Negative life stressors such as childhood trauma and adult physical and sexual violence are prevalent among HIV-infected (HIV+) women [1–5]. These stressors increase susceptibility to mood and anxiety disorders [6–8] and contribute to perturbations in cognition and brain functioning [9,10]. Among HIV+ women, psychological risk factors (PRFs), including perceived stress, anxiety, posttraumatic stress, and depressive symptoms, are associated with deficits in verbal learning, memory, and attention [11–14]. Cross-sectional results from the Women's Interagency HIV Study (WIHS, n = 1505) showed an interaction between PRFs and HIV status, such that perceived stress and anxiety were more strongly associated with deficits in learning and memory among HIV+ compared with HIV− women. By contrast, depressive symptoms were associated with a similarly lower level of cognitive performance in HIV+ and HIV− women. This pattern of behavioral effects suggests that the neurobiological effects of PRFs on cognition differs between HIV+ and HIV− women, potentially through differences in stress responsivity and immune function. Stress, posttraumatic stress disorder (PTSD), and depression influence the adaptive immune response in HIV+ women, but stress may have a stronger influence than depression because stress is more strongly associated with regulatory mechanisms necessary to maintain immune cell homeostasis  which may impact brain homeostasis . Consistent with that view, our neuroimaging studies in the WIHS suggest that HIV, perceived stress and posttraumatic stress, individually and in combination, affect the structure and function of the prefrontal cortex, regions dense in receptors that bind to the stress hormone, glucocorticoids [17,18].
PRFs and cognitive performance may change over time in HIV+ individuals. Understanding the dynamic nature of these associations over time is important to determine the reliability of associations across successive time-points and to determine whether associations become weaker or stronger over time, or show the same magnitude over time. We sought to examine the interactive associations between HIV and PRFs on cognitive functioning over time in a large cohort of women. Here we present the first series of longitudinal analyses examining these interactions in the WIHS cohort across three cognitive assessments conducted over a 4-year period. Given our previous cross-sectional results [12,14], we hypothesized that the negative effect of PRFs on cognition would be greater in the context of HIV. Moreover, given our cross-sectional findings, we expected that perceived stress and posttraumatic stress would exacerbate HIV-associated cognitive compromise particularly for verbal memory and this relationship would become stronger over time [13,17,18].
Participants were enrolled in the WIHS, a longitudinal, multisite cohort study of the natural and treated history of HIV+ and HIV− women (http://wihshealth.org). Study enrollment occurred in two waves. The first wave occurred between October 1994 and November 1995 and the second between October 2001 and September 2002 from six sites (Brooklyn, Bronx, Chicago, District of Columbia, Los Angeles, and San Francisco). Detailed information regarding recruitment procedures and eligibility criteria have been previously published [19,20].
Primary predictor variables
Concurrent with the neuropsychological test battery, questionnaires were administered measuring perceived stress, PTSD symptoms, and depressive symptoms. Stress was measured with the Perceived Stress Scale (PSS-10), a 10-item scale that assesses the degree to which life situations in the previous month are evaluated as unpredictable, uncontrollable, and overloaded (Likert scale, 0 = never, 4 = very often) [21,22]. Consistent with our previous work [14,17,18], the PSS-10 was dichotomized and considered to be higher when scores were in the top tertile (present sample ≥20 points) and lower when in the bottom two tertiles (<20 points). PTSD symptoms were measured with the PTSD Checklist-Civilian version (PCL-C), a 17-item measure of PTSD symptoms (re-experiencing, avoidance, hyperarousal) as defined by the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) . As in our previous work , probable PTSD was defined as meeting DSM-IV symptom criteria in the previous month (≥1 B item – re-experiencing, ≥3 C items – avoidance, and ≥2 D items – arousal) and the total severity score more than 44. Depressive symptoms were measured with the Center for Epidemiological Studies Depression (CES-D) scale. Elevated depressive symptoms in the past 2 weeks was defined using a standard cutoff score of 16 [24,25] which we have also used in our previous work [12,17,26].
Beginning in 2009, certified study personnel administered three longitudinal neuropsychological assessments to WIHS participants biennially over a 4-year period. The cognitive domains included learning and memory (primary outcomes of interest given previous cross-sectional studies [12–14,17,18]), attention, executive function, fluency, psychomotor speed, and motor skills. Table 1 provides the specific tests and outcomes used to assess each domain. Following methods used in other large HIV cohort studies [11–14], demographically adjusted T-scores were derived for each individual outcome adjusting for age, years of education, Wide Range Achievement-3 reading subtest (measure of premorbid intellect), race (African-American vs. not), ethnicity (Hispanic vs. not), and number of times the test had been administered in WIHS. Prior to the creation of T-scores, all timed outcomes were log transformed to normalize the distributions and then reverse scored so that higher scores equated to better performance across all domains. For each domain, a composite T-score was derived by averaging the T-scores for domains with at least two outcomes. If only one test in a domain was completed, the T-score for that test was used. A global neuropsychological composite T-score was derived for individuals who had T-scores for at least four out of six cognitive domains.
A series of mixed-effects regression models (MRM) were used to examine whether PRFs altered the pattern of neuropsychological performance (domain-specific and global cognitive T-scores) for HIV+ and HIV− women. Temporal ordering was structured into the analysis by the nature of the self-reported questionnaires used. For example, the PSS-10 and PCL-C assess stress and PTSD symptoms in the past month, whereas the CES-D assesses depressive symptom in the past 2 weeks. MRMs were selected to handle the repeated measurements of individuals over time and the nesting of individuals within site. Three primary sets of analyses were conducted – one for each of the three PRFs (PSS-10, PCL-C, and CES-D) which was done to avoid the issue of multicollinearity between measures (correlations ranged between 0.65 and 0.75). For each set of analyses, the primary predictor variables included the PRFs (time-varying predictor), HIV-serostatus, time, and all two-way and three-way interactions. Higher order interactions with nonsignificant P values (based on an alpha of P ≤ 0.05) were dropped one at a time in order of decreasing P value size. If there were no significant interactions with time, the average effects of the PRF and HIV-serostatus were also reported (Supplemental Tables 1, 2, and 3, http://links.lww.com/QAD/B151 for all final MRM models). All analyses included a standard set of covariates  including wave of enrollment (1994–1995, 2001–2002), self-reported annual household income (≤$12 000, >12 000, and missing), harmful alcohol use (>seven drinks/week or ≥four drinks in one sitting), smoking status (current refers to within the past week, former, never), marijuana use, and crack, cocaine, and/or heroin use (recent refers to within 6 months of the most recent WIHS visit, former, never), psychiatric antidepressant/antipsychotic medication (0, 1, or 2 medications), and positive hepatitis C (HCV) antibody. Observations were trimmed in which the studentized residuals were more than |4.5| to ensure effects were not driven by extreme values (<1% of observations for only motor skills and speed). When the interaction between HIV serostatus and a PRF were significant on a domain, planned analyses of HIV+ women only were conducted to examine interactions between PRFs and a standard set  of HIV-related characteristics including current HIV RNA (undetectable, <10 000 copies/ml, ≥10 000 copies/ml; determined using COBAS AmpliPrep/COBAS TaqMan HIV-1 Test; Roche Molecular Systems, Branchburg, New Jersey, USA; Oct 2008 through March 2011 sensitive to 48 copies/ml; April 2011 to present sensitive to 20 copies/ml), nadir and current CD4+ cell count (<200, 200–500, >500), reported clinical AIDS diagnosis, years on antiretroviral therapy, proportion of total WIHS visits with undetectable HIV RNA, cart refers to combination antiretroviral therapy (cART) use and adherence (cART use+≥95 adherence, cART use+<95% adherence, no cART), and current efavirenz (Bristol-Myers Squibb Company and Gilead Sciences LLC, Princeton NJ) use because of documented neuropsychological side effects. All analyses were conducted in SAS version 9.4 (SAS Institute Inc., Cary, North Carolina, USA). Significance was set at P less than 0.05 two-tailed.
Measures of neuropsychological performance and concurrent PRFs were available for 946 WIHS participants (646 HIV+ and 300 HIV− women) (Table 2). HIV+ women were significantly but slightly older, more likely to be HCV positive, and reported more antidepressants/antipsychotics use than HIV− women (P < 0.05). HIV+ women were also less likely to engage in recent heavy alcohol use as well as recent marijuana use compared with HIV− women (P < 0.05). All factors were included as covariates in the primary analyses except age which was accounted for in the creation of the T-score.
Longitudinal patterns of PSS-10, PCL-C, and CES-D were similar for HIV+ and HIV− women (Fig. 1). Specifically, among HIV+ women, 55% had PSS-10 scores in the bottom two tertiles (<20 points) at all three NC visits, 36% had PSS-10 scores in the top tertile (≥20 points) at one or two visits, and 9% had PSS-10 in the top tertile at all three visits compared with 53, 37, and 9% among HIV− women. For PCL-C, 27% of HIV+ and 27% of HIV− had probable PTSD at one or two visits; 5% of HIV+ and 5% of HIV− had probable PTSD at all three visits. Among HIV+ women, 32% had elevated CES-D at one or two visits and 12% at all three visits compared with 32 and 10% among HIV−women.
Separate and interactive effects of HIV-serostatus and psychological risk factors on neuropsychological performance
Verbal fluency was the only cognitive domain in which the magnitude of change in performance over time depended on the combined influence of HIV-serostatus and stress or PTSD (P < 0.05; Fig. 2). For both the PSS-10 and PCL-C, the PRF by time interaction was significant for HIV+ (P < 0.05) but not HIV− women (P > 0.37). Restricting the follow-up to HIV+ women, higher PSS-10 [B (unstandardized beta) = −0.7, SE (standard error) = 0.3, P = 0.02] and PTSD (B = −0.9, SE = 0.4, P = 0.02) were associated with a greater decline in performance over time compared with lower PSS-10 (B = −0.3 SE = 0.2, P = 0.07) and no PTSD (B = −0.4, SE = 0.2, P = 0.40). Essentially, the effect of PSS-10 and PCL-C is not apparent until 4 years. There was no cognitive domain in which the magnitude of change in performance over time depended on the combined influence of HIV-serostatus and depressive symptoms.
Regardless of time, performance on the two primary domains of interest – verbal memory and learning – depended on the combined influence of HIV-serostatus and stress or PTSD (Fig. 3). Across time points, higher PSS-10 was associated with lower performance on memory among HIV+ (B = −1.3, SE = 0.5, P = 0.009) but not HIV− women (B = 0.4, SE = 0.7, P = 0.59). Across time points, PTSD associated with lower performance on both learning (B = −2.7, SE = 0.6, P < 0.0001) and memory (B = −2.4, SE = 0.6, P < 0.0001) among HIV+ but not HIV− women (P > 0.31). Although PTSD was associated negatively with executive function in both HIV+ (B = −1.1, SE = 0.4, P = 0.01) and HIV− women (B = −2.8, SE = 0.6, P < 0.0001), the magnitude of the association was greater among HIV− compared with HIV+ women (P = 0.04). In addition, performance on attention/working memory depended on the combined influence of HIV-serostatus and CES-D (P = 0.01). On average, elevated depressive symptoms were associated with lower performance among HIV− (B = −2.4, SE = 0.7, P < 0.001) but not HIV+ women (B = −0.7, SE = 0.5, P = 0.12).
Regardless of time or HIV-serostatus, PRFs were associated with lower performance on a number of domains. On average, higher PSS-10 was associated with lower performance on global function (B = −0.9, SE = 0.02, P < 0.0001), verbal learning (B = −1.2, SE = 0.04, P = 0.004), attention/working memory (B = −1.1, SE = 0.04, P = 0.004), executive function (B = −1.1, SE = 0.03, P < 0.0001), and psychomotor speed (B = −1.4, SE = 0.3, P < 0.0001). On motor function, performance improved over time with lower PSS-10 (B = 0.7, SE = 0.3, P = 0.02) compared with higher PSS-10 (B = −0.8, SE = 0.5, P = 0.17). A similar, but slightly stronger, pattern was noted on the PCL-C. Across time points, PTSD was associated with lower performance on global function (B = −1.4, SE = 0.2, P < 0.0001), attention/working memory (B = −2.4, SE = 0.5, P < 0.0001), psychomotor speed (B = −1.8, SE = 0.3, P < 0.0001), and motor function (B = −1.2, SE = 0.5, P = 0.009). For the CES-D, elevated depressive symptoms were associated with lower performance on global function (B = −1.4, SE = 0.2, P < 0.0001), memory (B = −1.4, SE = 0.4, P = 0.001), executive function (B = −1.6, SE = 0.3, P < 0.0001), psychomotor speed (B = −1.4, SE = 0.3, P < 0.0001), verbal fluency (B = −1.0, SE = 0.3, P = 0.002), and motor function (B = −2.0, SE = 0.4, P < 0.0001) across time points.
In subanalyses among HIV+ women, HIV-related characteristics did not moderate the association of PSS-10 on verbal memory. However, current viral load moderated the effects of PTSD on both verbal learning (P = 0.04) and verbal memory (P = 0.03); the negative association of PTSD on verbal learning and verbal memory was only present when women had a detectable HIV RNA (Fig. 4). In addition, cART use/adherence (P = 0.005) and the proportion of virally suppressed visits in WIHS (P = 0.04) moderated the association between PTSD and verbal learning. Specifically, the negative association of PTSD with verbal learning was only present when women were not receiving cART or when women on cART reported non adherence (<95% adherence). Finally, a greater proportion of visits with viral suppression was associated with better verbal learning (P = 0.001) but only when women did not have PTSD.
In this longitudinal study, we provide evidence consistent with our cross-sectional findings  that elevated perceived stress and PTSD symptoms in the context of HIV are linked to alterations in verbal abilities (learning, memory, fluency) but not to other cognitive domains measured in this study. In individuals with HIV, the presence of perceived stress or PTSD symptoms compared with the absence of these factors are associated with a greater decline in verbal fluency over time and persistent negative effects on verbal learning and memory. Our results suggest that the effects of perceived and PTSD symptoms on fluency performance may be more delayed and require the occurrence of chronic periods of stress, whereas verbal learning and memory may be more impacted by acute periods of stress in the context of HIV. Our findings suggest that perceived stress and PTSD symptoms, more so than depressive symptoms, may contribute to different patterns of detrimental neuropsychological performance (stably declining or persistent impairment) among HIV+ individuals . Moreover, our findings suggest that perceived stress and PTSD symptoms are a possible treatment target for improving verbal abilities among HIV+ women.
There are a number of possible mechanistic explanations for perceived stress and PTSD symptoms negatively influencing verbal abilities in the context of HIV. One possibility is that HIV and these PRFs may individually or in combination impair cognition in HIV+ women through effects on the hippocampus and prefrontal cortex. Neuroimaging and postmortem studies show that alterations in the hippocampus and prefrontal cortex contribute to memory deficits among HIV+ individuals [28–30] and stress may compound these effects on the prefrontal cortex [17,18]. In addition, alterations in the hypothalamic–pituitary–adrenal (HPA) axis, the key mediator of the stress response system, may mediate the relationship between these PRFs and memory in HIV+ individuals. Acute and chronic stressors alter the HPA axis, leading to neuronal atrophy in the prefrontal cortex [31,32]. In addition, HIV+ individuals show disruptions in the HPA axis including elevated basal cortisol levels [33–37]. Thus, both HIV and chronic stress are associated with disruption in HPA axis activation including elevated basal cortisol level, and the combination of both HIV and stress may have additive or multiplicative effects on HPA dysregulation.
Glucocorticoid receptor function may also play an important role in stress-related memory impairments in HIV+ women. Chronic stress reduces glucocorticoid receptor expression in the hippocampus and frontoparietal cortex, although these studies were in men [38,39]. Animal studies demonstrate the importance of glucocorticoid receptor function to memory. For example, intracellular trafficking of the glucocorticoid receptor is diminished in the hippocampus of aged rats , especially in those with hippocampal-related memory impairments . Cumulative overexposure to glucocorticoids is also associated with age-related prefrontal impairments in rats . Thus, glucocorticoid receptor dysfunction and altered cortisol levels combined could predispose HIV+ women to stress-associated psychiatric disorders and memory impairment linked to glucocorticoid resistance.
Although perceived stress, PTSD symptoms, and depressive symptoms were negatively associated with global neuropsychological function, unlike perceived stress and PTSD symptoms, depressive symptoms did not interact with HIV-serostatus on verbal abilities. Rather, HIV-serostatus moderated the effects of depressive symptoms in the domain of attention/working memory. However, on average, elevated depressive symptoms were associated with worse performance among HIV−, but not HIV+, women. Important to note is that, irrespective of depression symptoms, the attention/working memory performance of HIV+ women was worse than HIV− women without depressive symptoms and similar to HIV− women with depressive symptoms suggesting that the effects of HIV infection on performance overwhelm any negative effect of depressive symptoms. Although it is unclear what drives the pattern of effects, our findings give rise to the greater importance of targeting perceived stress and PTSD symptoms among HIV+ compared with HIV− individuals.
In HIV+ women, perceived stress and PTSD symptoms may have a stronger influence on HPA axis regulation and immune function compared with depressive symptoms. Although CD4+ cell count is associated with both higher self-reported perceived stress, worry, and depressive symptoms, regulatory T cells are associated with higher self-reported perceived stress and worry but not depressive symptoms . Thus, although both stress, worry, and depression appear to be associated with the overall adaptive immune response in HIV+ women, stress and worry appear to be more strongly associated with regulatory mechanisms essential to maintain immune cell homeostasis  which may impact brain homeostasis .
Among HIV-related clinical characteristics, the strongest modifiers of the effect of PRFs on verbal learning and memory were current HIV RNA, cART use and adherence, and the proportion of time a woman achieves viral suppression over time. Specifically, the associations of PTSD symptoms with learning and memory were most pronounced among women with detectable HIV RNA and women who were not on cART nor adherent to their cART regimen. These findings are consistent with animal studies demonstrating that high levels of glucocorticoid exposure augment the negative effects of the neurotoxic viral protein, gp120, in the hippocampus through release of toxins by microglia [43,44].
The primary limitation is that we utilized self-report screeners of PTSD and depression rather than a structured diagnostic interview. Although studies indicate the CES-D and PCL-C are valid and reliable markers of mental health disorders, we have not validated scores in the WIHS. It is possible that the CES-D and PCL-C inventories may overestimate the number of individuals meeting criteria for a clinical diagnosis. Finally, our symptom-based measures may capture many mechanistic pathways linking mental health to cognition including inflammation and disordered sleep. Current and lifetime psychiatric diagnostic data are now available in the WIHS HIV+ women which will allow us to further examine whether associations we identified between mental health symptom based screening measures and NC performance are similar. Longer term follow-up is also needed to further determine the predictive nature of PRFs on cognition in HIV+ and HIV− women. Finally, other cognitive domains including social cognition may be impacted by PRFs in HIV+ and HIV− women; however, other domains such as visuospatial abilities and emotion processing were not part of the neurocognitive test battery administered in the WIHS.
In sum, HIV+ women are vulnerable to deficits in verbal abilities including verbal learning and memory. High perceived stress and PTSD symptoms, but not depressive symptoms, appear to be consistently linked to worse performance on these domains in the context of HIV. Stress reduction and posttraumatic stress prevention and treatment programs could help improve and maintain learning and memory function in women living with HIV and in turn may contribute to optimal HIV treatment adherence and viral suppression.
L.H.R.'s effort was supported by Grant Number 1K01MH098798-01 and V.G.V.'s by K24MH098759, each from the National Institute of Mental Health (NIMH). Data in this article were collected by the Women's Interagency HIV Study (WIHS). The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH). WIHS (Principal Investigators): UAB-MS WIHS (Michael Saag, Mirjam-Colette Kempf, and Deborah Konkle-Parker), U01-AI-103401; Atlanta WIHS (Ighovwerha Ofotokun and Gina Wingood), U01-AI-103408; Bronx WIHS (Kathryn Anastos), U01-AI-035004; Brooklyn WIHS (Howard Minkoff and Deborah Gustafson), U01-AI-031834; Chicago WIHS (Mardge Cohen and Audrey French), U01-AI-034993; Metropolitan Washington WIHS (Seble Kassaye), U01-AI-034994; Miami WIHS (Margaret Fischl and Lisa Metsch), U01-AI-103397; UNC WIHS (Adaora Adimora), U01-AI-103390; Connie Wofsy Women's HIV Study, Northern California (Ruth Greenblatt, Bradley Aouizerat, and Phyllis Tien), U01-AI-034989; WIHS Data Management and Analysis Center (Stephen Gange and Elizabeth Golub), U01-AI-042590; Southern California WIHS (Joel Milam), U01-HD-032632 (WIHS I–WIHS IV). The WIHS is funded primarily by the National Institute of Allergy and Infectious Diseases (NIAID), with additional cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), the National Institute on Drug Abuse (NIDA), and the National Institute on Mental Health (NIMH). Targeted supplemental funding for specific projects is also provided by the National Institute of Dental and Craniofacial Research (NIDCR), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute on Deafness and other Communication Disorders (NIDCD), and the NIH Office of Research on Women's Health. WIHS data collection is also supported by UL1-TR000004 (UCSF CTSA) and UL1-TR000454 (Atlanta CTSA).
Author contribution: L.H.R. and P.M.M. conceived the study idea. L.H.R. takes responsibility for the integrity of the statistical analyses and wrote the first draft of the article. All authors contributed to the writing of the manuscript and approved the final version of the article.
Conflicts of interest
V.G.V. has served as a consultant to Merck and ViiV healthcare on topics related to HIV and aging.
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