Helbert, Matthew Reginald; (1995) HIV infection in sub-populations of CD4+ lymphocytes defined by CD45. Doctoral thesis (Ph.D.), University College London.

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Abstract

Cardinal features of HIV infection are clinical loss of immunological memory and failure of CD4+lymphocytes to respond to recall antigens in vitro. CD4+ lymphocytes expressing the RO isoform of CD45 mediate immunological memory and are lost early in infection and infected more readily by HIV; the aim of this project was to investigate these predilections for CD45RO+ cells. CD4+ lymphocytes expressing CD45RO and CD45RA (antigen naive cells) express similar quantities of CD4, the receptor for HIV, and bind the viral envelope glycoprotein, gp120, equally well. Gp120 binding induces weak activation signals in both populations, reflected by influxes of calcium, somewhat greater in CD45RO+ cells. Gp120 also induces down-regulation of CD4, particularly in CD45RA+ cells; CD45RO+ cells may be protected from this effect by tyrosine kinase activity. CD45RO+ cells form syncytia with chronically infected T cell lines more efficiently than their CD45RA+ counterparts, possibly a consequence of increased integrin expression and affinity. In vitro, cell free HIV infection also precedes more effectively in CD45RO+ cells, possibly because reverse transcription proceeds more readily in the activated cells contained in this population. When CD45RA+ and RO+ cells are activated in vitro following infection, there are similar amounts of viral DNA in both populations, implying a degree of basal activation in un-stimulated CD45RO+ cells promotes cell free infection. TNF has been cited as a means of breaking viral latency in lymphocytes, particularly those expressing CD45RO. However, resting CD45RA+ and RO+ cells express minimal quantities of TNF receptor and are unable to transduce TNF signals. The "TNF autocrine loop" may not be important in up-regulating HIV transcription in resting cells. HIV may also indirectly affect the population kinetics of CD4+ lymphocytes, by affecting antigen presenting cell function; the differences shown here between CD45RA+ and CD45RO+ populations are not major, but together may contribute towards the understanding of the preferential infection of CD45RO+ cells.

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