Although HIV infection is generally associated with prolonged clinical latency, an expanding body of evidence points to the importance of early events for determining the outcome of HIV infection. Primary infection of humans with HIV-1 is often associated with an acute mononucleosis-like clinical syndrome characterized by fever, malaise, pharyngitis, lymphadenopathy, headache, diarrhea, rash and meningoencephalitis and is accompanied by a burst in virus replication detectable in the blood approximately 1-3 weeks following exposure. The appearance of specific antiviral immune responses is associated with dramatic reductions in the level of viremia, but there is no clearance of the virus. Limitations inherent in studying human subjects have precluded detailed investigation of many of the early events critical for virus transmission, dissemination and eventual disease progression. The SIV/macaque model will be used to address these critical issues. Whether there is selective transmission of particular SIV genotypes across the mucosal surface will be determined. The initial cellular targets of primary infection by the mucosal and intravenous routes will be identified and the sequential targets of the spreading viral infection will be- characterized. Analyses will include subsets of CD4+ lymphocytes and progenitor cells in thymus and bone marrow as possible preferential targets. The influence of varying viral genotype on transmission, dissemination to tissues and tissue-specific disease manifestations will be investigated. Finally, the importance of cytotoxic T lymphocytes for controlling the early burst in virus replication will be investigated in this manipulable experimental setting. These studies will be achieved through the cooperation of three principal investigators at the New England Regional Primate Research Center with extensive experience in the disciplines of Virology, Molecular Biology, Pathology and Immunology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI038559-01
Application #
2075619
Study Section
Special Emphasis Panel (SRC (55))
Project Start
1995-09-01
Project End
1999-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Kaur, A; Alexander, L; Staprans, S I et al. (2001) Emergence of cytotoxic T lymphocyte escape mutations in nonpathogenic simian immunodeficiency virus infection. Eur J Immunol 31:3207-17
Vajdy, M; Veazey, R S; Knight, H K et al. (2000) Differential effects of simian immunodeficiency virus infection on immune inductive and effector sites in the rectal mucosa of rhesus macaques. Am J Pathol 157:485-95
Kaur, A; Yang, J; Hempel, D et al. (2000) Identification of multiple simian immunodeficiency virus (SIV)-specific CTL epitopes in sooty mangabeys with natural and experimentally acquired SIV infection. J Immunol 164:934-43
Kaur, A; Hale, C L; Ramanujan, S et al. (2000) Differential dynamics of CD4(+) and CD8(+) T-lymphocyte proliferation and activation in acute simian immunodeficiency virus infection. J Virol 74:8413-24
Alexander, L; Weiskopf, E; Greenough, T C et al. (2000) Unusual polymorphisms in human immunodeficiency virus type 1 associated with nonprogressive infection. J Virol 74:4361-76
Alexander, L; Du, Z; Howe, A Y et al. (1999) Induction of AIDS in rhesus monkeys by a recombinant simian immunodeficiency virus expressing nef of human immunodeficiency virus type 1. J Virol 73:5814-25
Kaur, A; Grant, R M; Means, R E et al. (1998) Diverse host responses and outcomes following simian immunodeficiency virus SIVmac239 infection in sooty mangabeys and rhesus macaques. J Virol 72:9597-611
Howe, A Y; Jung, J U; Desrosiers, R C (1998) Zeta chain of the T-cell receptor interacts with nef of simian immunodeficiency virus and human immunodeficiency virus type 2. J Virol 72:9827-34
Veazey, R S; DeMaria, M; Chalifoux, L V et al. (1998) Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280:427-31
Wykrzykowska, J J; Rosenzweig, M; Veazey, R S et al. (1998) Early regeneration of thymic progenitors in rhesus macaques infected with simian immunodeficiency virus. J Exp Med 187:1767-78

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