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ARRA Investments in Improving HIV Therapeutics


Public Health Burden
Although progress has been made in the global fight against HIV/AIDS, the epidemic continues to devastate the United States and the international community with 56,300 new HIV infections each year in the U.S. and an estimated 33 million people living with HIV worldwide. As highly active antiretroviral therapy has dramatically reduced mortality among those with HIV, disease management of HIV and other co-morbidities remains increasingly complex.

Basic Research
A better understanding of the molecular mechanisms regulating HIV will facilitate the design of new therapeutic strategies. Many ARRA-funded projects on HIV are basic research projects that may provide insight into novel therapeutic or preventive strategies. For instance, some of these projects are:
  • Investigating a host protein called caveolin-1 that has been shown to suppress HIV expression. 1
  • Characterizing how certain cellular events within T cells, a type of white blood cells, influence the production of HIV2, and how a subset of T cells called regulatory T cells alters the immune response to HIV.3
  • Examining critical inflammatory pathways involving cytokine and chemokine production that appear important in the deterioration of the immune system as a result of HIV infection. 4
  • Clarifying the mechanism of action for HIV integrase, the enzyme that allows HIV to be integrated into the DNA of the host cell. 5
  • Understanding how host factors that contribute to innate immunity to retroviral infection can be effectively targeted for treatment of HIV infection6 , or similarly examining the innate immune response in HIV negative women known to be exposed to HIV. 7
Understanding Drug Resistance
Drug resistance continues to be a major concern for HIV-infected patients on antiretroviral therapy. A better understanding of the development of drug resistance is crucial to improving treatment effectiveness. ARRA-funded studies of drug resistance include:
  • Characterizing intracellular processes that influence the ability of HIV to escape the effects of drugs designed to block viral DNA synthesis. 8
  • Determining the effect of comprehensive HIV treatment on transmission in less developed countries, and the role of antiretroviral drug resistance in the efficacy of subsequent treatment regimens. 9
  • Investigating whether an increase in low blood levels of virus in patients on antiretroviral therapy is associated with the emergence of drug-resistant HIV variants. 10
  • Seeking to better understand the mechanisms of resistance to a certain class of HIV therapeutics. 11
  • Characterizing how drug-resistant HIV develops and spreads from person to person. 12
Applied Research
Several ARRA-funded grants are developing new therapeutic compounds, such as projects aimed at:
  • Optimizing the activity and testing the toxicity of newly discovered compounds for inhibiting HIV integrase. 13
  • Discovering an optimal triterpine compound that blocks the entry of HIV into cells. 14
Managing Co-Infections and Co-Morbidities
HIV-infected patients are susceptible to a large number of co-morbidities and co-infections. In addition, concurrent chronic diseases, especially those associated with aging, can further complicated treatment decisions. Several ARRA-funded projects aim to address these questions by:
  • Studying the epidemiology and mechanisms of accelerated aging in treated versus untreated HIV infected patients. 15
  • Defining which groups of women co-infected with HIV and hepatitis C virus would benefit from more aggressive antiretroviral therapy. 16
  • Examining the effectiveness of combination therapies used to treat patients co-infected with HIV and hepatitis B virus. 17
  • Investigating the relationship between HIV infection and pulmonary arterial hypertension to identify potential preventative measures and therapies. 18
  • Studying organ transplantation in HIV-infected patients in order to better control graft rejection while preserving immune responses to pathogens.19
  • Integrating clinical, genomic, and proteomic data to yield a comprehensive public database that can help predict how HIV-infected patients will respond to therapy. 20



  1. F31AI082950-01 -- Caveolin-1 and Negative Modulation of HIV-1 Replication -- Simmons, Glenn E (TN)
  2. R01AI062467-05S1 -- Regulation of HIV by T-Cell Signal Transduction -- Henderson, Andrew J (MA)
  3. R01AI065303-06S1 -- Immunobiology of Regulatory T Cells in HIV Infection -- Unutmaz, Derya (NY)
  4. K02AI076123-03S1 -- Heterogeneity in Cytokine Responses to HIV-1 Infection -- Tang, Jianming (AL)
  5. K02AI077341-02S1 -- HIV-1 Integrase Structure and Function as a Therapeutic Target -- Kvaratskelia, Mamuka (OH)
  6. K02AI080225-02S1 -- Mechanism of APOBEC3-Mediated Innate Immunity to HIV-1 -- Zheng, Yonghui (MI)
  7. R01AI084142-01 -- Cellular Innate Activation as a Tactic to Prevent HIV-1 transmission -- Montaner, Luis J (PA)
  8. R01AI039973-13A1 -- Biochemical Mechanisms of Drug Resistance in HIV RT -- Scott, Walter A (FL)
  9. R01AI058736-06S1 -- Optimizing HIV Care in Less Developed Countries -- Freedberg, Kenneth Alan (MA)
  10. R21AI084423-01 -- Rise of HIV-1 Low-Level Viremia as an Early Predictor of Virologic Rebound -- Mckinnon, John E (PA)
  11. R37AI055357-07S1 -- HIV-1 Resistance to Chemokine Receptor Antagonists -- Kuritzkes, Daniel R (MA)
  12. R01AI047033-08S1 -- The Transmission and Fitness of Drug Resistant HIV-1 -- Markowitz, Martin H (NY)
  13. R21AI084710-01 -- Discovery and Optimization of Novel Integrase Inhibitors as Anti-HIV Agents -- Buolamwini, John K (TN)
  14. R01AI077417-02S1 -- Modified Triterpines as Potent HIV Fusion Inhibitors -- Lee, Kuohsiung (NC)
  15. RC1AI086053-01 -- Epidemiology and Mechanisms of Accelerated Aging in HIV Infection -- Kirk, Gregory D (MD)
  16. R01AI052065-06S1 -- HCV and HIV Progression in Women on HAART -- Kovacs, Andrea A (CA)
  17. R21AI083106-01 -- Virologic and Serologic Outcomes of Persons with HIV and HBV co-infection on Mono -- Aberg, Judith Ann (NY)
  18. F31AI084460-01 -- HIV-induced 5-Lipoxygenase: Role in HIV-related Pulmonary Arterial Hypertension -- Porter, Kristi M (GA)
  19. U01AI052748-06S1 -- Solid Organ Transplantation in HIV: Multi-Site Study -- Stock, Peter G (CA)
  20. R01AI085569-01A2 -- Integration of Clinical, Genomic and Proteomic Data using a Bioinformatic Approac -- Schwartz, Stanley A (NY)


 
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