B lymphocyte responses in primary HIV-1 infection

Self-reactivity may explain the rarity of HIV-1-specific broadly neutralising antibodies directed against the highly conserved membrane-proximal epitope region (MPER) of gp41, because binding in the hydrophobic region abutting the viral membrane results in cross-reactivity with phospholipids. It was hypothesised that such antibodies are present early in infection before tolerance mechanisms remove them from the B cell repertoire, and that they emerge from transitional B cells which rapidly differentiate to antibody-secreting plasmablasts, since these populations are expanded during HIV 1 infection and express higher proportions of self-reactive clones.Sera from 313 primary infection patients was screened for neutralising activity using a single round of infection, Env-pseudotyped, flow cytometry-based neutralisation assay. 74 sera possessed neutralising activity and seventeen also had anticardiolipin activity. The correlation between neutralising ability and elevated anticardiolipin antibody was significant, however peptide blocking experiments revealed no MPER-specific antibodies.It was postulated that B cell phenotypic profiling during primary infection would predict patients who went on to control viraemia in chronic infection. 22 patients who controlled viraemia after 12 months without therapy (50000 copies/mL) and 15 healthy controls using thirteen-parameter flow cytometry on the first available sample in primary infection. Transitional B cell, naïve B cell, plasmablast and CD21-CD27- tissue-like memory B cell populations were all significantly expanded at this early time point in the non-controller group and as such may identify patients who fail to control viraemia. Only the CD21-CD27- subset was increased in eventual controllers. The changes are similar to those described in chronic infection, except that CD27+ memory B cell numbers were not significantly altered in primary infection.CD4+ T follicular helper cells (Tfh) provide B cell help in the germinal centre but have not been characterised in HIV 1 infection. Circulating Tfh-like PD 1highCD4+ T cells were increased in HIV non-controllers in primary infection but whether they represent true Tfh is unclear. Phenotypic and molecular assays were developed to identify Tfh in lymphoid tissue in the pigtail macaque SIV infection model. Tfh were infected at the same rate as other CD4+ memory T cells, yet surprisingly expanded proportionally as a population as infection progressed. It is proposed that this expansion underlies the dysregulation of B cell and antibody responses in HIV 1 infection. The impact of HIV 1 infection on Tfh function is under assessment. Careful manipulation of Tfh function has therapeutic potential and could improve vaccine responses