ABSTRACT
Monoclonal antibody 10-1074 targets the V3 glycan supersite on the HIV-1 envelope (Env) protein. It is among the most potent anti-HIV-1 neutralizing antibodies isolated so far. Here we report on its safety and activity in 33 individuals who received a single intravenous infusion of the antibody. 10-1074 was well tolerated and had a half-life of 24.0 d in participants without HIV-1 infection and 12.8 d in individuals with HIV-1 infection. Thirteen individuals with viremia received the highest dose of 30 mg/kg 10-1074. Eleven of these participants were 10-1074-sensitive and showed a rapid decline in viremia by a mean of 1.52 log10 copies/ml. Virologic analysis revealed the emergence of multiple independent 10-1074-resistant viruses in the first weeks after infusion. Emerging escape variants were generally resistant to the related V3-specific antibody PGT121, but remained sensitive to antibodies targeting nonoverlapping epitopes, such as the anti-CD4-binding-site antibodies 3BNC117 and VRC01. The results demonstrate the safety and activity of 10-1074 in humans and support the idea that antibodies targeting the V3 glycan supersite might be useful for the treatment and prevention of HIV-1 infection.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Antibodies, Neutralizing/administration & dosage , HIV Antibodies/administration & dosage , HIV Infections/drug therapy , Viremia/drug therapy , Adult , Animals , Antibodies, Monoclonal/pharmacokinetics , Antibodies, Neutralizing/pharmacology , CD4 Lymphocyte Count , CHO Cells , Cricetulus , Female , HIV Antibodies/pharmacology , HIV Envelope Protein gp120/immunology , HIV Infections/blood , HIV-1/genetics , HIV-1/immunology , Humans , Immunoglobulin G/administration & dosage , Immunoglobulin G/pharmacology , Male , Middle Aged , Peptide Fragments/immunology , RNA, Viral/blood , Recombinant Proteins , Viral Load , Viremia/blood , Young Adult , env Gene Products, Human Immunodeficiency Virus/geneticsABSTRACT
HIV-1-infected individuals harbor a latent reservoir of infected CD4+ T cells that is not eradicated by antiretroviral therapy (ART). This reservoir presents the greatest barrier to an HIV-1 cure and has remained difficult to characterize, in part, because the vast majority of integrated sequences are defective and incapable of reactivation. To characterize the replication-competent reservoir, we have combined two techniques, quantitative viral outgrowth and qualitative sequence analysis of clonal outgrowth viruses. Leukapheresis samples from four fully ART-suppressed, chronically infected individuals were assayed at two time points separated by a 4- to 6-mo interval. Overall, 54% of the viruses emerging from the latent reservoir showed gp160 env sequences that were identical to at least one other virus. Moreover, 43% of the env sequences from viruses emerging from the reservoir were part of identical groups at the two time points. Groups of identical expanded sequences made up 54% of proviral DNA, and, as might be expected, the sequences of replication-competent viruses in the active reservoir showed limited overlap with integrated proviral DNA, most of which is known to represent defective viruses. Finally, there was an inverse correlation between proviral DNA clone size and the probability of reactivation, suggesting that replication-competent viruses are less likely to be found among highly expanded provirus-containing cell clones.
ABSTRACT
Interruption of combination antiretroviral therapy in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117,a broad and potent neutralizing antibody against the CD4 binding site of the HIV-1 Env protein, during analytical treatment interruption in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Results show that two or four 30 mg kg(-1) 3BNC117 infusions,separated by 3 or 2 weeks, respectively, are generally well tolerated.Infusions are associated with a delay in viral rebound of 5-9 weeks after two infusions, and up to 19 weeks after four infusions, or an average of 6.7 and 9.9 weeks, respectively, compared with 2.6 weeks for historical controls (P < 0.00001). Rebound viruses arise predominantly from a single provirus. In most individuals,emerging viruses show increased resistance, indicating escape.However, 30% of participants remained suppressed until antibody concentrations waned below 20 µg ml(-1), and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks.We conclude that the administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during analytical treatment interruption in humans.
Subject(s)
Anti-HIV Agents/administration & dosage , Antibodies, Neutralizing/immunology , HIV Antibodies/immunology , HIV Infections/drug therapy , HIV Infections/virology , HIV-1/growth & development , HIV-1/immunology , Adolescent , Adult , Aged , Anti-HIV Agents/pharmacology , Anti-HIV Agents/therapeutic use , Antibodies, Monoclonal, Humanized , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/therapeutic use , Binding Sites/drug effects , Binding Sites/immunology , Broadly Neutralizing Antibodies , CD4 Antigens/metabolism , Disease Reservoirs/virology , Drug Administration Schedule , Female , HIV Antibodies/administration & dosage , HIV Antibodies/therapeutic use , HIV Envelope Protein gp160/antagonists & inhibitors , HIV Envelope Protein gp160/chemistry , HIV Envelope Protein gp160/immunology , HIV Envelope Protein gp160/metabolism , HIV Infections/immunology , HIV-1/drug effects , Historically Controlled Study , Humans , Male , Middle Aged , Proviruses/drug effects , Proviruses/growth & development , Proviruses/immunology , Time Factors , Tissue Distribution , Viral Load/drug effects , Viral Load/immunology , Young AdultABSTRACT
The various childhood suprasellar tumors, while pathologically distinct, present similar clinical and surgical challenges as a result of their common anatomic location. These lesions are in close proximity to or may invade the optic nerve and chiasm, pituitary gland and infundibulum, hypothalamus, and third ventricle, leading to presenting features including visual field loss, impairment in visual acuity, endocrine dysfunction, and hydrocephalus. Though many suprasellar lesions are relatively benign in pathology, treatment may be complicated by high surgical morbidity resulting from damage to the hypothalamic-pituitary axis. Here we review the most frequent pediatric lesions occurring in the suprasellar region: craniopharyngioma, chiasmatic glioma, germ cell tumor, Rathke cleft and arachnoid cysts, pituitary adenoma, and histiocytosis. This review outlines both common presenting features and differentiating aspects of these lesions. It also includes classic radiographic presentations and treatment considerations for each lesion.
Subject(s)
Brain Neoplasms/diagnosis , Brain Neoplasms/therapy , Central Nervous System Cysts/diagnosis , Central Nervous System Cysts/therapy , Child , HumansABSTRACT
Gliomatosis cerebri is a rare glial tumor that carries a poor prognosis. Seen in both adults and children, gliomatosis cerebri appears to differ in these populations as with adult versus pediatric glioblastoma. We present 10 children who either presented to the Weill Cornell Medical College or enrolled in the institution's Gliomatosis Cerebri International Registry alongside a cohort of 89 pediatric patients reported in the literature between 2000 and 2014. Age ranged from 4 months to 21 years, with a male to female ratio of 1.71. Median overall survival for patients in the registry cohort was 17 months (n = 10) and for the historic cohort was 13 months (n = 52). Overall survival was analyzed for the combined cohort and was significantly longer when presenting at age ≥ 10 (20 vs 10 months), for boys (18 vs 11 months), and with low-grade pathology (26.5 vs 12 months) but did not vary significantly by treatment approach.
