Dissecting the Neutralizing Antibody Specificities of Broadly Neutralizing Sera from Human Immunodeficiency Virus Type 1-Infected Donors

Abstract

Attempts to elicit broadly neutralizing antibody responses by human immunodeficiency virus type 1 (HIV-1) vaccine antigens have been met with limited success. To better understand the requirements for crossneutralization of HIV-1, we have characterized the neutralizing antibody specificities present in the sera of three asymptomatic individuals exhibiting broad neutralization. Two individuals were infected with clade B viruses and the third with a clade A virus. The broadly neutralizing activity could be exclusively assigned to the protein A-reactive immunoglobulin G (IgG) fraction of all three donor sera. Neutralization inhibition assays performed with a panel of linear peptides corresponding to the third hypervariable (V3) loop of gp120 failed to inhibit serum neutralization of a panel of HIV-1 viruses. The sera also failed to neutralize chimeric simian immunodeficiency virus (SIV) and HIV-2 viruses displaying highly conserved gp41-neutralizing epitopes, suggesting that antibodies directed against these epitopes likely do not account for the broad neutralizing activity observed. Polyclonal IgG was fractionated on recombinant monomeric clade B gp120, and the neutralization capacities of the gp120-depleted samples were compared to that of the original polyclonal IgG. We found that the gp120-binding antibody population mediated neutralization of some isolates, but not all. Overall, the data suggest that broad neutralization results from more than one specificity in the sera but that the number of these specificities is likely small. The most likely epitope recognized by the monomeric gp120 binding neutralizing fraction is the CD4 binding site, although other epitopes, such as the glycan shield, cannot be excluded.

High prevalence of neutralizing activity against multiple unrelated human immunodeficiency virus type 1 (HIV-1) subtype B variants in sera from HIV-1 subtype B-infected individuals: evidence for subtype-specific rather than strain-specific neutralizing activity

“…It was reported recently that cross-clade neutralizing activity is not directed only against the conserved regions of the envelope, such as the CD4-binding site (Dhillon et al, 2007;Doria-Rose et al, 2009;Guan et al, 2009;Li et al, 2007;Sather et al, 2009;Scheid et al, 2009) or the V3 loop (Li et al, 2009). It is likely that epitopes that are less well-conserved between subtypes, but conserved within a subtype, are capable of eliciting subtype-specific crossreactive neutralizing activity.…”

Neutralization of feline immunodeficiency virus by antibodies targeting the V5 loop of Env

“…A vaccine capable of protecting cats against infection with a wide range of virulent primary isolates remains a challenge, primarily because of the limited number of conserved neutralization epitopes that have been identified and the failure to present such epitopes appropriately in vaccines. Steric factors may render neutralization epitopes inaccessible to NAbs (Chiarantini et al, 1998;Labrijn et al, 2003), whilst most of the antibodies generated by vaccination may be directed against non-neutralizing epitopes (Dhillon et al, 2007;Richman et al, 2003). Accordingly, the identification of conserved determinants for neutralization will be an important advance in the design of the next generation of FIV vaccines.…”

“…be directed against non-neutralizing epitopes (Dhillon et al, 2007;Richman et al, 2003). Accordingly, the identification of conserved determinants for neutralization will be an important advance in the design of the next generation of FIV vaccines.…”

Enhanced HIV-1 neutralization by antibody heteroligation

“…Although antibodies that neutralize autologous viruses are common, only a fraction of the patients infected with HIV-1 develop broadly neutralizing serologic activity, and only 2 to 3 y after infection (3)(4)(5)(6)(7)(8)(9). Several broadly neutralizing antibodies (bNAbs) to HIV-1 gp160 have been isolated, including a group that binds to gp120 (10)(11)(12)(13)(14)(15)(16)(17)(18) and a group that is specific for gp41 (19)(20)(21).…”