Impact of Clade, Geography, and Age of the Epidemic on HIV-1 Neutralization by Antibodies

Abstract

Neutralizing antibodies (nAbs) are a high priority for vaccines that aim to prevent the acquisition of HIV-1 infection. Vaccine effectiveness will depend on the extent to which induced antibodies neutralize the global diversity of circulating HIV-1 variants. Using large panels of genetically and geographically diverse HIV-1 Env-pseudotyped viruses and chronic infection plasma samples, we unambiguously show that cross-clade nAb responses are commonly induced in response to infection by any virus clade. Nonetheless, neutralization was significantly greater when the plasma clade matched the clade of the virus being tested. This within-clade advantage was diminished in older, more-diverse epidemics in southern Africa, the United States, and Europe compared to more recent epidemics in Asia. It was most pronounced for circulating recombinant form (CRF) 07_BC, which is common in China and is the least-divergent lineage studied; this was followed by the slightly more diverse Asian CRF01_AE. We found no evidence that transmitted/founder viruses are generally more susceptible to neutralization and are therefore easier targets for vaccination than chronic viruses. Features of the gp120 V1V2 loop, in particular, length, net charge, and number of N-linked glycans, were associated with Env susceptibility and plasma neutralization potency in a manner consistent with neutralization escape being a force that drives viral diversification and plasma neutralization breadth. The overall susceptibility of Envs and potencies of plasma samples were highly predictive of the neutralization outcome of any single virus-plasma combination. These findings highlight important considerations for the design and testing of candidate HIV-1 vaccines that aim to elicit effective nAbs. IMPORTANCEAn effective HIV-1 vaccine will need to overcome the extraordinary variability of the virus, which is most pronounced in the envelope glycoproteins (Env), which are the sole targets for neutralizing antibodies (nAbs). Distinct genetic lineages, or clades, of HIV-1 occur in different locales that may require special consideration when designing and testing vaccines candidates. We show that nAb responses to HIV-1 infection are generally active across clades but are most potent within clades. Because effective vaccine-induced nAbs are likely to share these properties, optimal coverage of a particular clade or combination of clades may require clade-matched immunogens. Optimal within-clade coverage might be easier to achieve in regions such as China and Thailand, where the epidemic is more recent and the virus less diverse than in southern Africa, the United States, and Europe. Finally, features of the first and second hypervariable regions of gp120 (V1V2) may be critical for optimal vaccine design.

Comparison of Immunogenicity in Rhesus Macaques of Transmitted-Founder, HIV-1 Group M Consensus, and Trivalent Mosaic Envelope Vaccines Formulated as a DNA Prime, NYVAC, and Envelope Protein Boost

“…12). The BR025.9 virus, the tier 2 virus with the highest susceptibility to Con-S-elicited antibodies, is a primary isolate that has been classified as tier 2 (40) but is near the boundary for tier 1b and tier 2 classification and is quite sensitive. Thus, the moderate level of response to this virus 50 responses from the TZM-Bl assay, using the inclusive cutoff.…”

“…Plasma samples from monkeys were tested in a TZM-bl assay against a panel of 16 viruses: 4 tier 1A, 3 tier 1B, and 9 tier 2 viruses. As a cautionary note, although BR025.9 is a primary isolate, it is quite neutralization sensitive and at the border of tier 1B and tier 2 classification; we call it tier 2 here, as described by Hraber et al (40), but it is among the most sensitive tier 2 viruses. Seven were clade B, 2 were CRF01 (AE, recombinants, subtype E in Env), and 7 were clade C. Figure 11 shows the heat maps of 50% infective dose (ID 50 ) responses of plasma samples from three vaccine groups in the TZM-bl assay (panel A shows the inclusive cutoff, whereas panel C shows the more conservative, traditional cutoff).…”

“…Both antibody (40) and T cell immune responses to natural HIV infection (41) have enhanced within-clade cross-reactivity. These observations, together with the frequency of shared potential epitopes for the T/F B clade antigen B.1059 (Fig.…”

HIV Epidemic in Asia: Implications for HIV Vaccine and Other Prevention Trials

“…128 Whether various envelope immunogens eliciting V2 antibodies are functionally strain-specific, region-specific, or universal in a cross-clade manner and universal correlates of risk in populations with various modes of transmission remains to be demonstrated in future efficacy trials.…”

“…110 However, bivalent or trivalent subtype-specific vaccines targeting predominant circulating forms, such as CRF01_AE, subtype B, and, potentially, C seem more appropriate. 128 Other vaccine approaches such as prime-boost regimens using DNA and vectors (Ad26, MVA) expressing mosaic antigens 190,191 or conserved sequences must also be seriously considered as global HIV vaccine strategies. [192][193][194][195] The rationale and design of efficacy trials of combination prevention modalities such as HIV vaccine and PrEP have recently been explored.…”