Thesis advisor: Tricia H. Burdo / Human immunodeficiency virus-associated peripheral neuropathy (HIVPN) continues to be a prevalent comorbidity of HIV infection, despite virologic control due to effective antiretroviral therapy (ART). Symptoms include bilateral tingling, numbness, and pain in distal extremities. Severity of symptoms is associated with a loss of intraepidermal nerve fiber density (IENFD) in the feet. Damage to the dorsal root ganglia (DRG) has also been observed in postmortem tissue analysis from patients with HIV-PN. Treatment options are limited due to a lack of understanding of the disease pathogenesis. Chronic monocyte activation and accumulation of macrophages in peripheral nervous system (PNS) tissues has been reported but few studies have directly demonstrated the role of monocyte/macrophage activation and traffic in the pathogenesis of HIV-PN. The central hypothesis of this thesis is that monocyte activation and traffic mediates PNS neuronal damage. We addressed this hypothesis in several ways. In chapter 2, we describe pathology seen in a rapid disease progression animal model of HIV-PN. We found that an early loss of IENFD preceded a loss of small diameter DRG neurons. In chapter 3, we associated DRG pathology with an accumulation of inflammatory macrophages surrounding DRG neurons. Increased monocyte traffic to the DRG was associated with severity of DRG pathology and with a loss of IENFD. In chapter 4, we directly tested the impact of monocyte traffic on DRG pathology by blocking leukocyte traffic with an anti-VLA-4 antibody, natalizumab. Blocking cell traffic reduced accumulation of macrophages in the DRG and improved pathology. Next we treated animals with methylglyoxal-bisguanylhydrazone (MGBG) to specifically target myeloid cells and reduce their activation. MGBG treatment improved DRG pathology and reduced accumulation of macrophages in tissues. Having demonstrated the role of monocyte traffic and activation, we aimed to identify signaling proteins and inflammatory proteins associated with PNS pathology. We found elevated monocyte chemoattractants in DRG tissue and elevated markers of monocyte activation in plasma that were associated with a loss of IENFD. Together, these studies demonstrate that systemic monocyte activation, macrophage accumulation in DRG tissue, and monocyte traffic plays a major role in SIV-PN pathogenesis. These studies provide novel insight into immune mechanisms that impact neuronal loss during SIV infection. Thus, modulating macrophage activation and reducing monocyte traffic may have therapeutic benefits to patients suffering from or at risk of developing HIV-PN. / Thesis (PhD) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

Objective: This study aimed to evaluate the association between the intensity of menopausal symptoms and highly active antiretroviral therapy (HAART) adherence in middle-aged women with human immunodeficiency virus (HIV) infection. Methods: In this cross-sectional study, 313 Peruvian women with HIV infection (age 40-59 years) were surveyed and classified as adherent or non-adherent to HAART based on the Antiretroviral Treatment Adherence Evaluation Questionnaire. The intensity of menopausal symptoms was assessed with the Menopause Rating Scale, and categorized as none, mild, moderate, and/or severe. Age, sexual orientation, used HAART scheme, time since HIV diagnosis, menopausal status, risk of depression, and presence of comorbidities were also assessed. Poisson generalized linear models with robust variance were performed in order to estimate crude prevalence ratios (PRs) and adjusted PRs using statistical (a1PR) and epidemiological criteria (a2PR). Results: A total of 19.9%, 32.6%, and 15.0% of all women presented mild, moderate, and severe menopausal symptoms, respectively. Overall, 70.6% women were non-adherent to HAART. The probability of non-adherence was higher in women with mild, moderate, and severe symptoms as compared to asymptomatic women in the non-adjusted model (PR: 1.79, 95% confidence interval [CI]: 1.39–2.29; PR: 1.76, 95% CI: 1.38–2.23; and PR: 2.07, 95% CI: 1.64–2.61, respectively) and the adjusted model. Conclusion: The severity of menopausal symptoms was associated with HAART non-adherence in HIV-infected middle-aged women. / Revisión por pares

Indiana University-Purdue University Indianapolis (IUPUI) / Study 1: Background: Insomnia may be a risk factor for cardiovascular disease in HIV (HIV-CVD); however, mechanisms have yet to be elucidated. Methods: We examined cross-sectional associations of insomnia symptoms with biological mechanisms of HIV-CVD (immune activation, systemic inflammation, and coagulation) among 1,542 people living with HIV from the Veterans Aging Cohort Study (VACS) Biomarker Cohort. Past-month insomnia symptoms were assessed by the item, “Difficulty falling or staying asleep?,” with the following response options: “I do not have this symptom” or “I have this symptom and…” “it doesn’t bother me,” “it bothers me a little,” “it bothers me,” “it bothers me a lot.” Circulating levels of the monocyte activation marker soluble CD14 (sCD14), inflammatory marker interleukin-6 (IL-6), and coagulation marker D-dimer were determined from blood specimens. Demographic- and fully-adjusted (CVD risk factors, potential confounders, HIV-related factors) regression models were constructed, with log-transformed biomarker variables as the outcomes. We present the exponentiated regression coefficient (exp[b]) and its 95% confidence interval (CI). Results: For sCD14 and D-dimer, we observed no significant associations. For IL-6, veterans in the “bothers a lot” group had 15% higher IL-6 than veterans in the “I do not have this symptom” group in the demographic-adjusted model (exp[b]=1.15, 95%CI=1.02-1.29, p=.03). This association was nonsignificant in the fully-adjusted model (exp[b]=1.07, 95%CI=0.95-1.19, p=.25). Conclusion: We observed little evidence of relationships between insomnia symptoms and markers of biological mechanisms of HIV-CVD. Other mechanisms may be responsible for the insomnia-CVD relationship in HIV; however, future studies with comprehensive assessments of insomnia symptoms are warranted. Study 2: Background: While insomnia has been identified as a potential risk factor for cardiovascular disease in HIV (HIV-CVD), research on the underlying pathophysiological mechanisms is scarce. Methods: We examined associations between 0-to-12-week changes in sleep disturbance and the concurrent 0-to-12-week changes and the subsequent 12-to-24-week changes in markers of systemic inflammation, coagulation, and endothelial dysfunction among people living with HIV (n = 33-38) enrolled in a depression clinical trial. Sleep disturbance was measured using the Pittsburgh Sleep Quality Index. Inflammatory markers interleukin-6 (IL-6) and C-reactive protein (CRP) and coagulation marker D-dimer were determined from blood specimens; endothelial dysfunction marker brachial flow-mediated dilation (FMD) was determined by ultrasound. 0-to-12-week variables were calculated as 12-week visit minus baseline, and 12-to-24-week variables were calculated as 24-week minus 12-week. We constructed multivariate linear regression models for each outcome adjusting for age, sex, race/ethnicity, Framingham risk score, and baseline depressive symptoms. Results: We did not observe statistically significant associations between 0-to-12-week changes in sleep disturbance and 0-to-12-week or 12-to-24-week changes in IL-6, CRP, D-dimer, or FMD. However, we did observe potentially meaningful associations, likely undetected due to low power. For 0-to-12-weeks, every 1-standard deviation (SD) increase, or worsening, in the sleep disturbance change score was associated with a 0.41 pg/mL and 80 ng/mL decease in IL-6 and D-dimer, respectively. For 12-to-24-weeks, every 1-SD increase in sleep disturbance change score was associated with a 0.63 mg/L, 111 ng/mL, and 0.82% increase in CRP, D-dimer, and FMD, respectively. Conclusion: We observed potentially meaningful, though not statistically significant, associations between changes in sleep disturbance and changes in biological mechanisms underlying HIV-CVD over time. Some associations were in the expected direction, but others were not. Additional studies are needed that utilize larger samples and validated, comprehensive assessments of insomnia.

The human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic has surpassed forty years with many medical advancements in prevention and treatment. Often believed to be at negligible or low risk by society at large, sexual minority women have remained understudied regarding their risk of HIV and other sexually transmitted infections (STIs), leaving their sexual health inadequately understood and supported in healthcare and social services. The sexual health of young South Asian sexual minority women, who are multiply minoritized due to their intersecting identities, has been entirely overlooked. This qualitative study aimed to understand the knowledge, attitudes, and practices of young South Asian sexual minority women as it pertains to their HIV/STI risk. Barriers and facilitators to accessing community-based sexual health supports and services were also investigated. A community-engaged approach was taken to develop this study in partnership with the Alliance for South Asian AIDS Prevention to investigate the HIV/STI risk context and sexual health needs of this group residing in the Greater Toronto Area. A maximum variation sampling strategy was used to recruit six young South Asian sexual minority women and semi-structured in-depth interviews were conducted to collect narrative data. Narrative analysis of the data found socio-cultural and structural influences which guide the HIV/STI risk context for this group. The participants illuminated an inadequate understanding of sexual health when engaging in sex with women, an overall low HIV/STI risk perception, barriers to adequate sexual healthcare and health promotion resources, and multiple minority stressors which impacted their access to safe sex. These findings have major implications for school-based sexual health education, medical training for healthcare practitioners, and sexual health support and services provided by community-based sexual health organizations in the Greater Toronto Area. / Thesis / Master of Public Health (MPH)

Cardiovascular disease (CVD) has become one of the commonest causes of comorbidity and mortality among People living with human immunodeficiency virus (HIV) (PLWH) on antiretroviral therapy (ART). Nearly 50% of PLWH are likely to have an increased risk of developing CVD, including coronary heart disease, cerebrovascular disease, peripheral artery disease and aortic atherosclerosis. Aside from the common risk factors, HIV infection itself and side effects of antiretroviral therapy contribute to the pathophysiology of this entity. Potential non-pharmacological therapies are currently being tested worldwide for this purpose, including eating patterns such as Intermittent fasting (IF). IF is a widespread practice gaining high level of interest in the scientific community due to its potential benefits such as improvement in serum lipids and lipoproteins, blood pressure (BP), platelet-derived growth factor AB, systemic inflammation, and carotid artery intima-media thickness among others cardiovascular benefits. This review will focus on exploring the potential role of intermittent fasting as a non-pharmacological and cost-effective strategy in decreasing the burden of cardiovascular diseases among HIV patients on ART due to its intrinsic properties improving the main cardiovascular risk factors and modulating inflammatory pathways related to endothelial dysfunction, lipid peroxidation and aging. Intermittent fasting regimens need to be tested in clinical trials as an important, cost-effective, and revolutionary coadjutant of ART in the fight against the increased prevalence of cardiovascular disease in PLWH. / Revisión por pares

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Pre-exposure prophylaxis (PrEP) access is increasing in Latin America. We explored PrEP use among Spanish-speaking, Hornet geosocial networking application users from Latin American countries with limited PrEP data via an online survey completed between December 2018 and February 2019. A total of 718 Hornet users from 10 countries were included, of whom 72.1% reported PrEP awareness. Few (5.6%) were currently taking PrEP, though 32.1% intended to take PrEP in the subsequent 6 months. PrEP awareness was lower in 18–25 year olds compared to 26+ (62.4% vs. 75.6%, aOR 0.67, [95% CI 0.46–0.97]), and higher among those living in larger versus smaller cities (74.4% vs. 58.8%, aOR 1.96, [95% CI 1.25–3.07]) or countries with at least partial versus no PrEP policy adoption (79.1% vs. 60.8%, aOR 2.20, [95% CI 1.56–3.12]). Intention to use PrEP was higher among PrEP-eligible respondents (51.8% vs. 29.6%, aOR 2.26, [95% CI 1.26–4.07]) and those recently tested for a sexually transmitted infection (35.4% vs. 25.5%, aOR 1.58, [95% CI 1.01–2.48]). Efforts to expand PrEP use in Latin America should focus on national PrEP policy adoption, and research should explore barriers to awareness and use among young men who have sex with men. / National Institute of Mental Health / Revisión por pares

INTRODUCTION With effective highly active antiretroviral therapy (HAART), individuals with human immunodeficiency virus (HIV) infection now enjoy life expectancies approaching those of uninfected individuals. Prolonged longevity has increased the prevalence of non-communicable comorbidities within the HIV patient population. HIV is a known independent risk factor for atherosclerotic cardiovascular disease (ASCVD), imparting a 1.5-2 -fold higher incidence of major adverse cardiovascular events (MACE) on infected patients. Deaths from ASCVD have increased as a result, despite a decline in total mortality. The Center of Excellence for HIV/AIDS care established a Cardiovirology Clinic (CvC) focused on providing primary and secondary preventative cardiovascular care to its patients. To date, there are no known data on the efficacy of such an intervention. We sought to define the performance of this care model for primary prevention. METHODS Unique CvC patients (n=68) with a treatment delivery window between September 1, 2017 to August 31, 2018 were identified through billing records. All patients were receiving HAART as prescribed by their infectious disease provider. Those with established ASCVD (n=10) were excluded from analysis to limit the study to primary prevention patients. We collected data on ASCVD risk factors (family history of premature ASCVD and personal histories of smoking, diabetes, hypertension [with degree of control], dyslipidemia, drug and alcohol use, and exercise) from the electronic health record. Body-mass index and systolic (SBP) and diastolic (DBP) blood pressures were also collected. Laboratory values including CD4 cell count, HIV-1 viral load, proteinuria, glomerular filtration rate, total cholesterol (TC), triglycerides (TG), and high (HDL) and low density (LDL) lipoprotein were included in the data collection. Estimates of 5-year risk of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or need for major revascularization was calculated using the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) equations. Patient data were de-identified. Two-tailed, paired T-testing was performed for each factor comparing the initial and most recent follow-up values. Significance was defined as p value <0.05. RESULTS Using univariate analysis, reductions in D:A:D risk (relative 32.01%, absolute 1.49%, p CONCLUSION In this initial assessment, treated HIV patients appeared to enjoy meaningful reductions in MACE risk through the preventive care they received in this clinic, suggesting that CvCs could be a partial solution to the growing ASCVD morbidity and mortality among HIV-infected individuals. Limitations of this study include a small patient population (n=58) (limiting us to univariate analyses) and short duration of follow up (≤ 1 year). Data collection will continue annually for 4 additional years. With increasing subject numbers, multivariate analyses to determine if components of ASCVD risk reduction show interactions, and which factors, interactions and interventions impart the greatest risk reduction, will be performed in improve the quality of care.

Follicular dendritic cells (FDCs) reside in the lymphoid follicles of the secondary lymphoid tissues (sLTs). Following the infection of an individual with human immunodeficiency virus type 1 (HIV-1), viral particles are trapped in massive quantities on the surfaces of FDCs. HIV-1 viral compartments are cell types or tissues between which there is a restriction of virus flow. Compartmentalization of HIV-1 creates numerous sites within the body in which the virus can undergo independent evolution, giving rise to a more diverse total viral population. Given the sessile nature of the FDC, I hypothesized that contrary to common assumptions, FDC-trapped HIV-1 is compartmentalized between different sLTs. Furthermore, given that FDC-trapped HIV-1 represents the major source of virus in the host, I postulated that this compartmentalization would likely impact the diversity of HIV-1 associated with the sLTs. I isolated FDCs, macrophages, and T cells from various sLTs, and sequenced cloned HIV-1 associated with these three cell populations. I subjected the resulting DNA and cDNA sequence data to phylogenetic and other statistical analyses. In support of my hypothesis, I demonstrate that both HIV-1 gp120 and pol sequences cloned from FDCs are compartmentalized between different sLTs. This compartmentalization is even apparent between lymph nodes taken from the same lymph node chain. One of the apparent effects of this compartmentalization is to significantly increase the viral genetic diversity in multiple sLTs when compared with diversity in a single sLT. It also appears that the selective pressures on HIV-1 differ among the sLTs. In addition, when proviruses isolated from macrophages from different sLTs were compared, it was also evident that there is compartmentalization of HIV-1 associated with this cell type as well. Finally, I demonstrate that HIV-1 isolated from an unfractionated population of cells from a single sLT, may be an inadequate representation of the total viral population in that sLT. Taken together, my data suggest that the nature of HIV-1 in the sLTs may be more complex than currently appreciated.

South Africa has the highest global burden of HIV/AIDS with over 7.9 million people living with HIV/AIDS. Women and girls bear a disproportionate burden of the disease, which is potentially driven by low levels of correct HIV knowledge and high levels of gender-based violence. Our study aimed to determine the factors that influence uptake of HIV testing among reproductive aged women between 15-49 years in South Africa. Data from the 2016 (N=8514) iteration of the Demographic and Health Survey was utilized. Our outcome variable was HIV testing (yes/no) and our predictor variables were age at first sex, highest educational level, marital status, and recent condom use. We conducted descriptive statistics, chi-square analysis and T-test for our categorical and continuous variables (age at first sex), respectively. We further conducted multiple logistic regression to determine predictors of HIV testing. Frequencies, mean age at first sex, p-values, odds ratios, and 95% confidence intervals with alpha set to 0.05 were reported. Of 6489 women included in the final analysis, 5915 (91.15%) of women had ever been tested for HIV, 4964 (76.50%) and 746 (11.50%) had secondary and higher education as their highest educational level The mean age at first sex for women who had ever tested for HIV was 17.55 + 2732.7 years compared to 17.17 + 3119.7 years for women who had never tested for HIV (P<0.0001). The majority of respondents were never married (N=3415,52.63%) and 1746 women (26.91%) were married. Women who used condom during the last sex were 2883 (44.43%) compared to 3606 (55.57%) women who did not. The relationship between marital status and HIV testing (P=0.0009) and condom use and HIV testing (P=0.0471) were all statistically significant. After adjusting for confounders, we found that women with primary education had a 44.4% decrease in the odds of HIV testing and women with no education had a 61% decrease, compared to women to women who had secondary education (OR = 0.556, CI= 0.429-0.719, P<0.0001), (OR = 0.394, CI= 0.251-0.620, p<0.0001)., Women who had higher education had a 46% increase in the odds of HIV testing compared to women who had secondary education (OR = 1.460, CI= 1.049-2.033, P=0.0249). Being married and living with partner were associated with a 59.6% and 90% increase in the odds of having been tested HIV (OR = 1.596, CI= 1.276-1.996, P<0.0001) and (OR = 1.907, CI= 1.441-2.524, P<0.0001) compared to women who had never been married. No longer living together/separated was associated with a 4.5 times higher odds of HIV testing (OR = 4.491, CI= 1.826-11.045, P=0.0011) among women compared to never been married. Age at first sex was not significantly associated with HIV testing in the final model (OR = 1.028, CI= 0.995-1.062, P= 0.1020). Our study suggests the need to increase basic education up to secondary level and beyond among women in South Africa to increase uptake of HIV testing and reduce the burden of HIV/AIDS.

Introduction: HIV remains a leading cause of death globally, with over two-thirds of the cases in sub-Saharan Africa. Zimbabwe, a country located in East Africa, part of Sub-Saharan Africa, ranks in the top five countries with the highest prevalence of HIV in Africa (HIV prevalence in Zimbabwe estimated as 21.4% in 2019). Previous studies demonstrated HIV testing prevalence of 66.9% in East Africa. This study aimed to assess the prevalence of HIV testing amongst women of reproductive age in Zimbabwe, alongside some predictors of HIV testing amongst this population. Methods: Cross-sectional study design using the 2015 Demographic and Health Surveys (DHS) data for women aged 15-49. The prevalence of HIV testing as the outcome variable and the highest educational level, age at first sex, current marital status, and condom use as the predictor variables of interest were assessed. Descriptive statistics (frequencies, percents) and test of significance (using Chi-squared test)were conducted. Bivariate and multivariate logistic regression were completed to assess for the independent relationship between each predictor variable and HIV testing prevalence and, all predictor variables and HIV testing prevalence, respectively. Odds ratio estimates, 95% confidence intervals and p-values werereported. All analyses were performed using the Statistical Analysis System (SAS) version 9.4. The initial sample size included 9955 women. However, the effective sample size used in the statistical analysis was 7130 after accounting for missing variables. Results: About 9 in 10 women in the sample had ever been tested for HIV. Secondary education was the most prevalent highest level of education (64%). About 67% women had their first sex at age 15-19; peak incidence seen at ages 17 and 18 (15.3%). Multivariate analysis showed statistically significant associations between all independent variables and HIV testing (P-value Conclusion: Increasing highest educational level, age at first sex and condom use in Zimbabwe would likely increase the prevalence of HIV testing further. Focused education on the importance of HIV testing before the age of 15 will be beneficial in ensuring HIV testing as soon as sexual intercourse is established. Policy efforts are needed to address these HIV testing predictors. Causality is not implied.