Neutralization tiers of HIV-1

Abstract

Purpose of review: HIV-1 isolates are often classified on the basis of neutralization 'tier' phenotype. Tier classification has important implications for the monitoring and interpretation of vaccine-elicited neutralizing antibody responses. The molecular basis that distinguishes the multiple neutralization phenotypes of HIV-1 has been unclear. We present a model based on the dynamic nature of the HIV-1 envelope glycoproteins and its impact on epitope exposure. We also describe a new approach for ranking HIV-1 vaccine-elicited neutralizing antibody responses.

Recent findings: The unliganded trimeric HIV-1 envelope glycoprotein spike spontaneously transitions through at least three conformations. Neutralization tier phenotypes correspond to the frequency by which the trimer exists in a closed (tiers 2 and 3), open (tier 1A), or intermediate (tier 1B) conformation. An increasing number of epitopes become exposed as the trimer opens, making the virus more sensitive to neutralization by certain antibodies. The closed conformation is stabilized by many broadly neutralizing antibodies.

Summary: The tier 2 neutralization phenotype is typical of most circulating strains and is associated with a predominantly closed Env trimer configuration that is a high priority to target with vaccines. Assays with tier 1A viruses should be interpreted with caution and with the understanding that they detect many antibody specificities that do not neutralize tier 2 viruses and do not protect against HIV-1 infection.

Box 1

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FIGURE 1

Balance of conformational states in the HIV-1 Env trimer. Shown is a model based on the findings of Munroe et al.[^▪▪] and also proposed by Cai et al.[^▪▪]. Native Env trimers on the virus surface are structurally dynamic and constantly transitioning between at least three conformations that differentially expose a variety of epitopes for nonbNAbs. Env trimers on tier 2 viruses predominantly occupy a closed conformation that masks nonbNAb epitopes. Env trimers on tier 1A viruses frequently transition to an open conformation that exposes these epitopes, making the viruses highly sensitive to neutralization by polyclonal HIV-1 sera and many current vaccine-elicited antibodies. Tier 1B viruses may spend relatively more time in an intermediate conformation that partially exposes these epitopes.