Therapeutic strategies aimed at long-term suppression of viral replication through a combination of highly active antiretroviral therapy (HAART) and immune modulation, offer the best hope for HIV-1 infected patients worldwide. Clinical experience suggests that life-long HAART is generally not feasible but that a subset of patients may benefit from a limited period of HAART followed by strategic treatment interruption (STI). Clinical trials, some in early infection, are already ongoing to test this hypothesis. What is lacking from these trials -and what the UAB AIEDRP proposes to undertake -is a comprehensive, dynamic assessment of the molecular virologic and immunologic responses to HAART + STI (+/- vaccine) regimens as a means to rationally interpret and design long-term therapeutic strategies. The UAB AIEDRP proposes, for the first time, a coordinated, full viral genome-length assessment of CTL and neutralizing antibody control and escape in acute HIV-1 infection, including a systematic evaluation of the impact of therapy. We propose also to evaluate the initial innate immune responses and their impact upon subsequent HIV -specific immune responses. Underpinning these aims will be an emphasis on immunogenetic correlates of host immune control. These studies will be conducted in treatment-naive patients and in the context of two new clinical trial strategies: The first protocols (UAB201-3) are designed for patients from developed countries and aim to maximize the virus containment period while minimizing HAART exposure. The second strategy (UAB301) is designed for patients from developing countries where complicated and prolonged treatment is impractical but where there is an urgent need to alter viral load and clinical outcome by brief periods of therapy. UAB201-3, conducted at U.S. sites, will evaluate combinations of HAART, STI, therapeutic vaccination, and selective T-lymphocyte suppression, to test the hypothesis that immune-based therapies will result in sustained HIV -1 containment off therapy that can be correlated with specific measures of anti-HIV immunity. UAB301, conducted in Zambia, will be comprised of brief (3-month) HAART and will test the hypothesis that therapy initiated early after viral infection will reduce viral load setpoint. We will anchor and interpret our clinical observations with a detailed molecular assessment of viral dynamics, viral genetics, immunogenetics, and host immune responses. These studies will provide new insights into HIV-1 pathogenesis and early immune control and a comprehensive set of virologic and immunologic data important to the rational design of HAARTISTI/immunomodulation trials in both developed and developing countries. Finally, our proposal involves collaborations with other AIEDRP units where an important exchange of patient specimens, scientific expertise, technology, and data will continue.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI041530-08
Application #
6945820
Study Section
Special Emphasis Panel (ZAI1-HSD-A (M))
Program Officer
Bupp, Jane E
Project Start
1997-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
8
Fiscal Year
2005
Total Cost
$1,000,000
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Moore, Camille M; MaWhinney, Samantha; Forster, Jeri E et al. (2017) Accounting for dropout reason in longitudinal studies with nonignorable dropout. Stat Methods Med Res 26:1854-1866
Bar, Katharine J; Tsao, Chun-yen; Iyer, Shilpa S et al. (2012) Early low-titer neutralizing antibodies impede HIV-1 replication and select for virus escape. PLoS Pathog 8:e1002721
Meditz, Amie L; MaWhinney, Samantha; Allshouse, Amanda et al. (2011) Sex, race, and geographic region influence clinical outcomes following primary HIV-1 infection. J Infect Dis 203:442-51
Markowitz, Martin; Vaida, Florin; Hare, C Bradley et al. (2010) The virologic and immunologic effects of cyclosporine as an adjunct to antiretroviral therapy in patients treated during acute and early HIV-1 infection. J Infect Dis 201:1298-302
Apuzzo, Linda G; Vaida, Florin; Gallant, Joel E et al. (2009) Tolerability and efficacy of PI versus NNRTI-based regimens in subjects receiving HAART during acute or early HIV infection. J Acquir Immune Defic Syndr 50:267-75
Tang, Jianming; Shao, Wenshuo; Yoo, Yun Joo et al. (2008) Human leukocyte antigen class I genotypes in relation to heterosexual HIV type 1 transmission within discordant couples. J Immunol 181:2626-35
Keele, Brandon F; Giorgi, Elena E; Salazar-Gonzalez, Jesus F et al. (2008) Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci U S A 105:7552-7
Kilby, J Michael; Lee, Ha Youn; Hazelwood, J Darren et al. (2008) Treatment response in acute/early infection versus advanced AIDS: equivalent first and second phases of HIV RNA decline. AIDS 22:957-62
Yoo, Yun Joo; Tang, Jianming; Kaslow, Richard A et al. (2007) Haplotype inference for present-absent genotype data using previously identified haplotypes and haplotype patterns. Bioinformatics 23:2399-406
Hicks, C B; Gay, C; Ferrari, G (2007) Acute HIV infection: the impact of anti-retroviral treatment on cellular immune responses. Clin Exp Immunol 149:211-6

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