Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization

Abstract

The development of biomedical interventions to reduce acquisition of HIV-1 infection remains a global priority, however their potential effectiveness is challenged by very high HIV-1 envelope diversity. Two large prophylactic trials in high incidence, clade C epidemic regions in southern Africa are imminent; passive administration of the monoclonal antibody VRC01, and active immunization with a clade C modified RV144-like vaccines. We have created a large representative panel of C clade viruses to enable assessment of antibody responses to vaccines and natural infection in Southern Africa, and we investigated the genotypic and neutralization properties of recently transmitted clade C viruses to determine how viral diversity impacted antibody recognition. We further explore the implications of these findings for the potential effectiveness of these trials. A panel of 200 HIV-1 Envelope pseudoviruses was constructed from clade C viruses collected within the first 100 days following infection. Viruses collected pre-seroconversion were significantly more resistant to serum neutralization compared to post-seroconversion viruses (p = 0.001). Over 13 years of the study as the epidemic matured, HIV-1 diversified (p = 0.0009) and became more neutralization resistant to monoclonal antibodies VRC01, PG9 and 4E10. When tested at therapeutic levels (10ug/ml), VRC01 only neutralized 80% of viruses in the panel, although it did exhibit potent neutralization activity against sensitive viruses (IC50 titres of 0.42 μg/ml). The Gp120 amino acid similarity between the clade C panel and candidate C-clade vaccine protein boosts (Ce1086 and TV1) was 77%, which is 8% more distant than between CRF01_AE viruses and the RV144 CRF01_AE immunogen. Furthermore, two vaccine signature sites, K169 in V2 and I307 in V3, associated with reduced infection risk in RV144, occurred less frequently in clade C panel viruses than in CRF01_AE viruses from Thailand. Increased resistance of pre-seroconversion viruses and evidence of antigenic drift highlights the value of using panels of very recently transmitted viruses and suggests that interventions may need to be modified over time to track the changing epidemic. Furthermore, high divergence such as that observed in the older clade C epidemic in southern Africa may impact vaccine efficacy, although the correlates of infection risk are yet to be defined in the clade C setting. Findings from this study of acute/early clade C viruses will aid vaccine development, and enable identification of new broad and potent antibodies to combat the HIV-1 C-clade epidemic in southern Africa.

Use of broadly neutralizing antibodies for HIV‐1 prevention

“…These relatively conserved sites include: (i) the V1V2-glycan site at the apex of the Env trimer targeted by bnMAbs PG9, PGT145, PGDM1400 and CAP256-VRC26.25 (83–85), (ii) the V3-glycan site centered on the glycan at Asn332 targeted by bnMAbs PGT121 and 10-1074 (86, 87), (iii) an exclusively glycan epitope on the outer domain of gp120 targeted by 2G12 (88, 89), (iv) the CD4-binding site of gp120 targeted by the VRC01-class of bnMAbs that partially mimic CD4 receptor binding and include VRC01 and 3BNC117 (75, 76, 90), and additional non-VRC01 class CD4bs bnMAbs that neutralize by other modes of recognition (24, 91, 92), (v) the membrane-proximal external region (MPER) of gp41 targeted by 2F5, 4E10 and 10E8 (81, 89), (vi) an extended region including residues from both gp120 and gp41 between the MPER and gp120 protomers targeted by 35022 and PGT151 (93, 94) and more recently, (vii) the fusion peptide of HIV-1 targeted by VRC34 and PGT151 (95, 96). Importantly however, none of these bnMAbs neutralizes 100% of viral isolates and each bnMAb has a distinct profile of potency and breadth of neutralization (84, 97). This has led to substantial interest in the use of bnMAb combinations that would be complementary (98, 99).…”

“…95,96 Importantly, however, none of these bnMAbs neutralizes 100% of viral isolates, and each bnMAb has a distinct profile of potency and breadth of neutralization. 84,97 This has led to substantial interest in the use of bnMAb combinations that would be complementary. 98,99 Moreover, due to the lack of effective HIV-1 vaccines and the recent discovery of multiple highly potent bnMAbs, significant enthusiasm in the field is growing to investigate the use of these bnMAbs in both prevention and treatment of HIV-1 infection.…”

The Neutralizing Antibody Response to the HIV-1 Env Protein

“…Tier-2 viruses, which are defined by their overall relative resistance to neutralization [20] are representative of the majority of transmitted viruses [21]. This is unlike the rarely transmitted Tier-1 viruses which can be neutralized by V3 antibodies, a consequence of their unusually open envelope conformations [21, 22]. Until recently, Tier-1 responses were the only antibodies reliably elicited by HIV vaccination.…”

Computational analysis of antibody dynamics identifies recent HIV-1 infection

“…The humoral response to HIV-1 infection is marked by the dynamic appearance and disappearance of certain antibody isotypes and subclasses to different viral antigens from acute to longstanding infection. To harness this information for an HIV-1 incidence assay, we tested different antibody forms (i.e., IgM, IgG, IgG3, IgG4, IgA) in concert with a wide variety of HIV-1 antigens (i.e., peptides and proteins derived from env, gag, pol genes) to comprehensively cover the epitopes and antigen structures most likely to be reactive with immune sera from recent to chronic infection, including transmitted/ founder envelope (T/F) proteins (22)(23)(24)(25)(26). The analysis includes the presence or absence of the response along with the magnitude and avidity of the antibody response when present.…”