Abstract

The proposal is a response to Program AnnounCement 96-060, Acute Infection and Early Disease Research Network We propose to recruit 30-50 individuals, primarily injection drug users, with recent HIV- l infection for detailed studies of the effect of early, aggressive treatment of HIV-1 infection. The treatments that will be given include newly developed, highly potent antiretroviral drug combinations; study participants will be randomized to receive or not receive the immunostimulatory cytokine, interleukin-2 (IL-2). The effect of these treatments on the natural history and pathogenesis of HIV-1 infection will be studied. Hypotheses to be tested include l) antiretroviral therapy will suppress, but not eradicate, infectious and latent HIV in PBMC; 2) the extent of suppression of HIV-1 will correlate with the fitness of the early HIV-1 isolate, and with the resiStanCe of the virus to drug therapy; 3) IL-2 will enhance the degree of viral suppression and will augment HIV-specific CLT memory pools; 4) suppression of HIV replication by the drugs will correlate with establishment of in vitro resistance of PBMC to infection with HIV; 5) IL-2 reduces the extent of HIV-l acute damage to the T Cell repertoire and accelerates the recovery from this damage, which is reflected in depletion of memory Cells and development of """"""""holes"""""""" in the T Cell repertoire; and 6) production of IL-12, a key stimulater of all- mediated immunity, is defective from the onset of HIV infection, and this defect is mediated by a complement-CD46 interaction on mononuclear phagocytes. These hypotheses will be tested in an integrated design using several newly developed methods for assessing latent infection of cells with HIV-1, diversity of T Cell receptor expression, phenotypic expression of CD4+ lymphocytes, viral fitness, and cytokine levels in vivo and in vitro. The data obtained will help define the optimal use of the new, potent therapies for HIV-1 infection, and will also help to understand the mechanism of immune system damage in HIV-l infection.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI041532-02
Application #
2673034
Study Section
Special Emphasis Panel (ZAI1-SCO-A (M1))
Project Start
1997-07-01
Project End
2001-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

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
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
Hultin, Lance E; Chow, Marianne; Jamieson, Beth D et al. (2010) Comparison of interlaboratory variation in absolute T-cell counts by single-platform and optimized dual-platform methods. Cytometry B Clin Cytom 78:194-200
Kearney, M; Maldarelli, F; Shao, W et al. (2009) Human immunodeficiency virus type 1 population genetics and adaptation in newly infected individuals. J Virol 83:2715-27
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
Kearney, Mary; Palmer, Sarah; Maldarelli, Frank et al. (2008) Frequent polymorphism at drug resistance sites in HIV-1 protease and reverse transcriptase. AIDS 22:497-501
Norris, Philip J; Pappalardo, Brandee L; Custer, Brian et al. (2006) Elevations in IL-10, TNF-alpha, and IFN-gamma from the earliest point of HIV Type 1 infection. AIDS Res Hum Retroviruses 22:757-62
Sabundayo, Beulah P; McArthur, Julie H; Langan, Susan J et al. (2006) High frequency of highly active antiretroviral therapy modifications in patients with acute or early human immunodeficiency virus infection. Pharmacotherapy 26:674-81
Iyengar, Sujatha; Chin, Bennett; Margolick, Joseph B et al. (2003) Anatomical loci of HIV-associated immune activation and association with viraemia. Lancet 362:945-50
Rawal, Bhupat D; Degula, Azucena; Lebedeva, Ludmila et al. (2003) Development of a new less-sensitive enzyme immunoassay for detection of early HIV-1 infection. J Acquir Immune Defic Syndr 33:349-55

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