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While HIV-1-mediated CD4 downregulation protects infected cells from antibody-dependent cellular cytotoxicity (ADCC), shed gp120 binds to CD4 on uninfected bystander CD4+ T cells, sensitizing them to ADCC mediated by HIV+ plasma. Soluble gp120-CD4 interaction on multiple immune cells also triggers a cytokine burst. The small molecule temsavir acts as an HIV-1 attachment inhibitor by preventing envelope glycoprotein (Env)-CD4 interaction and alters the overall antigenicity of Env by affecting its processing and glycosylation. Here we show that temsavir also blocks the immunomodulatory activities of shed gp120. Temsavir prevents shed gp120 from interacting with uninfected bystander CD4+ cells, protecting them from ADCC responses and preventing a cytokine burst. Mechanistically, this depends on temsavir's capacity to prevent soluble gp120-CD4 interaction, to reduce gp120 shedding, and to alter gp120 antigenicity. This suggests that the clinical benefits provided by temsavir could extend beyond blocking viral entry. [Display omitted] • Temsavir prevents shed gp120 from interacting with uninfected bystander CD4+ cells • This protects uninfected cells from ADCC responses and prevents a cytokine burst • Temsavir reduces gp120-CD4 interaction and gp120 shedding • Temsavir alters soluble gp120 antigenicity Richard et al. provide extensive evidence suggesting that treatment with the HIV-1 attachment inhibitor temsavir can have beneficial effects that extend beyond viral neutralization, notably by preventing elimination of uninfected cells and induction of a cytokine burst caused by its soluble viral glycoprotein. [ABSTRACT FROM AUTHOR]

Summary HIV cure efforts are hampered by limited characterization of the cells supporting HIV replication in vivo and inadequate methods for quantifying the latent viral reservoir in patients receiving antiretroviral therapy. We combine fluorescent in situ RNA hybridization with detection of HIV protein and flow cytometry, enabling detection of 0.5–1 gag-pol mRNA + /Gag protein + -infected cells per million. In the peripheral blood of untreated persons, active HIV replication correlated with viremia and occurred in CD4 T cells expressing T follicular helper cell markers and inhibitory co-receptors. In virally suppressed subjects, the approach identified latently infected cells capable of producing HIV mRNA and protein after stimulation with PMA/ionomycin and latency-reversing agents (LRAs). While ingenol-induced reactivation mirrored the effector and central/transitional memory CD4 T cell contribution to the pool of integrated HIV DNA, bryostatin-induced reactivation occurred predominantly in cells expressing effector memory markers. This indicates that CD4 T cell differentiation status differentially affects LRA effectiveness. [ABSTRACT FROM AUTHOR]

Small CD4-mimetic compounds (CD4mc) sensitize HIV-1-infected cells to antibody-dependent cellular cytotoxicity (ADCC) by facilitating antibody recognition of epitopes that are otherwise occluded on the unliganded viral envelope (Env). Combining CD4mc with two families of CD4-induced (CD4i) antibodies, which are frequently found in plasma of HIV-1-infected individuals, stabilizes Env in a conformation that is vulnerable to ADCC. We employed new-generation SRG-15 humanized mice, supporting natural killer (NK) cell and Fc-effector functions to demonstrate that brief treatment with CD4mc and CD4i-Abs significantly decreases HIV-1 replication, the virus reservoir and viral rebound after ART interruption. These effects required Fc-effector functions and NK cells, highlighting the importance of ADCC. Viral rebound was also suppressed in HIV-1+-donor cell-derived humanized mice supplemented with autologous HIV-1+-donor-derived plasma and CD4mc. These results indicate that CD4mc could have therapeutic utility in infected individuals for decreasing the size of the HIV-1 reservoir and/or achieving a functional cure. [Display omitted] • CD4mc with CD4-induced Abs decrease the HIV-1 reservoir in SRG15-hu-mice • This treatment significantly delays viral rebound after ART interruption • This approach is dependent on Fc-effector function • CD4mc and HIV+ donor plasma suppress rebound in patient-cell-derived hu-mice Rajashekar et al. show that a small molecule CD4 mimetic, in concert with non-neutralizing antibodies, decreases the size of HIV-1 reservoir in new generation humanized mice supporting antibody and NK cell functions. Since these non-neutralizing antibodies exist in most HIV-1-infected individuals, CD4mc could translate to a functional cure strategy for HIV-AIDS. [ABSTRACT FROM AUTHOR]

Natural killer (NK)-cell killing of virus-infected cells is regulated in part by the engagement of activation and coactivation receptors. In this issue of Cell Host & Microbe, demonstrate that HIV-1 protects infected cells from NK-cell-mediated killing by hindering NK-cell degranulation through downmodulation of NTB-A coactivation receptor ligands by the Vpu accessory protein. [ABSTRACT FROM AUTHOR]