'Immunization during ART and ATI for HIV-1 vaccine discovery/development'

Abstract

Purpose of review: Explore whether immunization with germline-targeting Env immunogens during ART, followed by ATI, leads to the identification of viral envelope glycoproteins (Envs) that promote and guide the full maturation of broadly neutralizing antibody responses.

Recent findings: The HIV-1 envelope glycoprotein (Env) does not efficiently engage the germline precursors of broadly neutralizing antibodies (bnAbs). However, Env-derived proteins specifically designed to precisely do that, have been recently developed. These 'germline-targeting' Env immunogens activate naïve B cells that express the germline precursors of bnAbs but by themselves cannot guide their maturation towards their broadly neutralizing forms. This requires sequential immunizations with heterologous sets of Envs. These 'booster' Envs are currently unknown.

Summary: Combining germline-targeting Env immunization approaches during ART with ATI could lead to the identification of natural Envs that are responsible for the maturation of broadly neutralizing antibody responses during infection. Such Envs could then serve as booster immunogens to guide the maturation of glBCRs that have become activated by germline-targeting immunogens in uninfected subjects.

Box 1

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FIGURE 1

Guided maturation of a bnAb precursor during prime-boost immunizations. To elicit bnAbs through immunization, the first immunogen will activate the glBCR of interest (‘germline-targeting’ immunogen) and heterologous immunogens (‘booster’ immunogens) will be administered, in a specific order, to select and further activate those BCRs that have accumulated appropriate mutations (green).

FIGURE 2

Combining germline-targeting immunization with ATI. (a) B cells expressing BCRs of diverse Env epitope specificities that give rise to nonneutralizing antibodies become activated following HIV-1 infection, but B cells expressing germline BCR precursors of broadly neutralizing antibodies (white B cells) are not activated by the replicating virus, despite the gradual increase in viral Env diversity. (b) Immunization with specifically-designed germline-targeting Env-derived immunogens will lead to the activation of the latter B cells which will enter the germinal center reaction where their B cell receptors will accumulate mutations (Light blue B cells). These B cells will become further activated by specifically viral variants that emerge during ATI and will accumulate additional mutations and become broadly neutralizing (red B cells).