HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned. However, recently developed ...single-cell-based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies to HIV-1 (refs 4, 5). These antibodies can prevent infection and suppress viraemia in humanized mice and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated. Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody, in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favourable pharmacokinetics. A single 30 mg kg(-1) infusion of 3BNC117 reduced the viral load in HIV-1-infected individuals by 0.8-2.5 log10 and viraemia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that, as a single agent, 3BNC117 is safe and effective in reducing HIV-1 viraemia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy and cure.
BACKGROUND:Adherence is critical to achieve the benefits of antiretroviral therapy. A smart-pill bottle service that transmits real-time adherence data via cellular networks to a central service and ...prompts nonadherent patients with phone or text messages may improve adherence.
METHODS:Adults with HIV taking a tenofovir-containing regimen with suboptimal adherence were randomized to adherence counseling ± a smart-pill bottle service for 12 weeks. Tenofovir diphosphate (TFV-DP) levels by dried blood spot, HIV RNA levels, CD4 cell counts, and self-reported adherence were collected.
RESULTS:Sixty-three participants (22% women; 48% black, 25% Latino) were randomized30 to the smart-pill bottle (2 of whom were lost to follow-up before the baseline visit), and 33 to control arms. At baseline, 49% of participants had HIV RNA ≤20 copies/mL and 61% reported 100% adherence with ART over 4 days. From baseline to week 12, median TFV-DP levels were +252 and −41 fmol/punch in the bottle and control arms, respectively (P = 0.10). Exploratory exclusion of 3 participants with known or suspected drug–drug interactions found median TFV-DP levels of +278 and −38 fmol/punch, respectively (P = 0.04). There were no differences in study discontinuations, HIV RNA suppression, CD4 cell counts, or self-reported adherence at week 12.
CONCLUSIONS:In a diverse group of participants with suboptimal adherence to ART, the smart-pill bottle service was associated with higher TFV-DP levels.
Recent evidence has demonstrated a sex-specific role of the gut microbiome on social behavior such as anxiety, possibly driven by a reciprocal relationship between the gut microbiome and gonadal ...hormones. For instance, gonadal hormones drive sex differences in gut microbiota composition, and certain gut bacteria can produce androgens from glucocorticoids. We thus asked whether the gut microbiome can influence androgen-dependent socio-sexual behaviors. We first treated C57BL/6 mice with broad-spectrum antibiotics (ABX) in drinking water to deplete the gut microbiota either transiently during early development (embryonic day 16-postnatal day PND 21) or in adulthood (PND 60–85). We hypothesized that if ABX interferes with androgens, then early ABX would interfere with critical periods for sexual differentiation of brain and thus lead to long-term decreases in males' socio-sexual behavior, while adult ABX would interfere with androgens’ activational effects on behavior. We found that in males but not females, early and adult ABX treatment decreased territorial aggression, and adult ABX also decreased sexual odor preference. We then assessed whether testosterone and/or cecal microbiota transplantation (CMT) via oral gavage could prevent ABX-induced socio-sexual behavioral deficits in adult ABX-treated males. Mice were treated with same- or other-sex control cecum contents or with testosterone for two weeks. While testosterone was not effective in rescuing any behavior, we found that male CMT restored both olfactory preference and aggression in adult ABX male mice, while female CMT restored olfactory preference but not aggression. These results suggest sex-specific effects of the gut microbiome on socio-sexual behaviors, independent of androgens.
•Antibiotic-mediated gut bacterial depletion induced socio-sexual behavior deficits in males.•Cecal microbiota transplantation (CMT) with male cecum contents reversed all deficits.•CMT with female cecum reversed deficits in sexual preferences but not aggression.•Testosterone treatment was insufficient to rescue these behaviors.
HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned
1
–
3
. However, recently ...developed single cell based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies (bNAbs) to HIV-1
4
,
5
. These antibodies can prevent infection and suppress viremia in humanized mice (hu-mice) and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated
6
–
10
. Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody
11
, in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favorable pharmacokinetics. A single 30 mg/kg infusion of 3BNC117 reduced the viral load (VL) in HIV-1-infected individuals by 0.8 – 2.5 log
10
and viremia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that as a single agent 3BNC117 is safe and effective in reducing HIV-1 viremia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy, and cure.
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