Protective versus pathogenic anti-CD4 immunity: insights from the study of natural resistance to HIV infection

Abstract

HIV-1 exposure causes several dramatic unbalances in the immune system homeostasis. Here, we will focus on the paradox whereby CD4 specific autoimmune responses, which are expected to contribute to the catastrophic loss of most part of the T helper lymphocyte subset in infected patients, may display the characteristics of an unconventional protective immunity in individuals naturally resistant to HIV-1 infection. Reference to differences in fine epitope mapping of these two oppositely polarized outcomes will be presented, with particular reference to partially or totally CD4-gp120 complex-specific antibodies. The fine tuning of the anti-self immune response to the HIV-1 receptor may determine whether viral exposure will result in infection or, alternatively, protective immunity.Along this line, an efficacious anti-HIV strategy can rely on the active (i.e., through immunization) or passive targeting of cryptic epitopes of the CD4-gp120 complex, including those harboured within the CD4 molecule. Such epitopes are expected to be safe from genetic drift and thus allow for broad spectrum of efficacy. Moreover, since these epitopes are not routinely exposed in uninfected individuals, they are expected to become targets of neutralizing antibodies or other specifically designed molecules only after viral exposure, with a predictable low impact in terms of potentially harmful anti-CD4 self-reactivity.The experimentum naturae of naturally resistant individuals indicates a strategy to design innovative strategies to neutralize HIV-1 by acting on the sharp edge between harmful and protective self-reactivity.

Figure 1

Schematic representation of the interaction between CD4 and gp120, with reference to the formation of new epitopes. The indicated monoclonal antibodies are either exclusively (CG10) or preferentially (DB-81) binding to CD4 complexed to gp120 (right part of the figure), as compared to CD4 only (left part of the figure). Similarly, the anti-gp120 D19 monoclonal antibody is represented, which binds with higher affinity to gp120 complexed to CD4, as compared to (R5-coreceptor restricted) gp120 only. The affinities of the antigen-antibody interactions are proportional to the thickness of the arrow pointing to the epitope.

Figure 2

B factors (as a measure of local backbone mobility, on the y-axys) of C-alpha atoms for the free (gray) and the gp120-complexed (red) CD4 protein (C-alpha residue numbering is on the x-axis, according to UniProtKB/Swiss-Prot P01730).The first Ig-like V-type (residues 26 -- 125) and the second Ig-like C2-type 1 (residues 126 -- 203) were included in this analysis. Data were calculated from PDB files 3CD4 and 2NXY for free and complexed CD4, respectively. The third and forth domains were not considered due to the expected influence on B factors of these portions of the molecule by physiological CD4 dimerization.

Figure 3

Regions of CD4 structure (within the first and the second CD4 domain) that display (in red) the greatest changes in C-alpha B factor between the free form and the one complexed with gp120. The C-alpha B-factor was calculated as a measure of local backbone flexibility.

Figure 4

Local differences in the conformation of CD4 in the gp120-bound versus free state. Absolute variations of dihedral backbone angles Φ (upper panel) ad Ψ (lower panel) between bound and free CD4 structure are plotted on the y-axis against the single residues (on the x-axis) whose local geometry is influenced by the interaction between the two moieties.