Virus tropism and neutralization response in SIV infection
Simian immunodeficiency virus (SIV) infections in macaques are commonly used as models to study the pathogenesis of human immunodeficiency virus (HIV). Both SIV and HIV normally use the CD4 receptor and an additional coreceptor for cell entry. The most common coreceptors used by HIV are CCR5 and CXCR4. SIV use CCR5 and rarely CXCR4 but may use other coreceptors as alternatives. We have studied virus tropism and evolution of the humoral immune response in relation to pathogenesis in cynomolgus macaques experimentally infected with SIVsm (of sooty mangabey origin) by intravenous (IV) or intrarectal (IR) route. Route of transmission did not influence disease progression or virus tropism. CCR5 was the major coreceptor used and isolates were in general multitropic, using CCR5, CXCR6 and/or gpr15. Furthermore, both macrophages and peripheral blood mononuclear cells (PBMC) could be readily infected with all the SIVsm reisolates. CXCR4-using viruses could be isolated, but only when human cells were used for virus isolation. Human cells may also select for virus variants with increased CD4-dependence. Comparisons of SIV and HIV-1 showed differences in mode of CCR5 use which in turn may explain the CD4-independence of SIVsm. Virus production after CD4-independent infection occurred both intracellularly and extracellularly. Neutralizing antibodies appeared earlier in IV-infected animals than in IR-infected animals. In progressors, this early humoral immune response was accompanied by early appearance of neutralization resistant variants. The majority of monkeys with progressive disease showed broadening of coreceptor use, stable coreceptor use or fluctuation in the use of different coreceptors. Viruses maintained effective replication in macrophages and PBMC and evolved to escape neutralizing antibodies already at three months after infection. In contrast, viruses from long-term non-progressor (LTNP) monkeys became less fit as shown by decreased frequency of successful virus isolations, narrowing of coreceptor use or stable CCR5 use and evolution to a more limited macrophage-tropism. Appearance of neutralization escape variants was delayed as compared to the early neutralization resistance in progressors. Neutralization resistance, whenever evident correlated with increased CD4-dependence in LTNP monkeys.
Source Type:Doctoral Dissertation
Keywords:MEDICINE; Natural science; Naturvetenskap; Medicin (människa och djur); Medicine (human and vertebrates); HIV; SIV; mode of CCR5 use; CD4-independence; macrophage tropism; coreceptor use; neutralization; evolution; pathogenesis
Date of Publication:01/01/2006