2 research outputs found
Rationally Designed Vaccines Targeting the V2 Region of HIV-1 gp120 Induce a Focused, Cross-Clade-Reactive, Biologically Functional Antibody Response
Strong antibody (Ab) responses against V1V2 epitopes of the human immunodeficiency virus type 1 (HIV-1) gp120 envelope (Env) correlated with reduced infection rates in studies of HIV, simian-human immunodeficiency virus (SHIV), and simian immunodeficiency virus (SIV). In order to focus the Ab response on V1V2, we used six V1V2 sequences and nine scaffold proteins to construct immunogens which were tested using various immunization regimens for their ability to induce cross-reactive and biologically active V2 Abs in rabbits. A prime/boost immunization strategy was employed using gp120 DNA and various V1V2-scaffold proteins. The rabbit polyclonal Ab responses (i) were successfully focused on the V1V2 region, with weak or only transient responses to other Env epitopes, (ii) displayed broad cross-reactive binding activity with gp120s and the V1V2 regions of diverse strains from clades B, C, and E, (iii) included V2 Abs with specificities similar to those found in HIV-infected individuals, and (iv) remained detectable \u3e /=1 year after the last boosting dose. Importantly, sera from rabbits receiving V1V2-scaffold immunogens displayed Ab-dependent cellular phagocytosis whereas sera from rabbits receiving only gp120 did not. The results represent the first fully successful example of reverse vaccinology in the HIV vaccine field with rationally designed epitope scaffold immunogens inducing Abs that recapitulate the epitope specificity and biologic activity of the human monoclonal Abs from which the immunogens were designed. Moreover, this is the first immunogenicity study using epitope-targeting, rationally designed vaccine constructs that induced an Fc-mediated activity associated with protection from infection with HIV, SIV, and SHIV.
IMPORTANCE: Novel immunogens were designed to focus the antibody response of rabbits on the V1V2 epitopes of HIV-1 gp120 since such antibodies were associated with reduced infection rates of HIV, SIV, and SHIV. The vaccine-induced antibodies were broadly cross-reactive with the V1V2 regions of HIV subtypes B, C and E and, importantly, facilitated Fc-mediated phagocytosis, an activity not induced upon immunization of rabbits with gp120. This is the first immunogenicity study of vaccine constructs that focuses the antibody response on V1V2 and induces V2-specific antibodies with the ability to mediate phagocytosis, an activity that has been associated with protection from infection with HIV, SIV, and SHIV
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Safety and efficacy of an oncolytic viral strategy using bortezomib with ICE/R in relapsed/refractory HIV-positive lymphomas
HIV-associated lymphomas (HALs) have high rates of latent infection by gammaherpesviruses (GHVs). We hypothesized that proteasome inhibition would induce lytic activation of GHVs and inhibit HIV infectivity via preservation of cytidine deaminase APOBEC3G, improving lymphoma control. We tested this oncolytic and antiviral strategy by using bortezomib combined with ifosfamide, carboplatin, and etoposide (ICE) alone or with rituximab (ICE/R) in relapsed/refractory HAL. A 3+3 dose-escalation design was used with a 7-day lead-in period of single-agent bortezomib. Bortezomib was administered intravenously on days 1 and 8 of each cycle at 1 of 4 dose levels: 0.7, 1.0, 1.3, or 1.5 mg/m
ICE began day 8 of cycle 1 and day 1 of subsequent cycles. Rituximab was included on day 1 of cycles 2 to 6 for CD20
lymphomas. Twenty-three patients were enrolled. The maximum tolerated dose of bortezomib was not reached. Grade 4 toxicities attributable to bortezomib were limited to myelosuppression. Responses occurred in 17 (77%) of 22 patients receiving any protocol therapy. The 1-year overall survival was 57%. After bortezomib alone, both patients with Kaposi sarcoma herpesvirus (KSHV)-positive lymphoma had more than a 1-log increase in KSHV viral load. In 12 patients with Epstein-Barr virus (EBV)-positive lymphoma, median values of EBV viral load increased. Undetectable HIV viremia at baseline in the majority of patients limited evaluation of HIV inhibition. APOBEC3G levels increased in 75% of evaluable patients. Bortezomib combined with ICE/R in patients with relapsed/refractory HAL is feasible with response and survival comparing favorably against previously reported second-line therapies. Changes in GHV viral loads and APOBEC3G levels trended as hypothesized. This trial was registered at www.clinicaltrials.gov as #NCT00598169