UCSF-GIVI Center for AIDS Research

The viral transactivator Tat and its cellular interaction partners play a critical role in regulating HIV-1 transcription. Tat stimulates transcription elongation by recruiting the cyclinT1/CDK9 complex to TAR RNA. We and others have previously shown that acetylation of Tat by the p300 acetyltransferase is an essential step for Tat transactivation. New results in the laboratory show that Tat is also subject to lysine methylation. It is the goal of this proposal to define the hierarchy and crosstalk between lysine methylation and acetylation in Tat and study its relevance to HIV replication.

HIV-1 replicative cycle within host cells often includes events that occur in distinct subcellular structures. mRNA processing bodies (P bodies) and stress granules (SGs) are distinct cytoplasmic RNA granules that function in translational repression and mRNA decay. Since HIV-1 relies on the host translational machinery for its protein synthesis, it is likely that P bodies and SGs function in the viral replicative cycle, either in a negative or positive manner. However, the relationship between HIV-1, P bodies or SGs is poorly understood. This proposal aims to address the role of P bodies and SGs in viral replication. In this study, we will induce or disrupt SGs or P bodies to investigate the general role of these RNA granules in viral replication. Moreover we will address the mechanism by which P bodies and SGs affect HIV-1 replicative cycle. Back to top

Street children carry a greater risk of HIV/AIDS infection than their peers, yet this sub-epidemic has been largely ignored by the HIV research community. Our ability to design interventions that will improve the health of street children is compromised by the absence of answers to fundamental questions, including: What are their rates of HIV and STIs? What are the modifiable social and contextual factors that increase their risk for infection? How can they best be reached and recruited? We propose to collect pilot data in Kisumu, Kenya to begin to answer these questions. We will conduct interviews with street children and with providers to assess the feasibility of conducting respondent-driven sampling (RDS) with this vulnerable population. Respondent-driven sampling is a recruitment method that employs Markovian modeling to make population-level estimates based on a network-recruited sample. We will conduct STI and HIV testing and collect demographic and behavioral information from a sample of fifty 13-to-17 year old street children recruited using RDS. Finally, we will re-interview participants two months later to demonstrate our capacity to track and locate youth. To our knowledge, our data will provide the first published data regarding prevalence of HIV and STIs in a sample of street children in this region in Africa. Such data, along with the understanding of the social determinants of infection, are critical to designing appropriate interventions for street children. Back to top

HIV-infected individuals face increased rates of cardiovascular events and mortality compared with non-infected controls. The etiology of these abnormalities in HIV infection is not well established, and may be related to viral infection, treatment, or host immune responses. What remains unknown is whether early versus late initiation of HAART affects cardiovascular risk, and how CD4+ counts may influence this risk. The overall hypothesis of our proposal is that higher CD4+ counts lead to decreased cardiovascular risk in HIV-infected individuals on HAART. We also hypothesize that this CD4+ T cell effect is due to persistent low-level inflammation. To address these hypotheses, we propose to study the relationship between CD4+ count and vascular function as assessed by brachial artery flow-mediated vasodilation. We will also evaluate possible mechanisms of endothelial dysfunction by assessing systemic vascular and inflammatory mediators. Back to top

Family planning is an effective way of decreasing vertical transmission of HIV and maternal and neonatal morbidity and mortality associated with untreated HIV and pregnancy. Many of the barriers to access to family planning among HIV-infected individuals are surmountable with sufficient financial, political, and logistical support. However, the impact that socio-cultural norms, and culturally influenced gender-based power dynamics, have on fertility outcomes and contraceptive choice in Western Africa, an area with high HIV prevalence and a history of polygamy, remains elusive. Providers and clients alike have reported the importance of including men in contraceptive-decision making in order to decrease unintended pregnancies among HIV-infected individuals in Kenya. The goal of this study is to perform qualitative, hypothesis-generating research among HIV-infected and affected men to better understand the current role men play in contraceptive decision-making in western Kenya. Data from this study will be used to inform the creation of a community-based intervention geared towards educating men about family planning and HIV and incorporating men into the contraceptive decision-making process. Back to top

Although the mechanism(s) resulting in HIV-induced chronic immune activation are not completely understood, it is likely there is a delicate balance between anti-HIV effector functions and aberrant immune activation. The neuroendocrine system utilizes cortisol to signal through the glucocorticoid receptor to maintain immune activation homeostasis. The goal of this proposal is to utilize phenotypic and functional studies to investigate whether aberrant HIV immune activation is caused by a change in immune cell glucocorticoid receptor expression and/or sensitivity. Understanding how immune cell glucocorticoid receptor expression and sensitivity are affected by HIV infection may provide novel means to reduce the deleterious effects of chronic immune activation associated with HIV disease progression. Back to top

Tuberculosis (TB) is the leading cause of death in persons living with HIV (PLHIV) in sub-Saharan Africa and TB incidence is increasing worldwide despite infection control efforts as the two epidemics fuel one another. In Kampala, Uganda, roughly one in four HIV-infected household contacts of TB patients have active TB. Reducing household TB transmission is likely to significantly reduce TB incidence in PLHIV. We hypothesize that household TB transmission is related to poor ventilation. This proposal seeks to describe determinants of ventilation in 200 homes in Kampala with a standardized survey tool, to correlate them to measures of home air exchange rate (AER) using an innovative carbon dioxide (CO2) tracer decay technique, and to conduct a case-control study comparing AER in homes with and without demonstrated TB transmission to determine the impact of ventilation on household TB transmission. Back to top

Elite controllers represent less than 1 in 300 patients infected with HIV-1 and are known for their remarkable ability to suppress viral replication to undetectable levels, rarely suffering infectious complications associated with AIDS. The molecular mechanisms of this intriguing process remain poorly defined. We postulate that a subset of elite controllers mount a potent innate defense against HIV through genetic or post-transcriptional differences in host restriction or virus-targeted factors. A systematic investigation to identify and characterize host factors critical for HIV suppression in elite controllers is proposed. First, candidate subjects for intensified study will be identified by isolating patient CD4 cells and demonstrating a post-entry restriction to HIV. Secondly, characterizing the step in retroviral restriction will be determined by specific polymerase chain reaction (PCR) quantification of viral nucleic acid in infected CD4 cells. Finally, interrogating the potential role of variable splicing in host factors and HIV control is explored. Back to top