack long terminal repeats (LTRs). Using an intact provirus detection assay, we observed that resting CD4+ T cells and monocyte-derived macrophages (MDMs) are biased towards generating defective HIV-1 proviruses. Multiplex reverse transcription droplet digital PCR identified env and nef transcripts which lacked 5' untranslated regions (UTR) in acutely infected CD4+ T cells and MDMs indicating transcripts are generated that do not utilize the promoter within the LTR. 5'UTR-deficient env transcripts were also identified in a cohort of people living with HIV (PLWH) on ART, suggesting that these aberrant RNAs are produced in vivo. Using 5' rapid amplification of cDNA ends (RACE), we mapped the start site of these transcripts within the Env gene. This region bound several cellular transcription factors and functioned as a transcriptional regulatory element that could support transcription and translation of downstream HIV-1 RNAs. These studies provide mechanistic insights into how defective HIV-1 proviruses are persistently expressed to potentially drive inflammation in PLWH.

Stress-Related Mental Health Disorders and Inflammation in Pregnancy: The Current Landscape and the Need for Further Investigation.

Many studies have focused on psychoimmunological mechanisms of risk for stress-related mental health disorders. However, significantly fewer studies have focused on understanding mechanisms of risk for stress-related disorders during pregnancy, a period characterized by dramatic changes in both the innate and adaptive immune systems. The current review summarizes and synthesizes the extant literature on the immune system during pregnancy, as well as the sparse existing evidence highlighting the associations between inflammation and mood, anxiety, and fear-related disorders in pregnancy. In general, pregnant persons demonstrate lower baseline levels of systemic inflammation, but respond strongly when presented with an immune challenge. Stress and trauma exposure may therefore result in strong inflammatory responses in pregnant persons that increases risk for adverse behavioral health outcomes. Overall, the existing literature suggests that stress, trauma exposure, and stress-related psychopathology are associated with higher levels of systemic inflammation in pregnant persons, but highlight the need for further investigation as the existing data are equivocal and vary based on which specific immune markers are impacted. Better understanding of the psychoimmunology of pregnancy is necessary to reduce burden of prenatal mental illness, increase the likelihood of a successful pregnancy, and reduce the intergenerational impacts of prenatal stress-related mental health disorders.