Project Abstract: In 2006, the Centers for Disease Control and Prevention (CDC) estimated that 1 in 5 Americans infected with HIV were unaware of their HIV status, and that half of new HIV infections occurring yearly were transmitted by individuals unaware that they were infected. Many of these individuals present late to care, despite revised CDC guidelines in 2006 advocating routine, universal screening for HIV. Work by us and others have shown high rates of late presentation (defined as AIDS diagnosis at presentation) among racial/ethnic minority groups, with the highest rates among Hispanics/Latinos. There is limited data regarding the social and behavioral factors driving late presentation to care in all racial/ethnic groups, and a paucity of literature on late presentation, barriers to testing, and engagement in care among Hispanics/Latinos. As the Hispanic/Latino population is expected to triple between 2000-2050, it is essential to understand the reasons for late presentation in this group to improve HIV prevention efforts. We propose studying patients presenting for initial care at the CORE Center, a large, urban, safety net HIV clinic, to fully characterize predictors of late presentation to care across racial and ethnic groups. Building upon our previous descriptive data of late presentation, we will explore the demographic, behavioral, and cultural predictors of late presentation using epidemiologic, qualitative, and quantitative survey techniques. In keeping with the goals of the National HIV/AIDS strategy, we believe this approach will provide an opportunity to formulate interventions that can target and tailor testing programs to insure earlier engagement in care.

Principle Investigator: Vadim Gaponenko, PhD, University of Illinois at Chicago

Vadim Gaponenko is an Assistant Professor in the Department of Biochemistry and Molecular Genetics at the University of Illinois at Chicago.  Dr. Gaponenko's research is aimed at understanding how peptide molecules assemble into nanostructures and how these nanostructures can antagonize membrane receptor function. Using this technology nanoscale devices were developed to inhibit signal transduction initiated by CXCR4 chemokine receptor. CXCR4 is one of the major portals used by HIV viruses for cellular entry. Dr. Gaponenko's investigation of the use of peptide-based nanoparticles to inhibit CXCR4 function in cancer is funded by an R01 grant from the National Cancer Institute. Although CXCR4 can be used by HIV to infect patients, CCR5 chemokine receptor is preferred by the viruses for cell entry. More virulent strains of HIV can even use both CXCR4 and CCR5 portals to initiate infection. This pilot grant will be used develop nanoparticle antagonists of CCR5 that could be employed in conjunction with CXCR4 antagonists as inhibitors of HIV cellular entry through CCR5 and CXCR4 portals.

Project Title: Design of peptide-based nanoscale devices to act as HIV entry inhibitors

Project Abstract: HIV viruses mutate rapidly to change their modes of infectivity and to overcome the effects of drugs that prevent HIV infection.  Novel therapeutic strategies are urgently needed to treat HIV infections that evade common modes of treatment.  HIV entry inhibitors designed to stop the infection at the virus-host interaction interface hold significant promise as HIV prevention agents and therapeutics for treatment of progressed disease.  We propose to interfere with the transmembrane portion of human cellular membrane receptors that facilitate HIV cellular entry.  This mode of inhibition would permanently disrupt the structure and function of membrane receptors making them incapable to serve as efficient entry portals for HIV viruses.  The use of peptide molecules inserting into the cellular membrane and disrupting cognate receptors can be a viable alternative to drugs interacting with viral surface proteins or with the extracellular portions of host receptors.  The most common human receptor utilized by HIV viruses is the chemokine receptor CCR5.  CCR5 inactivation in humans by an inherited mutation is not associated with any severe medical condition suggesting that CCR5 inhibition by a membrane fusogenic peptide may be safe.  Peptide therapeutic agents are susceptible to degradation in the blood stream and require additional design of cellular delivery mechanisms.  Peptide nanoparticles can solve problems with peptide HIV entry inhibitors.  In aqueous solutions peptides may exhibit a conformation allowing assembly into spherical nanoparticles that protect peptides from protelysis and recongnize their target proteins.  Nanoparticles disassemble in the lipid environment, insert into the plasma membrane, change their conformation, and inhibit target proteins.  CXCR4 is an alternative to CCR5 for HIV cellular entry.  We designed a transmembrane helix peptide analog x4-2-6 can target CXCR4 receptors for inhibition of HIV entry.   Based on what we know about the mode of action of x4-2-6, we designed a peptide analog of the fifth helix in CCR5 (CCR5-5) that can be used in together with x4-2-6 to inhibit dual tropic viruses.  We hypothesize that the selected transmembrane peptide analog of helix 5 in CCR5 will display properties similar to x4-2-6. It will assemble into nanoparticles in the aqueous solution, insert into the plasma membrane, acquire a helical conformation in the lipid environment, and inhibit CCR5 mediated HIV entry.   In addition to the fifth helix of CCR5, other CCR5 transmembrane analogs will be studied as well.  The proposed research is likely to significantly impact the general approach to the development of HIV therapeutics.

Cycle #4 - May, 2011

Principle Investigator: Kyle Popovich, MD, Rush University Medical Center

Kyle Popovich is currently an Assistant Professor in the Section of Infectious Disease at Rush University.  She has experience in epidemiology research in the area of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and infection control research for infection prevention.  Her research to date from a project funded by the Rush/County Collaborative Grant and her NIAID K23 award has demonstrated the significant impact the CA-MRSA epidemic has had on HIV patients.  This pilot grant would be used to expand into HIV/AIDS research to further investigate the disproportionate impact CA-MRSA has had on HIV patients, in particular those who have formerly been incarcerated.

Project Title: Impact of HIV status and Incarceration on MRSA Infection

Project Abstract: The CA-MRSA epidemic has disproportionately impacted certain patient groups, in particular HIV patients. Individuals with a history of incarceration may also be at increased risk for CA-MRSA. The goal of this project is to further understand the extent to which incarceration exposure and factors within the jail are associated with CA-MRSA among HIV-infected patients.

Principle Investigators: Elizabeth Abrams, PhD and Crystal Patil, PhD, University of Illinois at Chicago

Dr. Abrams and Dr. Patil are assistant professors in the Anthropology Department at the University of Illinois at Chicago. They have both worked in East Africa on women's health issues since 2000. Dr. Abrams, a biomedical anthropologist, focuses on social and ecological determinants of health, particularly pregnancy and birth outcomes. Dr. Patil, an applied medical anthropologist, employs a biocultural approach to health and specializes in using mixed methods research to promote health equities. Drs. Patil and Abrams have collaborated since 2008 on a project investigating the complexities of the choices around place of birth in rural Tanzania. Because antenatal care (ANC) was shown to play such an important role in shaping pregnancy behavior and birth outcomes, the focus on quality ANC that incorporates locally-important content, particularly HIV education for all women, is a natural extension of this research.

Project Title: Integrating HIV Prevention Into Innovative Group Antenatal Care

Project Abstract: For this project, Drs. Abrams and Patil will adapt a successful and innovative model of group ANC, CenteringPregnancy, to sub-Saharan African healthcare contexts. Current ANC in sub-Saharan Africa reflects the situation of many developing countries: providers are constrained by low resources, overcrowding, understaffing and the burden of intensive one-on-one counseling of HIV positive women at ANC. CenteringPregnancy offers an opportunity to shift the ANC paradigm to be in line with the goals of the World Health Organization’s primary health care initiative by offering comprehensive, continuous and person-centered ANC without increasing staff or budgets. For this pilot project, the team will develop and integrate HIV-related content into CenteringPregnancy ANC manuals. We will then test the feasibility and acceptability of the CenteringPregnancy model in sub-Saharan Africa. The specific aims of this pilot study are to 1) develop the CenteringPregnancy model to integrate preconceptual, antenatal, and postnatal HIV-related health promotion content; and 2) establish the acceptability of the adapted CenteringPregnancy model to healthcare administrators, staff and women attending ANC and establish its feasibility within the current constraints of sub-Saharan African healthcare and ANC contexts. This innovative group ANC approach will allow providers to offer high quality and comprehensive ANC that will retain women in care, improve health outcomes and reduce HIV stigma within current time and budgetary constraints; it is a powerful tool for meeting maternal, infant, and community health goals.

Principle Investigator: Lijun Rong, PhD, University of Illinois at Chicago

As the Principal Investigator of the application, I have the expertise, leadership and motivation necessary to successfully carry out the proposed work. I have a broad background and training in molecular virology. I have more than 15 years of research experience in studying the entry mechanism and viral replication of several viruses including retroviruses (Rous sarcoma virus and HIV), filoviruses, influenza viruses, and HCV, leading to publications of more than 35 peer reviewed papers in molecular virology. Recently, in collaborations with other groups, we have identified several antiviral (including HIV) inhibitors, some of which have potentials to become therapeutic agents. In addition, I have successfully administered the projects (e.g. staffing, research protections, budget), collaborated with other researchers. As a result of these previous experiences, I am aware of the importance of frequent communication among project members and of constructing a realistic research plan, timeline, and budget. In summary, I have a demonstrated record of successful and productive research projects in an area of high relevance for HIV entry and infection, and my expertise and experience have prepared me to lead the proposed project.

Project Title: Identification of the Host Proteins that Restrict HIV Replication

Project Abstract: Acquired immunodeficiency syndrome (AIDS) was first report in the United States in 1981 and it is estimated that over 25 million people have died from AIDS and that roughly 33 million people are infected with human immunodeficiency virus (HIV), the causative agent of AIDS. There is no effective vaccine or a cure for the virus. Thus mechanistic insights on HIV replication and pathogenesis are important for us to understand the nature of HIV persistent infection and to develop novel therapeutics against HIV/AIDS. This application is based on our exciting preliminary results that HIV replication was enhanced when expression of some human genes was interrupted by siRNAs. Based on these results, we hypothesize that the proteins encoded by these genes can restrict HIV replication in the host cells. Because little is known about the roles of restrictive host genes of HIV replication in the literature, we believe that characterization of these proteins may provide insights on HIV replication, and potentially become novel therapeutic targets in HIV/AIDS disease. Two specific aims are proposed here: (1) Analysis and validation of “hit” genes, and (2) the ability of the “hit” genes to restrict replication- competent HIV strains in vitro.