Immune perturbations in HIV-1–infected individuals who make broadly neutralizing antibodies

Abstract

Induction of broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development. BnAbs occur in some HIV-1-infected individuals and frequently have characteristics of autoantibodies. Here we have studied cohorts of HIV-1-infected individuals that made bnAbs and compared them to those who did not do so, and determined immune traits associated with the ability to produce bnAbs. HIV-1-infected individuals with bnAbs had a higher frequency of blood autoantibodies, a lower frequency of regulatory CD4+ T cells, a higher frequency of circulating memory T follicular helper CD4+ cells and a higher T regulatory cell level of programmed cell death-1 expression compared to HIV-1-infected individuals without bnAbs. Thus, induction of HIV-1 bnAbs may require vaccination regimens that transiently mimic immunologic perturbations in HIV-1-infected individuals.

Antibody‐virus co‐evolution in HIV infection: paths for HIV vaccine development

“…Third, the adjuvant to be used is critical, and will need to selectively drive high levels of T follicular helper cells (T fh ) and not activate or induce low levels of T regulatory cells (T reg ) in germinal centers (103, 104)(Borrow and Moody, this volume and Havenar-Daughton, Lee and Crotty, this volume).…”

“…Other bnAb types such as CD4bs antibodies are either not deleted in bone marrow or less so than gp41 antibodies, but rather antibody poly-reactivity or auto-reactivity is acquired later in bnAb B cell lineage maturation (17). Thus, for many types of bnAbs, the concept has arisen that a component of a successful vaccine for induction of bnAb B cell lineages to full neutralization breadth will be the formulation of Env vaccines in adjuvants that promote a profile of the immune system in bnAb development with high T fh and low T reg and promote repeated rounds of affinity maturation in germinal centers (103, 104). In addition, HIV-1 infection induces autoimmune manifestations in ~50% of individuals, and those HIV-1 infected individuals that make bnAbs have higher frequencies of autoantibodies than those that do not make bnAbs, indicating that bnAbs arise in the setting of HIV-1-induced loosening of immune tolerance controls (103).…”

“…Thus, for many types of bnAbs, the concept has arisen that a component of a successful vaccine for induction of bnAb B cell lineages to full neutralization breadth will be the formulation of Env vaccines in adjuvants that promote a profile of the immune system in bnAb development with high T fh and low T reg and promote repeated rounds of affinity maturation in germinal centers (103, 104). In addition, HIV-1 infection induces autoimmune manifestations in ~50% of individuals, and those HIV-1 infected individuals that make bnAbs have higher frequencies of autoantibodies than those that do not make bnAbs, indicating that bnAbs arise in the setting of HIV-1-induced loosening of immune tolerance controls (103). Thus, depending on the bnAb lineage, adjuvants or other inhibitors of immune tolerance controls may need to be utilized to achieve full bnAb maturation (Kelsoe and Haynes, this volume).…”

What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination?

“…These requirements for immunization success can be achieved by the work of antibody–virus coevo-lution and mapping (Liao et al 2013; Bon-signori et al 2016), optimization of sequential immunogensto recreate crucial events in HIV-1 infection and bnAb induction (Haynes et al 2012), and vaccine formulations that perturb immune responses to facilitate bnAb development (Gray et al 2009; Moody 2016). …”

“…Second, studies of infected individuals making bnAbs show that HIV-1 infection induces a perturbed immune state characterized by increased frequencies and levels of autoreactive antibody, increased T FH cell numbers, and decreased numbers of T regulatory cells (Treg)—a phenotype similar to the immune dysfunction observed in SLE (Gray et al 2009; Moody 2016). Combined with the autoreactive phenotypes commonly observed in bnAb KI mice (Verkoczy et al 2010; Chen et al 2013; Doyle-Cooper et al 2013; Haynes and Verkoczy 2014) and the identification of host molecules mimicked by HIV-1 Env determinants (Yang et al 2013; Liu et al 2015), these observations suggest that the reason bnAbs are not elicited by vaccines is not the inability to drive sufficient levels of V(D)J mutation but rather limitations of on-target mutation and directed affinity maturation imposed by central and peripheral immune tolerance mechanisms.…”