Date of Award

1997

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Dr. Kenneth L. Rosenthal

Abstract

Cytotoxic T-lymphocytes (CTL) are important in resistance to HIV-1 infection, and modulate disease progression through various effector functions. Conventional CTL recognizing antigenic peptides in the context of major histocompatibility (MHC) class I molecules eliminate virally-infected cells, and have been shown to modulate the course of disease progression. Other functions of CD8⁺ lymphocytes include non-lytic suppresion of viral transcription and replication, and induction of programmed cell death in activated CD4⁺ cells. In the work presented here, the interactions of CD8⁺ lymphocytes with activated CD4⁺ cells were examined. Lysis of activated CD4⁺ cells was unique for CTL derived from HIV-1 infeced persons, and was not restricted by MHC molecules. The interaction was dependent on target cell activation, correlated with cell proliferation, and was independent of viral replication. Furthermore, the lytic process was biochemically consistent with apoptosis, and resulted in nuclear fragmentation in the target cells. In vitro susceptibility to infection by primary HIV-1 isolates was assessed in a cohort of couples consisting of an infected and an uninfected, but exposed, partner. These findings were correlated with the genetic integrity of the HIV-1 co-receptors, and with the presence of CTL specifically directed against the partner's primary isolate. Individuals with partial or complete resistance to infection were identified, as well as some individuals that had CTL recognizing the partner's viral isolate. The latter results suggested that cellular immune responses comprise a major component of resistance to HIV infection, and that they influence resistance even in individuals lacking the main HIV-1 co-receptor. The later studies were extended by examining the in vitro infectivity of CD4⁺ cells from a group of highly exposed, but persistently uninfected, Kenyan sex workers. No barrier to infection of CD4⁺ lymphocytes with primary Kenyan HIV isolates was identified, however, CD8⁺ cells from these subjects were able to efficiently limit viral replication in autologous CD4⁺ cells. In summary, the broadly different CTL effector functions described in these studies illustrate the importance of the cellular immune system in resistance to HIV infection, and in modulating the disease pathogenesis.

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