Antibodies That Are Cross-Reactive for Human Immunodeficiency Virus Type 1 Clade A and Clade B V3 Domains Are Common in Patient Sera from Cameroon, but Their Neutralization Activity Is Usually Restricted by Epitope Masking

Abstract

Sera from human immunodeficiency virus type 1 (HIV-1)-infected North American patients recognized a fusion protein expressing a V3 loop from a clade B primary isolate virus (JR-CSF) but not from a clade A primary isolate virus (92UG037.8), while most sera from Cameroonian patients recognized both fusion proteins. Competition studies of consensus V3 peptides demonstrated that the majority of the cross-reactive Cameroonian sera contained cross-reactive antibodies that reacted strongly with both V3 sequences. V3-specific antibodies purified from all six cross-reactive sera examined had potent neutralizing activity for virus pseudotyped with envelope proteins (Env) from SF162, a neutralization-sensitive clade B primary isolate. For four of these samples, neutralization of SF162 pseudotypes was blocked by both the clade A and clade B V3 fusion proteins, indicating that this activity was mediated by cross-reactive antibodies. In contrast, the V3-reactive antibodies from only one of these six sera had significant neutralizing activity against viruses pseudotyped with Envs from typically resistant clade B (JR-FL) or clade A (92UG037.8) primary isolates. However, the V3-reactive antibodies from these cross-reactive Cameroonian sera did neutralize virus pseudotyped with chimeric Envs containing the 92UG037.8 or JR-FL V3 sequence in Env backbones that did not express V1/V2 domain masking of V3 epitopes. These data indicated that Cameroonian sera frequently contain cross-clade reactive V3-directed antibodies and indicated that the typical inability of such antibodies to neutralize typical, resistant primary isolate Env pseudotypes was primarily due to indirect masking effects rather than to the absence of the target epitopes.

Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates

“…Zolla-Pazner and colleagues have produced a human mAb, 447-52D that was reported to neutralize approximately 40% of Clade B strains [80], but a subsequent study reported that this antibody rarely neutralizes typical (Tier 2) primary patient isolates [89]. Therefore, it appears that most HIV-1 Clade B strains either are in a conformation that obscures the V3 loop neutralizing determinants [87], or that induced antibodies do not bind the V3 loop sufficiently to neutralize Tier 2 (relatively more difficult to neutralize) HIV-1 [90].…”

“…With Korber, we have studied a panel of V3 peptides selected to represent a spectrum of potential higher order V3 motifs of Krachmarov and colleagues have now made human mAbs against non-B V3s and found antibodies that neutralize a subset of non-B HIV-1 strains [90]. The structure of a V3-containing HIV-1 gp120 core has recently been published and provides evidence that the V3 loop functions as a molecular 'hook', not only for binding to coreceptor but also for modulating sub-unit associations within the viral spike of the HIV-1 envelope trimer [93].…”

“…Similarly, with the difference in neutralization sensitivity between T-cell line adapted (TCLA) HIV-1 and primary isolates that was observed with V3 antibodies [85,86], it was realized that the envelope structure of TCLA viruses was likely quite different than the native HIV-1 trimer of primary isolates [87]. Hope for a practical V3 immunogen has resurfaced with the work of Zolla-Pazner and colleagues who have shown similarity of the V3 loop with chemokine receptor structure, and human anti-V3 mAbs that can neutralize a subset of HIV-1 grown in PBMC [80,81].With Korber, we have studied a panel of V3 peptides selected to represent a spectrum of potential higher order V3 motifs of Krachmarov and colleagues have now made human mAbs against non-B V3s and found antibodies that neutralize a subset of non-B HIV-1 strains [90]. The structure of a V3-containing HIV-1 gp120 core has recently been published and provides evidence that the V3 loop functions as a molecular 'hook', not only for binding to coreceptor but also for modulating sub-unit associations within the viral spike of the HIV-1 envelope trimer [93].…”

Human Immunodeficiency Virus Type 2 (HIV-2)/HIV-1 Envelope Chimeras Detect High Titers of Broadly Reactive HIV-1 V3-Specific Antibodies in Human Plasma

“…Conversely, most primary (non-laboratory adapted) CCR5-tropic viruses, including molecularly derived transmitted/ early founder viral Envs from more than 50 subjects acutely infected with clade B virus (49), were found to be resistant to neutralization by V3-specific NAbs, including the human MAbs 447-52D and F425 B4e8. If, however, the V3 region of primary HIV-1 viruses was exchanged for the V3 region of a neutralization-sensitive HIV-1 strain (e.g., HIV-1 SF162 ), then the resulting HIV-1 Env V3 chimeras were rendered sensitive to V3-specific NAbs (53,54).…”

“…To address these questions, investigators have pursued different strategies to detect HIV-1 V3 NAbs. One approach has been to isolate human MAbs from infected individuals for analysis of V3-specific neutralizing activity (26)(27)(28)(29)53). This has the advantage of generating replenishable reagents for definitive structure-function studies, but it has the disadvantage that it cannot illuminate the relative contributions of V3 antibodies compared with other antibody specificities to neutralization by complex polyclonal serum.…”