B cell responses to HIV-1 infection and vaccination: pathways to preventing infection

Abstract

The B cell arm of the immune response becomes activated soon after HIV-1 transmission, yet the initial antibody response does not control HIV-1 replication, and it takes months for neutralizing antibodies to develop against the autologous virus. Antibodies that can be broadly protective are made only in a minority of subjects and take years to develop--too late to affect the course of disease. New studies of the earliest stages of HIV-1 infection, new techniques to probe the human B cell repertoire, the modest degree of efficacy in a vaccine trial and new studies of human monoclonal antibodies that represent the types of immune responses an HIV-1 vaccine should induce are collectively illuminating paths that a successful HIV-1 vaccine might take.

Figure 1. Onset of immune responses to HIV-1 in AHI

The first systemically detectable immune responses to HIV-1 infection are the increases in levels of acute-phase proteins in the plasma, which are observed when virus replication is still largely restricted to the mucosal tissues and draining lymph nodes (eclipse phase). When virus is first detected in the plasma (T₀), broad and dynamic increases in plasma cytokine levels are also observed. Within days, as plasma viremia is still increasing exponentially, the first antibody–virus immune complexes are detected. Expansion of the earliest HIV-1-specific CD8⁺ T cell responses also commences prior to peak viremia, followed by detection of the first free gp41-specific but non-neutralizing IgM antibodies. Complete virus escape from the first CD8⁺ T cell responses can occur rapidly, within 10 days of T cell expansion. By this time, viral reservoirs exist, possibly becoming established within days of infection. The earliest autologous-virus-nAbs are detected around day 80 following infection, as viral loads are still declining prior to the onset of the viral set point. Antibody escape virus mutants emerge in the plasma within the following week. Figure is reproduced with permission from McMichael AJ, Haynes BF et al. Nature Medicine, 10:11–23, 2010. © Nature Publishing Group.

Figure 2. The cytokine storm in AHI

The relative kinetics of elevation of acute-phase proteins, cytokines and chemokines in the plasma during AHI. There are two initial waves of cytokines produces: IL-15and IFN-α, followed by TNF, IL-18 and IL-10. Abbreviations: CXCL10, CXC-chemokine ligand 10 The figure is reproduced with permission from Stacey AR, Borrow P et al. Journal of Virology, 83:3719-33, 2009. © American Society for Microbiology from reference .

Figure 3. Changes in terminal ileum B cell germinal center follicular dendritic cells in early HIV-1 infection

Terminal ileum tissues were stained with mAbs specific for follicular dendritic cells (FDCs). Left image shows a fine reticular pattern typical of a normal germinal center taken from terminal ileum Peyer’s patch of an uninfected control subject. Right image shows disruption of the normal germinal center architecture in tissue taken from a subject infected with HIV-1 approximately 105 days prior to biopsy. FDCs are clumped and have lost the typical reticular pattern of germinal center FDCs. Potential causes of germinal center damage include: direct virion binding to B cells and FDCs; inflammatory cytokines including INF-α, TNF, and IL-6; induction of TRAIL, Fas ligand, and TNF receptor-2; induction of CD8+ cytotoxic T lymphocytes; natural killer cell cytolysis; activation-associated exhaustion and apoptosis of B cells; B cell apoptosis due to loss of CD4 T cells; FDC loss due to B and CD4 T cell loss (i.e. loss of FDC positioning cues); and macrophage-mediated ADCC. Images taken at 20x; black bar equals 50 μm.