The Acquired Immune Deficiency Syndrome is a progressive debilitating disorder, of viral origin, which eventually destroys the cellular immune system and lays the affected individual open to devastating bouts of infection. The Human Immunodeficiency Virus (HIV) infects both T-helper lymphocytes and macrophages and, in early stages of the disease, stimulates a vigorous yet non- protective immune response. It is my objective to understand the pathogenesis of this disease by examining the relationships between immune responses and the spread of viral infection. The most direct effect of viral infection in vivo is the drastic depletion of T-helper cells. Immunological stimulation of Th cells causes them to become activated and to progress through defined stages of cellular differentiation under the influence of well- described factors. The initial objective of this proposal is to define particular stages of T-cell differentiation which are susceptible to viral infection and discern the immunological signals required to establish that stage. In addition, we will examine the relationships between T-cell activation and virus production. A variety of evidence suggests that a virus reservoir exists in addition to infected T-cells. It is known that cells from the monocyte/macrophage lineage are also infected in AIDS, and evidence exists that phenotypic and functional properties of this population are affected. Other lentiviruses, in particular the Visna virus of sheep, are known to infect monocytes and to establish a low level, persistent viremia; this is the virus reservoir. Viral persistence is established in these cells because of immune response by T-cell to the presence of infected monocytes. The second objective of this proposal seeks to assess the effects of HIV infection on human monocyte differentiation in and, conversely, to examine the effect monocyte differentiation has on virus production. These studies are designed to determine if these cells have the potential to establish a virus reservoir in AIDS. An understanding of the roles played by the immune system in promoting the spread of viral infection at the cellular level, will elucidate the factors which regulate the slow, progressive nature of AIDS during its early stages and may uncover the conditions which cause the precipitous transition to the fatal stage of the disease. In addition, we may discover potential new mechanisms for the action of cofactors, such as other viral or microbial pathogens, which may increase susceptibility to HIV infection and promote the onset of AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI024591-03
Application #
3137683
Study Section
Special Emphasis Panel (SSS (G))
Project Start
1988-09-30
Project End
1992-04-30
Budget Start
1990-09-01
Budget End
1992-04-30
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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Trivedi, P; Meyer, K K; Streblow, D N et al. (1994) Selective amplification of simian immunodeficiency virus genotypes after intrarectal inoculation of rhesus monkeys. J Virol 68:7649-53
Pauza, C D; Trivedi, P; McKechnie, T S et al. (1994) 2-LTR circular viral DNA as a marker for human immunodeficiency virus type 1 infection in vivo. Virology 205:470-8

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