Browsing by Subject "HIV Infections"
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Item ADAP1 Promotes Latent HIV-1 Reactivation by Tuning the KRAS-ERK-AP-1 Signaling-Transcriptional Axis(December 2021) Ramirez, Nora-Guadalupe Piña; Schoggins, John W.; D'Orso, Iván; Pfeiffer, Julie K.; Alto, NealImmune stimulation fuels cell signaling-transcriptional programs that induce biological responses to eliminate virus-infected cells. Yet, retroviruses that integrate into host cell chromatin, such as HIV-1, co-opt these programs to switch between latent and reactivated states. However, many regulatory mechanisms are still unfolding. As such, here I take advantage of the unique intrinsic reliance HIV-1 has on host cell signaling-transcriptional programs to discover undescribed cell signaling regulators. Specifically, I implemented a functional screening platform, given HIV-1 gene expression relies on CD4+ T cell activation state, to identify host factors modulating CD4+ T cell signaling-transcriptional axes and consequently HIV-1 fate. Among the hits, I focus on ADAP1 (ArfGAP with Dual PH Domains 1), a previously thought neuro-restricted factor, and discover it is an amplifier of select human CD4+ T cell signaling programs. Using physiological models, I characterize ADAP1 expression is low in naïve and memory CD4+ T cells, but largely induced upon immune stimulation where it interacts with the immune signalosome. Using complementary biochemical and cellular assays, I demonstrate ADAP1 directly stimulates the GTPase activity of KRAS to amplify CD4+ T cell signaling through targeted activation of ERK-AP-1 axis. In primary CD4+ T cells which I have genetically ablated ADAP1, I show loss of ADAP1 function blunts gene expression programs in response to stimulation thereby reducing CD4+ T cell expansion and dampening latent HIV-1 reactivation. Supporting the impact of these findings, I propose the reduced CD4+ T cell programs and proliferation upon ADAP1 loss validates Genome-wide Association Studies linking ADAP1 single nucleotide polymorphisms in non-coding enhancers to an altered T lymphocyte count trait, potentially attributed to ADAP1 haploinsufficiency. Through these combined experimental approaches, I was able to define ADAP1 as an unexpected tuner of CD4+ T cell activation programs and co-opted by HIV-1 to escape latency.Item AIDS and the gastrointestinal tract(1988-05-12) Spady, David K.Item Anal Cancer Screening in a High-Risk Population: A Quality Improvement Initiative(2019-03-29) Bieterman, Andrew; Reed, W. Gary; Anandam, Joselin; Lau, Abby; Quinn, AndrewBACKGROUND: The main risk factor for the development of anal cancer is acquisition of the human papilloma virus (HPV). Individuals infected with the human immunodeficiency virus (HIV) have a higher prevalence of HPV and subsequently developing HPV induced dysplasia. The incidence of anal cancer among HIV positive men who have sex with men (MSM) has been estimated to be approximately twice that of HIV negative MSM with rates as high as 112-144 per 100,000. By relying on similarities between the anus and the cervix, and the established success of cervical cytology screening in reducing the incidence of cervical cancer, anal cancer screening programs have been established to identify pre-cancerous lesions. LOCAL PROBLEM: A retrospective chart review of anal cancer incidence at Parkland Hospital revealed a significant burden of anal cancer amongst HIV positive patients. As such, Parkland has decided to implement a policy of annual anal cancer screening among all HIV patients via anal cytology screening and referrals to proctology for any abnormal anal cytology samples. METHODS: In order to assess the monthly anal cancer screening rate, we looked at the absolute number of anal cytology samples performed in a 28 day period. The list of anal cytology samples performed was pulled from the Cerner laboratory information system (LIS) and correlated with a quarterly chart review using the electronic medical record (EMR). Utilizing, QI MACROS in EXCEL, we were able to create a run chart to identify trends in anal cancer screening rates over the duration of the project. We used chi-squared test of independence and unpaired t-test to determine statistical significance. INTERVENTIONS: We implemented a multi-step process involving over 10 Plan-Do-Study Act (PDSA) cycles for increasing the number of anal cytology samples performed in the clinic. The three most impactful PDSA cycles are discussed in the article. RESULTS: The primary outcome of monthly anal cancer screening rate increased over the duration of the project from an average of 19.5 in 2015 to 58.6 samples collected per month in 2018, a 199.3% increase relative to baseline (p < 0.001). While the interventions implemented were successful in increasing anal cancer screening rates, we were unable to determine which of the PDSA intervention cycles had the biggest impact on altering the clinic practice. Over the duration of the project, we screened 1908 patients. Of the patients screened, we identified 249 patients with abnormal anoscopy findings. Amongst the patients that had anal lesions on anoscopy, 10 developed anal cancer, 4.0%. When taking a closer look at these individuals and the electronic medical record, 3 patients were found to be completely asymptomatic at the most recent clinic prior to collection of the anal pap and would not have been referred to proctology if it weren't for the screening test, which ultimately resulted in an earlier diagnosis CONCLUSION: We were successful in taking previously proven interventions for increasing cervical cancer and adapting them for anal cancer. By increasing awareness to both patients and providers on the risks of anal cancer, instructing providers on the methods to screen for the disease, and providing timely feedback, we were able to increase the anal cancer screening rate in this large urban clinic with limited resources.Item Aspects of solid organ transplantation in HIV- infected patients(2010-06-25) Wada, SuzanneItem A Comparison of HIV/AIDS Management in the US and Brazil: Historical Context and Lessons Learned(2020-03-16) Zou, Michael; Mihalic, Angela; Kitchell, Ellen; Lazarte, SusanaBACKGROUND: Since its initial appearance in the early 1980s, the HIV pandemic has presented a worldwide challenge not just in biomedical innovation but in social and political mobilization as well. The groundbreaking innovation of HAART (highly active antiretroviral therapy) in 1996 was buttressed by an era of public health mobilization to limit the scale of the epidemic prior to 1996 and an era to ensure access to this treatment. The actions taken in these two eras have shaped the current character of the epidemic in all countries; the US and Brazil are no different. On the one hand, the US lags behind its countries in metrics such as the UN AIDS 90-90-90 initiative. In contrast, Brazil has emerged as the leader in Latin America in the 90-90-90 metric, achieving marks that are comparable to the US despite differing levels of development. OBJECTIVE: Brazil implemented bold public health policies that led to it becoming one of the leaders in Latin America in HIV management. This thesis will explore the historical context and implementation of these policies with an eye towards possible application in the US. METHODS: Historical analysis was performed on the public health policies of Brazil and the US regarding HIV/AIDS management. Sources include but are not limited to contemporaneous newspapers, presidential recordings and speeches, congressional legislation and briefings, documentaries, epidemiologic figures, interviews, government and activist images and posters, mathematical models of the HIV epidemic, and other studies comparing the two countries. RESULTS: To a much greater extent in the United States, there was alignment in values and action between federal and local governments, civil society, the Constitution, and international donors. This led to the historic and controversial decree in 1996, proclaiming universal and free HAART for all Brazilians. Since then, Brazil has maintained a successful and solvent HIV program through partnerships with community leaders to increase outreach, aggressive negotiation for medication pricing internationally, and sophisticated centralized databases permitting cutting-edge patient care and research. In contrast, the early HIV movement in the United States was characterized by conflict between the federal government and activists who fought for recognition and treatment for people living with HIV (PLWHIV). Other branches of the federal government in addition to local governments provided some leadership, but the lack of a unified response led to an increase in the scope of the epidemic, ultimately making it more difficult to manage. Both countries find their HIV programs at a crossroads. In Brazil, an increasingly conservative government and a defunding of the public health system (SUS) has led to a disturbing increase in incidence, especially among the youth of Brazil. In contrast, the United States has reinvigorated its domestic response to AIDS with the 'National HIV/AIDS Strategy' of President Obama and the 'Ending the Epidemic' initiative of President Trump. However, ultimate success in the HIV epidemic in the US may require a more fundamental rethinking of the healthcare system. CONCLUSION: Prior work comparing the the the Brazilian and American response to the HIV epidemic have centered on the roles of activism, executive leadership, and international factors that have shaped policies, in particular the policy of universal and free HAART in Brazil. This thesis builds on this work by examining interventions that Brazil has implemented in the last decade with an examination of recent policies enacted by the Obama, Trump, and Bolsonaro administrations. Such a comparative approach may prove useful to policymakers interested in using the experiences of other nations to devise innovative approaches to the HIV epidemic.Item Decreased microRNA-122 Levels with HCV Clearance in HIV-HCV Co-Infections(2013-01-22) Dubin, Perry H.; Yuan, Hejun; Devine, Robert K.; Jain, Mamta K.; Hynan, Kinda S.; Lee, William M.BACKGROUND AND AIMS: Micro RNA-122 (miR-122) is under investigation as a target for direct antiviral agents against the hepatitis C virus (HCV), and as a biomarker for both cancer and acute liver injury. Previous data suggest HCV mono-infection is associated with increased serum miR-122 levels. This study sought to determine outcomes in regard to miR-122 levels following clearance of HCV in human immunodeficiency virus (HIV) co-infected patients. METHODS: Nine HCV-HIV co-infected patients undergoing antiviral therapy were treated with interferon and ribavirin for 48 weeks between January 2009 and March 2011, and had serial miR-122 levels measured in triplicate from serum with mirVanaTM PARISTM kit according to the instructions from the manufacturer (Ambion, AM1556). Values were measured at baseline, 1 week, 4 weeks, end of treatment (EOT; 48 weeks), and at 24 weeks after treatment completion (SVR24). SAS V9.3 was used to analyze these data. Change from baseline (copies/μL) was calculated as Log10 (Baseline)-Log 10(time), where time was 1 week, 4weeks, EOT, and SVR24; a repeated measures ANOVA was used to compare the results over time for the patients. If the ANOVA was found significant, post hoc, pairwise comparisons were used to examine change from baseline across the four time points. RESULTS: Six of nine achieved SVR24, 1 was undetectable at EOT but relapsed, and 2 patients were non-responders. Among the 6 patients achieving SVR, all showed a decrease in miR-122 levels between 0.16 and 1.46 logs, between baseline and SVR24. The ANOVA confirmed a significant decrease in miR-122 levels from 1 week to SVR24 (p=0.0225). Significant pairwise comparisons for change from baseline were found at 1 week versus SVR24 (p=0.0063), 4 weeks versus SVR24 (p=0.0086), and EOT versus SVR24 (p=0.0458). CONCLUSION: Clearance of chronic HCV is associated with decreased miR-122 levels in HIV co-infected patients and was not improved in patients with continued infection who failed to respond to treatment.Item Demographics, Clinical Presentation, and Outcomes of HIV Infected and Uninfected Patients with Hepatocellular Carcinoma(2023-01-31) Zhang, Lucia; Chang, Gloria; Rich, Nicole; Singal, Amit; Yopp, AdamWith highly active antiretroviral therapy (HAART), HIV infected individuals have seen longer survival, which is associated with increased mortality and morbidity from chronic liver diseases (CLD). Patients with HIV are 7 times more likely to develop HCC. To date, the clinical course and outcomes of patients with HIV and HCC is not well defined. We compared the survival of HCC patients with and without HIV infection, and we expected demographic factors, clinical presentation, and treatment patterns to impact survival differently between the two groups. We performed a retrospective cohort study of HCC patients at two hospitals within the same system in Dallas between January 2010 and June 2022. We excluded patients without a known HIV diagnosis status. Demographics, prognostic measures, tumor characteristics, treatment modalities, and survival were compared between patients with and without HIV infection. Survival curves were generated using Kaplan- Meier plots and compared with the log rank test. Of the 1,391 patients with HCC, 43 (3.1%) were HIV infected. HIV infected patients were more likely to have Medicare (51% vs 29%; P=0.012) and less likely to be uninsured (0% vs 9.9%; P=0.012). CLD etiologies differed between the groups with HIV infected patients less likely to have alcohol-related liver disease (4.7% vs 17.6%; P<0.001) and more likely to have HBV infection (32.6% vs 5.1%, P<0.001). There were no significant differences in the prognostic measures and tumor characteristics between the two groups. Median overall survival (OS) was similar between HIV infected and uninfected patients (17.2 months vs 21.1 months; P=.318). Median OS was also compared between controlled and poorly controlled HIV infected patients and found to be similar (19.2 months vs 16.0 months; P=.521). On multivariable analysis, factors associated with worse OS included underlying fatty liver disease (HR 1.533, 95% CI 1.1-2.1) and HBV (HR 1.703, 95% CI 1.2-2.5). ECOG functional status>=2 (HR 1.331, 95% CI 1.0-1.7), Child Pugh class B (HR 1.278, 95% CI 1.1-1.5), and having multiple lesions at time of diagnosis (HR 1.213, 95% CI 1.1-1.4) were also associated with worse survival. HIV infection was not independently associated with worse survival (HR 1.295, 95% CI .858-1.955). The relationship between HIV infection and HCC in affecting clinical outcomes remains complex. HIV infected patients present with different underlying liver disease but similar prognostic and tumor characteristics. Overall survival was ultimately found to be similar between HIV infected and uninfected patients with HCC.Item Evolving Characteristics of HIV Infected Pregnancies at a Single Institution(2013-01-22) Cooper, Sara J.; Stewart, Robert D.; Duryea, Elaine L.; McIntire, Donald D.; Roberts, Scott W.; McElwee, Barbara; Sheffield, Jeanne S.OBJECTIVE: Over the past 26 years, significant advances have been made in the understanding and management of patients infected with HIV. We sought to determine if these changes in HIV care have had an impact on the characteristics of pregnant women with HIV and their pregnancies in a large cohort of HIV infected women at a single institution. STUDY DESIGN: This was a retrospective review of all pregnancies infected with HIV who presented for prenatal care at our institution from January 1986 through November 2012. Medical records were reviewed, and maternal, neonatal, and delivery data were ascertained. The data were divided into three cohorts representing different levels of antiretroviral therapy and analyzed for trends. Cohort 1 (pre-HIV interventions) includes data from 1986-1991, Cohort 2 (introduction of ZDV) includes data from 1992-2002, and Cohort 3 (multi-drug therapy) comprises the remaining data from 2003-2012. RESULTS: During the 26 year study period 1005 HIV infected pregnancies were identified. The incidence of HIV in pregnancy has remained stable at 0.2 -0.3% of all deliveries. The vast majority of our HIV infected obstetric population receives prenatal care and the number of patients receiving no prenatal care has decreased over time (27% to 6%, p<0.001). There has been a significant increase in maternal age and number of prenatal visits during the study period. The estimated gestational age at delivery has remained steady throughout the entire data set and there have been no changes in birthweight, 5-minute APGAR <7, prematurity, stillbirth, or neonatal deaths. The rate of cesarean section doubled (24% to 55%, p<0.001) for deliveries after 2000 following the release of guidelines recommending scheduled c-section for patients with viral loads >1000 copies/mL. Median maternal viral load and CD4 count have not changed significantly throughout the cohorts, with HIV viral load usually becoming non-detectable by delivery. CONCLUSION: Over the past two decades, HIV infected women have presented for prenatal care at an older age, entered prenatal care earlier with more frequent visits and overall have decreased maternal viral copy number at delivery with antiretroviral therapy. Despite increased maternal age, pregnancy outcomes remain excellent. This study highlights the fact that appropriate prenatal care is associated with excellent pregnancy outcome in this high risk population.Item Excess mortality in treated HIV-infection(2015-11-20) Drechsler, Henning J.Item Generation of HIV-Resistant T-Cells and Correction of the Sickle Cell Mutation by Targeted Genome Engineering(2013-07-23) Voit, Richard Alexander 1983-; Goodman, Joel M.; Porteus, Matthew H.; Sternweis, Paul C.; Graff, Jonathan M.Targeted genome engineering is a powerful method to create specific modifications at chromosomal loci. This technique makes it feasible to precisely alter DNA sequences by introducing a specific DNA double-strand break, which is repaired by the natural cellular machinery. These double strand breaks are induced by engineered chimeric nucleases – either zinc finger nucleases (ZFNs) or Tal effector nucleases (TALENs) – and depending on the experimental design, can result in gene disruption, gene correction or targeted transgene integration. In this thesis, I present two applications of this approach in the context of two prevalent human diseases, HIV infection and sickle cell disease. HIV infects CD4+ T-cells by binding to the CD4 receptor and either the CCR5 or CXCR4 co-receptor on the surface of those cells. Previously, ZFNs were described that create gene specific knockouts of CCR5, protecting cells against CCR5-tropic (R5) HIV, but not against CXCR4-tropic (X4) HIV. I hypothesized that combining ZFN-mediated CCR5 disruption with targeted integration of a cassette of anti-HIV genes would confer higher levels of resistance against R5-tropic virus and also be protective against X4-tropic virus. In a T-cell reporter line, I showed that CCR5 disruption alone conferred 16-fold protection against R5-tropic virus but had no effect against X4-tropic HIV. In contrast, CCR5 disruption, combined with targeted gene integration into that locus, of the anti-HIV restriction factors human-rhesus hybrid TRIM5α, APOBEC3G D128K and Rev M10 was completely protective against both viral tropisms. Sickle cell disease is caused by a point mutation in the β-globin gene, and I sought to correct this mutation by synthesizing TALENs specific for that site. The β-globin TALENs stimulated integration of therapeutic β-globin cDNA in approximately 20% of cells prior to selection. Using FDA-approved drugs to select for modified cells, I showed virtually complete enrichment of targeted cells. Furthermore, I used the β-globin TALENs to target GFP to the β-globin start codon and designed TALENs to target tdTomato to the start codon of the γ-globin gene, upregulation of which is a goal of sickle cell disease pharmacotherapy. In this way, I developed an endogenous dual promoter reporter system and screened for drugs that preferentially upregulated γ-globin.Item HIV anti-retroviral trials: a paradigm for clinical research(1995-02-09) Keiser, PhilipItem HIV associated Kaposi sarcoma: the case for an interdisciplinary approach(2022-03-04) Jones, Amy; Knights, Sheena; Lau, Abby; Lazarte, SusanaItem Improving the HIV care continuum in 2021(2021-06-25) Chow, JeremyItem Infectious diseases and the criminal justice system: a public health perspective(2015-08-07) Nijhawan, Ank E.Item Investigation of the Effectiveness of Anal Cancer Screening in HIV Patients(2017-01-17) Bieterman, Andrew; Barnes, Arti; Quinn, Andrew; Anandam, JoselinBACKGROUND: The main risk factor for the development of anal cancer is acquisition of human papilloma virus (HPV), which occurs at a higher probability in human immunodeficiency virus (HIV)-infected individuals. Our hypothesis is that annual screening amongst the highly vulnerable HIV population will result in earlier detection of anal cancer and improved patient outcomes. OBJECTIVE: The main objective of this project is to improve patient outcomes by increasing the number of monthly anal pap smears performed at Amelia Court by 20%, by January 2017. METHODS: The project was conducted at Amelia Court, an HIV clinic attached to a larger safety net hospital in an urban setting. Our baseline data was determined by studying the absolute number of anal Paps performed in a 28 day period. The project utilized a variety of quality improvement tools to analyze the effects of a two-step educational process. Implementation 1: provider re-education program focusing on the importance of anal cancer screening in HIV patients. Implementation 2: creation of an infographic to be displayed in patient rooms, encouraging patients to request anal cancer screening from their providers. RESULTS: Implementation 1: demonstrated a 21.33% increase in the number of anal Paps collected. Implementation 2: anticipated results will be available by November, representing a 28 day cycle. CONCLUSION: The provider re-education program showed an increase in the absolute number of anal Paps performed at Amelia Court. The limited time frame since implementation precludes further analyses at this point. However, initial results suggest that these processes will improve anal cancer outcomes in vulnerable populations.Item Lethal Hypermutation Induced by the Innate Cellular Restriction Factor APOBEC Destroys HIV-1 in Infected Humanized Mice(2010-01-12) Krisko, John Frank; Garcia-Martinez, J. VictorTwenty eight years after the initial case reports of what would become known as AIDS, HIV-1 remains a major health issue both globally and locally. Current antiretroviral interventions are effective at suppressing virus replication; however, they must be maintained for life as the removal of these drugs resulting in the rapid return of viremia. Novel therapeutic approaches targeting HIV may be required to ultimately achieve a drug-free remission for infected individuals. Identification of the innate immune factor, APOBEC, has revealed one such approach. The cytidine deaminases APOBEC3G and 3F have potent antiretroviral activity; however, they are neutralized by the HIV-1 Vif protein. In vitro, the absence of Vif allows the enzymatic activity of APOBEC3G and 3F to induce hypermutation of the HIV-1 genome. These observations make the Vif/APOBEC axis a tantalizing therapeutic target. The ability of APOBEC to restrict HIV in vivo however remains to be addressed. The adaptive capability of HIV allows the virus to develop escape mutations to evade antiretroviral drugs and persist in infected individuals; thus the possibility that HIV will be able to evade APOBEC restriction in vivo exists. Humanized mice used as an in vivo model to study the capacity of APOBEC to restrict Vif-defective HIV revealed that the ability of the virus to replicate is severely crippled. HIV lacking Vif is heavily hypermutated by APOBEC, however, if the virus can restore Vif, the result is a fully replication competent virus that is resistant to APOBEC restriction. The goal of this dissertation project was to utilize a humanized mouse model to assess the ability of Vif-defective HIV to replicate, persist and ultimately escape restriction by APOBEC in vivo. My conclusions are that in the absence of Vif, restriction by APOBEC is absolute; however, this extreme selective pressure placed on the virus in some instances leads to the restoration of Vif, resulting in a fully APOBEC resistant pathogenic HIV. Thus, the Vif/APOBEC axis is an excellent candidate for antiretroviral intervention and furthermore, the humanized mouse will serve as a good model for assessing the in vivo efficacy of novel Vif-targeting compounds.Item Liver Fibrosis and Steatosis in HIV-Infected Patients: Impact of Race/Ethnicity, Gender, BMI, and ART(2019-04-02) Rucker, Danielle; Cutrell, James; Bedimo, Roger; Luque, AmnerisBACKGROUND: The advent of antiretroviral therapy (ART) led to a decline in morbidity and mortality related to AIDS and its related complications. With this decline, an increasing proportion of morbidity and mortality in people living with HIV (PLWH) is secondary to liver and cardiovascular disease. Previous studies have shown that PLWH have traditional risk factors for these diseases, such as obesity, as well as risk factors that are unique to their population, including direct metabolic effects of HIV and ART. Several factors, such as race, ethnicity, gender, and BMI, have been shown to have an impact on the course of liver steatosis and fibrosis in general population. The impact of these factors on the course of liver steatosis and fibrosis in the setting of hepatitis B and C co-infections in PLWH have been studied, but there is a paucity of literature detailing the impact in the absence of viral hepatitis co-infection. NAFLD, APRI, and FIB-4 scores have been shown to be effective noninvasive markers for clinically significant liver steatosis and fibrosis. However, these non-invasive markers have not been validated for use in patients without viral hepatitis co-infection. This study aims to determine if race, ethnicity, gender, BMI, and the specific ART regimen have a differential impact on non-invasive markers of liver steatosis and fibrosis in PLWH. OBJECTIVE: Determine if race, ethnicity, gender, BMI, and specific ART regimen will modulate changes in non-invasive markers of liver steatosis and fibrosis. METHODS: All patients initiating ART at the Parkland Memorial Hospital HIV clinic from 2009-2017 were analyzed. Exposure to ART was defined as concurrent receipt of at least two nucleoside reverse transcriptase inhibitor (NRTI) drugs plus at least one protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or integrase inhibitor (INSTI). The existing patient database includes demographics (notably, gender, race, and ethnicity), CD4 and HIV RNA levels, co-morbidities, laboratory values (most notably, liver function tests), ART regimen, and body mass index (BMI). An analysis of yearly changes in BMI was calculated based on specific ART drugs, and differences between groups stratified by gender or race/ethnicity were compared. For subjects who meet certain pre-determined liver function test minimums, non-invasive markers for liver fibrosis (APRI, NAFLD, and FIB-4 scores) will be utilized and trended over time. Manual chart extraction will be examined for patients with clinically-indicated imaging (abdominal ultrasound, computed tomography, or magnetic resonance imaging) to estimate the incidence and prevalence of liver fibrosis or steatosis in this population and to determine whether race/ethnicity or gender modifies these risks. RESULTS: The difference in yearly BMI change was statistically significant for the INSTI dolutegravir (DTG; p=<0.01) between Blacks and non-Hispanic whites (NHW) but not for any other ART drugs tested. The difference in yearly BMI change showed a trend for statistical significance for DTG (p=0.06) between Hispanics and NHW but not for any other ART drugs tested. The difference in yearly BMI change by ART drug in men versus women was statistically significant for atazanavir (ATV; p=0.03), darunavir (DRV;p=<0.01), lopinavir (LPV; p=0.03), and dolutegravir (DTG; p=<0.01) but not with elvitegravir (EVG; p=0.72). CONCLUSIONS AND NEXT STEPS: Our preliminary results indicate that particular ART drugs, principally the INSTI DTG, appear to be associated with greater BMI gains than other agents. Additionally, in PLWH on ART, women demonstrated greater BMI gains than men, and Blacks and Hispanics demonstrated greater BMI gains than NHW in our cohort. The next steps will be to analyze the trends of APRI, FIB-4, and NAFLD scores over time in our cohort as non-invasive markers of liver fibrosis and to determine the demographic, HIV, and ART-related factors associated with higher rates of liver fibrosis. We will also conduct a review of clinically-indicated abdominal imaging for evidence of hepatic fibrosis in a subset of our cohort to validate the use of these non-invasive markers in PLWH without viral hepatitis. Given that HIV has been transformed into a chronic disease and that PLWH are now living decades on these ART regimens, it is of paramount importance to determine the long-term metabolic and hepatic consequences of these medications to better inform patient care and practice guidelines. We believe that our large cohort of demographically diverse PLWH on contemporary ART regimens and with detailed clinical follow-up data offers an important population to further our understanding of these critical issues.Item Mechanisms of non-AIDS complications of HIV disease: role of hepatitis C co-infection(2015-02-20) Bedimo, RogerItem Mucosal HIV-1 Transmission in Humanized Mice(2008-05-13) Denton, Paul Wesley; Garcia-Martinez, J. VictorHIV-1 infects ~6,800 people each and every day, transmitting predominantly through unprotected sexual contact. On a global scale, vaginal transmission now accounts for more than half of newly acquired HIV-1 infections. In developed countries intrarectal infection represents a major form of HIV-1 transmission. The social and economic toll of this disease has created an urgency to develop and implement novel approaches capable of preventing HIV-1 transmission. Yet this process has been hindered by the lack of adequate small animal models for pre-clinical efficacy and safety testing. Given the importance of mucosal HIV-1 transmission, the susceptibility of humanized mice to intrarectal and intravaginal HIV-1 infection was investigated. Human lymphocytes, including CD4+ T cells, generated in situ from hematopoietic stem cells reconstitute the gastrointestinal tract and the female reproductive tract of Bone marrow Liver Thymus (BLT) mice. The presence of human CD4+ T cells in these mucosal tissues renders BLT mice susceptible to both intrarectal and intravaginal HIV-1 transmission. Mucosally transmitted HIV-1 disseminates systemically in BLT mice. Effects of disseminated HIV-1 infection include a systemic loss of CD4+ T cells, particularly in gut associated lymphoid tissue, which closely mimics what happens in HIV-1 patients. The utility of humanized mice to study mucosal HIV-1 transmission is particularly highlighted by the demonstration herein that pre-exposure prophylaxis with antiretroviral drugs can prevent intravaginal HIV-1 transmission. This experimental finding has important implications for the clinical implementation of antiretroviral-based pre-exposure prophylactic measures to prevent the spread of AIDS. The goal of this dissertation project was to determine the suitability of the BLT mouse to serve as an animal model of HIV-1 transmission and as a model for assessing interventions aimed at preventing HIV-1 transmission. My conclusions are that BLT mice are susceptible to both intrarectal and intravaginal HIV-1 transmission and that pre-exposure prophylaxis with FDA approved antiretroviral drugs does prevent vaginal transmission in BLT mice. Thus, the BLT mouse system is an excellent candidate for pre-clinical evaluation of both microbicides and pre-exposure prophylactic regimens to prevent mucosal HIV-1 transmission.Item Rheumatic manifestations of HIV infection(1990-03-08) Lipsky, Peter E.