How can HIV-type-1-Env immunogenicity be improved to facilitate antibody-based vaccine development?

Abstract

No vaccine candidate has induced antibodies (Abs) that efficiently neutralize multiple primary isolates of HIV-1. Preexisting high titers of neutralizing antibodies (NAbs) are essential, because the virus establishes infection before anamnestic responses could take effect. HIV-1 infection elicits Abs against Env, Gag, and other viral proteins, but of these only a subset of the anti-Env Abs can neutralize the virus. Whereas the corresponding proteins from other viruses form the basis of successful vaccines, multiple large doses of HIV-1 Env elicit low, transient titers of Abs that are not protective in humans. The inaccessibility of neutralization epitopes hinders NAb induction, but Env may also subvert the immune response by interacting with receptors on T cells, B cells, monocytes, macrophages, and dendritic cells. Here, we discuss evidence from immunizations of different species with various modified Env constructs. We also suggest how the divergent Ab responses to Gag and Env during infection may reflect differences in B cell regulation. Drawing on these analyses, we outline strategies for improving Env as a component of a vaccine aimed at inducing strong and sustained NAb responses.

FIG. 1.

The early effects of HIV-1 infection on the immune system pose atypical demands on a vaccine. On the one hand, the inflammatory response benefits the virus by providing an expanded pool of susceptible cells (e.g., lymphocyte activation leads to increased CCR5 expression). Conversely, CD4⁺ T lymphocytes are rapidly destroyed in the gut-associated lymphoid tissue (GALT), which deprives the B cell response of much early T cell help. Studies of the timing of postexposure passive immunization after SHIV challenge of macaques show that to prevent infection, the Ab must be given earlier than 24 h after the virus. The time window for immune prevention of the establishment of infection may be similar, and hence too short for an anamnestic response to be effective; the most feasible safety net would be preexisting high titers of neutralizing antibodies.

FIG. 2.

The interplay among gp120, interferon (IFN)-α, interleukin (IL)-10, B cell-activating factor of the TNF family (BAFF), and the receptors CD4, CXCR4, CCR5, IFN-α-R, BAFF-R, mannose-binding C-type lectin receptors (MCLRs), IL-10R, and B cell receptors (BCRs). gp120 (or other forms of Env) can be present on infected cells, on the virion surface, as a soluble protein, or attached to MCLR- or CD4-expressing cells. gp120 and IL-10 together promote IgG and IgA class switch recombination (CSRs), but Ab secretion requires BAFF and BCR engagement; gp120 may induce IL-10 secretion from B cells, monocytes, and dendritic cells via MCLR binding, and it triggers BAFF secretion from monocytes and macrophages. IL-10 and IFN-α also induce BAFF, which can upregulate MCLRs. Env proteins may also engage stereotypical BCRs. The net result of this CD40L-independent circuitry may be impaired development of high-affinity Abs to Env, particularly of the rare cross-neutralizing specificities. (Copyright 2006. The American Association of Immunologists, Inc.)

FIG. 3.

(A) The characteristic saw-tooth pattern of anti-gp120 titers after vaccination is shown on a log scale as a function of time. After each immunization (black arrows) with typically 200 μg of purified, recombinant gp120 in Alum, the binding-Ab titer rises by a log. The titers then decline rapidly. When infection occurs (gray arrow), the titers tend to stabilize at a high plateau. The kinetics of neutralization titers against a hypersensitive HIV-1 strain such as a TCLA virus or SF162 would look similar to the saw-tooth pattern of the first part of the curve, but there would be little or no cross-neutralization of primary isolates. However, several months after infection, significant titers of primary virus-neutralizing Abs do often develop. In (B), three schematic curves illustrate distinct features of immune responses to viral vaccines and infections. Time 0 can represent the time of completion of an immunization series or the initiation of antiretroviral therapy (ART) during infection. In the latter case phases with different rates of decline have been observed; in the former they are hypothetical. The magnitude of the antibody titer decline to a stable level is at least as important as the half-life of the early response. The black curve shows the response with the shortest half-life in the initial phase, ∼4 days, but it also has the smallest decline. The dark gray curve shows a longer initial half-life (10 days), but the decline is large. The light gray curve shows a biphasic decline with an initial intermediate half-life of ∼6 days, and ∼70 days in the second phase. If a minimal protective level equal to a reciprocal titer of 30 (dashed black line) is postulated, the plateau of the black curve falls above that cut-off, the dark gray curve below it. Thus, only the black curve with the initial shortest half-life remains safely above minimal protective levels (although it should be noted that no vaccine-induced Ab titer has been proven to confer protection against HIV-1). This diagram illustrates that the maximum degree of decline can be more important than the initial half-life in determining whether residual Ab levels are protective.