Entry of human immunodeficiency virus type 1 (HIV-1) into host cells is mediated by conformational changes in the envelope glycoprotein (Env) that are triggered by Env binding to cellular CD4 and chemokine receptors. These conformational changes involve the opening of the gp120 surface subunit, exposure of the fusion peptide in the gp41 transmembrane subunit, and refolding of the gp41 N- and C-terminal heptad repeat regions (HR1 and HR2) first into an extended prehairpin intermediate and then into a compact 6-helix bundle (6HB) that facilitates fusion between viral and host cell membranes. Previously, we reported that Envs resistant to HR1 peptide fusion inhibitors acquired key resistance mutations in either HR1 or HR2 that increased 6HB stability. Here, we identify residues in HR1 that contribute not only to fusion inhibitor resistance and 6HB stability but also to reduced reactivity to CD4-induced conformational changes that lead to 6HB formation. While all Envs show increased neutralization sensitivity to mimetic CD4 (mCD4), Envs with either the E560K or Q577R HR1 mutation reduced conformational reactivity to CD4 that resisted viral inactivation and triggering to the 6HB. Using a panel of monoclonal antibodies (mAbs), we further determined that Envs from both HR1 and HR2 resistance pathways exhibit a relaxed trimer conformation due to gp120 adaptive mutations in different regions of Env that segregate by resistance pathway. These findings highlight regions of cross talk between gp120 and gp41 and identify HR1 residues that play important roles in regulating CD4-induced conformational changes in Env. Binding of the HIV envelope glycoprotein (Env) to cellular CD4 and chemokine receptors triggers conformational changes in Env that mediate virus entry, but premature triggering of Env conformational changes leads to virus inactivation. Currently, we have a limited understanding of the network of residues that regulate Env conformational changes. Here, we identify residues in HR1 of gp41 that modulate conformational changes in response to gp120 binding to CD4 and show that the mutations in HR1 and HR2 that confer resistance to fusion inhibitors are associated with gp120 mutations in different regions of Env that confer a more open conformation. These findings contribute to our understanding of the regulation of Env conformational changes and efforts to design new entry inhibitors and stable Env vaccine immunogens.

Waves of migration to and flight from Atlanta by both White and Black residents and businesses have constantly imagined and re-imagined the city as both politically regressive and racially progressive, and from an environmental health perspective, as both a riskscape and a safe haven. We argue that the persistent racial, social, environmental, and health inequities in Atlanta have been fostered and exacerbated by the exponential growth of the city and the persistent rhetoric of it being "the city too busy to hate." This paper is informed by extant research on housing and transportation policies and processes at work in Atlanta since the end of the Civil War, and in particular, the predatory and subprime lending practices during the past thirty years. This paper examines how young people, living in a neighborhood where over 50% of the houses are currently vacant and contending with threats of school closures, experience the contemporary foreclosure crisis. Using qualitative data from focus groups with middle school youth, this paper offers youth-informed perspectives and local knowledge by offering responses of marginalized populations in Atlanta who inhabit, rather than flee, their built and social environments.

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Viral entry of HIV-1 is mediated by the envelope glycoprotein (Env), which consists of gp120 and gp41 trimer subunits. Entry begins when gp120 binds the CD4 receptor on the host cell. This induces conformational changes that expose the binding site for the CCR5 or CXCR4 chemokine co-receptors. Subsequently, heptad repeat 1 (HR1) and heptad repeat 2 (HR2) of gp41 self-assemble to form a 6-helix bundle (6HB) that drives membrane fusion needed for viral entry. Previously, we identified HR1 peptide resistant Envs with key resistance mutations in HR1 or HR2 of gp41 that impact 6HB stability. These key gp41 resistance mutations defined 2 resistance pathways that were each associated with additional mutations in gp120 and gp41. Here, we further characterized the relative contribution of individual gp120 and gp41 mutations on Env conformational structure and sensitivity to CD4-induced conformational changes. Mutant Envs were assessed using a panel of conformation-dependent broadly neutralizing antibodies, temperature sensitivity studies, and soluble CD4-mediated entry into CD4-CCR5+ cells. Our data show that Envs from both resistance pathways have relaxed (more open) trimer conformations in their native state that is primarily mediated by individual mutations in gp120. Despite increased sensitivity to CD4 neutralization, gp41 mutations decrease conformational reactivity to CD4 binding by altering the transition of Envs from a fusion-competent to the inactive form. Our findings identify gp41 residues, particularly those in HR1, as important regulators of Env conformational transitions.