The balance between latent and productive human immunodeficiency virus (HIV) infection is the result of a complex interplay of viral and host factors. In the first part of this study I investigated a group of 6 HIV+ haemophilic long term nonprogressor~ (LTNP) for maintenance of functional defects of their HIV-I nefgene. Our results showed that Nef alleles from these nonprogressor hemophiliacs are defective in enhancing virus replication and CD4 down-regulation. This was not predictive of disease outcome as 3 out of the 6 individuals studied progressed later to full HIV disease. The primary viral isolates from these the 3 'late progressors' showed an extension of gpl20 Env dependent entry co-receptor use from CCR5 only to CCR5/CXCR4, a known correlate of disease progression, while the non I f progressors maintained monotropic CCR5 use. In addition to viral genes, several pro-inflammatory cytokines upregulated in HIV infection influence HIV latency and replication via activation of cellular transcription factors. Peripheral blood mononuclear cells from HIV+ individuals frequently show a constitutive activation of the cytokine-related Janus kinase/Signal Transducer and Activator of Transcription (JAKISTAT) pathway, and particularly of a C-terminally truncated isoform of STAT5 (STAT5 ). I investigated whether STAT5 and STAT5~ could affect HIV transcription and replication. STAT5 induced HIV transcription driven by the long terminal repeats (LTR). Chromatin immunoprecipitation and related molecular assays showed that STAT5~ actually bound to the HIV LTR and suppressed viral transcription and expression. Thus, a key finding from the present thesis is that the constitutiveIy activated STAT5~ present in the leukocytes of most HIV-positive individuals acts as a negative regulator of HIV expression. Thus, both viral factors, such as the evolution of gp120 Env coreceptor use towards CXCR4 in individuals maintaining functional nef mutations, and host transcription factors, including STAT5/STAT58, regulate HIV- I replication in vitro and, likely, its pathogenicity in infected individuals.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:487160 |
| Date | January 2007 |
| Creators | Crotti, Andrea |
| Publisher | Open University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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