Intestinal endothelial cells increase HIV infection and latency in resting and activated CD4 + T cells, particularly affecting CCR6 + CD4 + T cells.

BACKGROUND: With suppressive antiretroviral therapy, HIV infection is well-managed in most patients. However, eradication and cure are still beyond reach due to latent viral reservoirs in CD4 + T cells, particularly in lymphoid tissue environments including the gut associated lymphatic tissues. In HIV patients, there is extensive depletion of T helper cells, particularly T helper 17 cells from the intestinal mucosal area, and the gut is one of the largest viral reservoir sites. Endothelial cells line lymphatic and blood vessels and were found to promote HIV infection and latency in previous studies. In this study, we examined endothelial cells specific to the gut mucosal area-intestinal endothelial cells-for their impact on HIV infection and latency in T helper cells. RESULTS: We found that intestinal endothelial cells dramatically increased productive and latent HIV infection in resting CD4 + T helper cells. In activated CD4 + T cells, endothelial cells enabled the formation of latent infection in addition to the increase of productive infection. Endothelial-cell-mediated HIV infection was more prominent in memory T cells than naïve T cells, and it involved the cytokine IL-6 but did not involve the co-stimulatory molecule CD2. The CCR6 + T helper 17 subpopulation was particularly susceptible to such endothelial-cell-promoted infection. CONCLUSION: Endothelial cells, which are widely present in lymphoid tissues including the intestinal mucosal area and interact regularly with T cells physiologically, significantly increase HIV infection and latent reservoir formation in CD4 + T cells, particularly in CCR6 + T helper 17 cells. Our study highlighted the importance of endothelial cells and the lymphoid tissue environment in HIV pathology and persistence.

Body Dissatisfaction in a Diverse Sample of Young Men Who Have Sex With Men: The P18 Cohort Study.

Young men who have sex with men (YMSM) may be at greater risk for body dissatisfaction, compared to their heterosexual peers. However, differences within YMSM populations are understudied, precluding the identification of YMSM who are at greatest risk. This study examined body dissatisfaction in a racially/ethnically diverse sample of YMSM ages 18-19 in New York City. Using cross-sectional data from the baseline visit of a longitudinal cohort study of YMSM (N = 591), body dissatisfaction was assessed using the Male Body Attitudes Scale. Three outcomes were modeled using linear regression: (1) overall body dissatisfaction, (2) muscularity dissatisfaction, and (3) body fat dissatisfaction. Covariates in the models included race/ethnicity, sexual orientation, BMI, gay community affiliation, and internalized homonegativity. White YMSM experienced greater body dissatisfaction across the three models. Internalized homonegativity was a statistically significant predictor of dissatisfaction across the three models, though its association with body dissatisfaction was relatively small. The findings point to future avenues of research, particularly qualitative research to explore demographic and cultural nuances in body attitudes among YMSM.

Facilitators and Barriers to HIV Status Disclosure Among HIV-positive MSM Age 50 and Older.

OBJECTIVE: Most HIV-positive men who have sex with men (MSM) ages 50 and older feel a responsibility to protect their sex partners from HIV transmission risk. For some, this is enacted through HIV disclosure, for others, this is realized through reduced risk behaviors. METHODS: To examine this, we analyzed interviews of 23 HIV-positive MSM ages 50 and older. RESULTS: We identified several contextual, relational, and psychosocial factors that served as either barriers or facilitators to HIV disclosure. CONCLUSIONS: Our findings suggest HIV status disclosure is multifaceted and continues to impact sexual communication in the lives of MSM as they enter middle age.

Acceptability of PrEP Uptake Among Racially/Ethnically Diverse Young Men Who Have Sex With Men: The P18 Study.

Pre-exposure prophylaxis (PrEP) is considered an effective biomedical approach for HIV prevention. However, there is limited understanding of PrEP uptake among racially/ethnically and socioeconomically diverse young men who have sex with men (YMSM). This study examined attitudes and perceptions toward PrEP uptake among YMSM by conducting semistructured interviews with a sample (N = 100) of YMSM in New York City. Thematic analysis was employed to explore key issues related to attitudes and perceptions toward PrEP utilization. Findings suggest that self-perceived risk for HIV transmission, enjoying unprotected sex, and being in a romantic relationship were associated with PrEP uptake. The most prominent barriers to PrEP uptake included costs, adherence regimen, and access. In summary, these findings underscore the importance of addressing behavioral and structural factors in maximizing the effectiveness of PrEP. In addition, PrEP implementation programs ought to consider the role of social and structural challenges to PrEP uptake and adherence among YMSM.

Genetic and pharmacological modulation of the steroid sulfatase axis improves response control; comparison with drugs used in ADHD.

Maladaptive response control is a feature of many neuropsychiatric conditions, including attention deficit hyperactivity disorder (ADHD). As ADHD is more commonly diagnosed in males than females, a pathogenic role for sex-linked genes has been suggested. Deletion or point mutation of the X-linked STS gene, encoding the enzyme steroid sulfatase (STS) influences risk for ADHD. We examined whether deletion of the Sts gene in the 39,X(Y*)O mouse model, or pharmacological manipulation of the STS axis, via administration of the enzyme substrate dehydroepiandrosterone sulfate or the enzyme inhibitor COUMATE, influenced behavior in a novel murine analog of the stop-signal reaction time task used to detect inhibitory deficits in individuals with ADHD. Unexpectedly, both the genetic and pharmacological treatments resulted in enhanced response control, manifest as highly specific effects in the ability to cancel a prepotent action. For all three manipulations, the effect size was comparable to that seen with the commonly used ADHD therapeutics methylphenidate and atomoxetine. Hence, converging genetic and pharmacological evidence indicates that the STS axis is involved in inhibitory processes and can be manipulated to give rise to improvements in response control. While the precise neurobiological mechanism(s) underlying the effects remain to be established, there is the potential for exploiting this pathway in the treatment of disorders where failures in behavioral inhibition are prominent.

Psychosocial burdens negatively impact HIV antiretroviral adherence in gay, bisexual, and other men who have sex with men aged 50 and older.

We sought to characterize HIV antiretroviral therapy (ART) adherence and psychosocial correlates of adherence in a sample of gay, bisexual, and other non-gay or -bisexual identified men who have sex with men aged 50 and over. As part of a cross-sectional study we recruited a community-based sample of 199 men and assessed adherence to current ART medications along four domains: (1) missing doses in the past 4 days, (2) taking doses on the specified schedule in the past 4 days, (3) following instructions about how to take the medications (e.g., to take medications with food), and (4) missing doses in the last weekend. A total adherence score was also computed. Bivariable analyses indicated negative associations between depression, sexual compulsivity, and HIV-related stigma with each of the individual adherence variables and the composite adherence score, while an older age was found to be protective. In multivariable analyses, controlling for age and educational attainment, a higher likelihood of missing doses and failing to follow instructions were related to higher levels of HIV-related stigma, while dosing off-schedule and missing doses on weekends was associated with higher levels of sexual compulsivity. These results indicate that psychosocial burdens undermine the adherence behaviors of older HIV-positive sexual minority men. Programming and services to address this compromising health behavior must embrace a holistic approach to health as informed by syndemics theory, while attending to the developmental and age-specific needs of older men.

Sociodemographic Factors Contribute to Mental Health Disparities and Access to Services Among Young Men Who Have Sex with Men in New York City.

Young men who have sex with men (YMSM) may be at increased risk for mental health problems including depression, post-traumatic stress (PTSD), and suicidality. The overriding goal of the current investigation was to examine mental health and mental health services in a diverse sample of YMSM. We analyzed cross-sectional data from a cohort study of 598 YMSM, including sociodemographics, mental health, and mental health care. We then tested for bivariate associations, and used multivariable modeling to predict depression, PTSD, suicidality and mental health care utilization. Lower socioeconomic status, unstable housing, and school non-enrollment predicted depression and PTSD scores, while unstable housing and school non-enrollment predicted recent suicide attempt(s). These recent suicide attempt(s) also predicted current utilization of counseling or treatment, any history of psychiatric hospitalization, and any history of psychiatric diagnosis. Black and API men were less likely to have ever accessed mental health counseling or treatment. There were significant class-based differences with regard to mental health outcomes, but not mental health services. Further, recent crises (i.e., suicide attempt, hospitalization) were strong predictors of accessing mental health services. Improving the mental health of YMSM requires addressing the underlying structural factors that influence mental health outcomes and service access.

A novel translational assay of response inhibition and impulsivity: effects of prefrontal cortex lesions, drugs used in ADHD, and serotonin 2C receptor antagonism.

Animal models are making an increasing contribution to our understanding of the psychology and brain mechanisms underlying behavioral inhibition and impulsivity. The aim here was to develop, for the first time, a mouse analog of the stop-signal reaction time task with high translational validity in order to be able to exploit this species in genetic and molecular investigations of impulsive behaviors. Cohorts of mice were trained to nose-poke to presentations of visual stimuli. Control of responding was manipulated by altering the onset of an auditory 'stop-signal' during the go response. The anticipated systematic changes in action cancellation were observed as stopping was made more difficult by placing the stop-signal closer to the execution of the action. Excitotoxic lesions of medial prefrontal cortex resulted in impaired stopping, while the clinically effective drugs methylphenidate and atomoxetine enhanced stopping abilities. The specific 5-HT2C receptor antagonist SB242084 also led to enhanced response control in this task. We conclude that stop-signal reaction time task performance can be successfully modeled in mice and is sensitive to prefrontal cortex dysfunction and drug treatments in a qualitatively similar manner to humans and previous rat models. Additionally, using this model we show novel and highly discrete effects of 5-HT2C receptor antagonism that suggest manipulation of 5-HT2C receptor function may be of use in correcting maladaptive impulsive behaviors and provide further evidence for dissociable contributions of serotonergic transmission to response control.

Evidence for a Syndemic in Aging HIV-positive Gay, Bisexual, and Other MSM: Implications for a Holistic Approach to Prevention and Healthcare.

The theory of syndemics has been widely applied in HIV prevention studies of gay, bisexual, and other MSM over the last decade. Our investigation is the first to consider the applicability of the theory in a sample of aging (ages 50 and over) HIV-positive MSM, which is a growing population in the United States. A sample of 199 men were actively recruited and assessed in terms of mental health and drug use burden, as well as sexual risk behaviors. Bivariate and multivariable analyses indicate a high level of association between psychosocial burdens (i.e., drug use and mental health) and same-sex unprotected sexual behaviors, providing initial support for the applicability of the theory of syndemics to this population. Further support can be seen in participants' narratives. Findings suggest the mutually reinforcing nature of drug use, psychiatric disorders, and unprotected sexual behavior in older, HIV-positive, gay, bisexual, and other MSM, highlighting the need for holistic strategies to prevention and care among this population of older and sexually active individuals. In short, the generation of gay men who came of age in the late 1970s and 1980s, "the AIDS Generation," are continuing to mature such that further efforts must be enacted to meet the multidimensional nature of these men's physical, mental, and sexual health needs.