There may be several explanations for this discrepancy between expected and observed results. While in vitro studies predict potent immune suppression, they examine isolated cells in an artificial culture condition that may not reflect the more complex interactions that occur during antigen-presentation in vivo. The concentrations of THC and exposure periods that are studied in vitro and in animal models may similarly differ from those occurring at the cellular level in the peripheral blood, tissues and lymphoid organs of MJ smokers. While our subjects are characterized as moderate to heavy habitual MJ users, it is difficult to directly compare the transient exposures that occur from smoking with the continuous high-level exposure that occurs during in vitro cultures. Peak THC concentrations in the blood of MS are reported in the range of 30–300 ng/ml, but quickly fall to much lower levels within 15– 30 minutes after smoking . In contrast, in vitro studies often examine the effects of chronic THC exposure that lasts for days and are in the range of 1–10 μM . In order to assure uniform and significant exposure conditions we admitted patients and had them smoke three MJ cigarettes on the day of vaccination and another the following morning. However, even in this setting, the inhalation of mg quantities of THC may not recapitulate the systemic administration of 4–10 mg/kg dosing that is often administered in mouse models. Furthermore,equipment for growing weed while models examine the effects of purified THC, MJ smoke exposes the user to scores of cannabinoids and hundreds of other inhaled substances with potentially disruptive or even counteracting effects that have not been studied and are hard to recapitulate with controlled exposure models.
As our study examined habitual MJ users, it is also possible that long term exposure to MJ may allow for compensatory mechanisms or tolerance to develop and therefore mask the potentially deleterious effects observed following acute exposure to THC. Redundancy of regulatory pathways and maintenance of immune homeostasis are key features of human immunity and receptor signaling. Similar to our findings in habitual MJ smokers, the chronic exposure of male rhesus macaques to THC for up to 12 months was not associated with altered immune cell subsets or function in control animals or evidence of increased morbidity or mortality in animals exposed to simian immunodeficiency virus infection . In conclusion, this prospective analysis of immune responses to HBV vaccination in healthy naive NS and MS failed to identify a significant difference with respect to either the frequency or nature of the vaccine response. However, the small sample size employed here was based on the assumption that habitual MJ use would have a rather profound effect on the generation of adaptive immunity. That underlying assumption appears to be incorrect. Further, our goal of enrolling up to 20 subjects per group in order to detect more subtle differences was impaired by a number of factors including the changing frequency of routine HBV vaccination in the general population, the stringent nature of our inclusion and exclusion criteria which excluded many subjects that appeared to be eligible at preliminary screening, and the difficulty in retaining subjects in a rather demanding and protracted protocol. As such, while our findings argue that the potent immunosuppression demonstrated by in vitro models and mouse studies does not likely represent the biologic impact of habitual MJ use, it remains possible that more subtle differences between our two study groups exist but could not be detected.
Ongoing clinical research carried out in active MS is needed in order to better interpret the reason for this discrepancy and to assess the presence or absence of clinically important health effects associated with MJ smoking.HIV-infected women may be more vulnerable to developing neurocognitive impairment than HIV+ men . Among HIV studies showing male/female NCI differences, some demonstrate greater impairments in females than males overall, whereas others demonstrate male/female differences in the pattern of NCI1. For example, in a large study combining the two longest-running U.S. multisite, longitudinal studies of HIV progression in the U.S., the Women’s Interagency HIV Study and the Multi-center AIDS Cohort Study , HIV was associated with alterations in the pattern of sex differences in executive function , attention, psychomotor speed, and motor function1 . Performance was consistently worse among HIV+ women versus HIV+ men even after adjusting for HIV related characteristics. This female-specific vulnerability may be due to biological influences , sociodemographics, mental health factors or disorders. Here we examine whether associations between MDD and NCI differs between men and women as MDD is the most common neuropsychiatric complication among people with HIV and is more prevalent than in the general U.S. population The only nationally representative study among PWH reported an 18.5% 12-month prevalence of MDD which is two- to three-times higher than the general U.S. population. Prevalence estimates in U.S. cohort studies are similarly high. In the WIHS, current MDD via diagnostic interview was 20% and lifetime MDD was 32% versus 10% and 23% nationally. In cognitive studies, about 30% of WIHS women report elevated depressive symptoms,an estimate about 10% higher than other large-scale cohort studies of healthy midlife women. Additionally, HIV+ women often have higher rates of depression and more depressive symptoms than HIV+ men.
It cannot be assumed; however, that the magnitude of the male/female depression difference will be similar among PWH, due to greater depression severity in sexual minority men versus heterosexual men. The presence and/or severity of depression may contribute to the greater cognitive vulnerability in HIV+ women versus HIV+ men. Among HIV-uninfected individuals, depression severity is commonly associated with poorer episodic memory, executive function, psychomotor speed, and attention27. Across cross-sectional studies in PWH, the domains most reliably associated with depression are psychomotor speed , executive function , learning and memory , and motor function followed by attention and working memory . Longitudinal WIHS studies demonstrate associations between depression and psychomotor speed , executive function , memory , motor function , and fluency. In the MACS, depression is also associated with psychomotor speed and executive function ; however, other domains have not been examined. It remains unknown whether these associations differ by sex. We examine combined and independent associations between three factors known to influence NCI—HIV, biological sex , and depression. Associations were analyzed in the same large sample of MACS men and WIHS women where we examined HIV by sex interactions on NCI1 . Biological mechanisms that may contribute to sex differences in the depression-NCI relationship include, among others, sex differences in neuroinflammation, dopamine transmission,grow tables 4×8 genetics and the HPA axis. Given our prior work demonstrating an HIV by sex interaction on NCI 1 and given that depression influences many of those domains, we hypothesized that depression would predict greater HIV-related NCI in females versus men, particularly in attention, executive function, and motor function. Longitudinal data collected through September 2016 were extracted from WIHS and MACS in August 2017. In brief, the WIHS was established in August 1994 at 6 clinical sites . The MACS was established in 1984 at 4 clinical sites . MACS data were limited to participants recruited during the most recent enrollment period , as those participants more similar to WIHS participants in race and socioeconomic status38 . For the present analysis, there were 3,766 WIHS participants who enrolled in the study during 1994–1996 or 2001–2002 . Based on these numbers, we drew identical numbers of HIV+ and HIV- men from 1735 individuals enrolled in the MACS1 . To be included, all participants completed four tests administered by both cohorts––TMT-A and TMT-B, SDMT, Comalli Stroop color-word test39, and GP. We analyzed data collected by WIHS from May 2009-September 2016 and by MACS from October 2001-May 2014 of which 97% of all selected visits had complete data. We also limited the tests to the first five years of testing as men had more tests administered versus women, and the restricted time span limited the differences between cohorts in neuropsychological test exposure. Participants were excluded based on history of toxoplasmosis, CNS lymphoma, cryptococcal meningitis or cryptococcal infection , progressive multifocal leukoencephalopathy, AIDS-defining or other dementia, transient ischemic attack/stroke, use of antiseizure/antipsychotic drugs, head injury with loss of consciousness , and preference for Spanish as first language.
Neuropsychological tests included measures of: psychomotor speed/attention ; executive function ; and motor function . Outcomes for all tests was time to completion except SDMT which was total correct. All timed outcomes were log transformed to normalize distributions and reverse scored so higher values represented better performance. Demographically-adjusted T-scores were derived for each outcome based on the entire HIV- population with impairment defined as T-score < 40. A number of covariates were included based on prior WIHS and MACS studies1,29,30 including age , race/ethnicity, income, education , sexual orientation, heavy alcohol use classified using NIAAA standards , recreational drug use since the previous visit , cigarette smoking, HIV RNA and CD4 Tcell counts, antiretroviral therapy, nadir pre-HAART CD4+ T-cell count, ever having clinical AIDS diagnosis, and count of neuropsychological test exposures. Generalized linear mixed models were conducted to assess combined and separate associations of depression , biological sex , and HIV-serostatus on NCI. The GLMM include a random-subject effect which accounts for within-person correlation of the repeated assessments . Primary initial predictors included depression, HIVserostatus, sex, all two-ways, and the three-way interaction. Of particular interest was the three-way interaction. A significant three-way interaction would indicate that depression exacerbates the interactive associations between HIV-serostatus and sex on NCI. Nonsignficant three-way interactions were removed from the models so that we could assess whether depression exacerbates a general: 1) female versus male difference and/or 2) HIV-serostatus difference on NCI. If none of the two-way interactions were significant they were removed from the models so that we could examine whether depression, irrespective of HIVserostatus and sex, predicts NCI. All models adjusted for race , ethnicity , education and time-varying factors including age, heavy alcohol, marijuana, cocaine/crack use , smoking , income , time from enrollment, and number of prior neuropsychological testing administrations . In HIV only analyses, models also adjusted for the following time-varying factors: antiretroviral use, log10-transformed HIV RNA, current CD4 count , CD4 nadir <200, and prior AIDS diagnosis. Odds ratios and 95% confidence intervals are presented and predicted probabilities from models including all two- and three-way interactions are plotted for visual interpretation. Participants included 858 HIV+ and 562 HIV- individuals, ranging in age from 20–66 years, with 67% non-Hispanic, African American and 20% Hispanic per group. Table 1 provides socio-demographic, behavioral, and clinical characteristics stratified by sex, HIV-serostatus, and depression status. Groups differed on numerous factors during visits categorized as depressed versus not depressed. Depressed individuals had lower income levels and were more likely to have increased alcohol, marijuana, and cocaine use, and more likely to be current/former smokers. Across study duration, depression was reported by HIV+ and HIV- women on fewer visits versus HIV+ and HIV- men . Similarly, men were more likely to ever be depressed regardless of HIV-serostatus than women . In the MACS, 50% of HIV+ men reported ever being depressed versus 47% of HIVmen; 3% difference . In the WIHS, 34% of HIV+ women reported ever being depressed versus 25% of HIV- women; 9% difference . Among PWH, the difference between men and women ever being depressed was 16% . Similarly, among HIV- individuals the difference between men and women ever being depressed was 22% . To ensure the reversal of conventional rates of depression in men and women was not due to the higher rates of crack/cocaine in men, we re-ran the frequency of depression among those who never used crack/cocaine. In this subgroup, depression remained higher in men than women . Among PWH, depressed individuals were more likely to have higher plasma HIV RNA but the higher rates of depression among HIV+ men versus HIV+ women remained after controlling for HIV RNA . These data add to the growing body of evidence that in the era of effective antiretrovirals, factors other than HIV are at least as important, and often more important determinants of NCI, than HIV serostatus among HIV+ men and women. In 1420 HIV+ and HIV- adults, we demonstrated that HIV+ women with elevated depressive symptoms are at 5-times the odds of impaired performance on Stroop color-word [interference] versus both depressed HIV+ and HIV- men and HIV- women.