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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.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>An 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.<\/jats:p>","DOI":"10.1128\/jvi.01705-14","type":"journal-article","created":{"date-parts":[[2014,8,21]],"date-time":"2014-08-21T06:52:11Z","timestamp":1408603931000},"page":"12623-12643","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":87,"title":["Impact of Clade, Geography, and Age of the Epidemic on HIV-1 Neutralization by Antibodies"],"prefix":"10.1128","volume":"88","author":[{"given":"Peter","family":"Hraber","sequence":"first","affiliation":[{"name":"Los Alamos National Laboratory, Los Alamos, New Mexico, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bette T.","family":"Korber","sequence":"additional","affiliation":[{"name":"Los Alamos National Laboratory, Los Alamos, New Mexico, USA"},{"name":"New Mexico Consortium, Los Alamos, New Mexico, 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