Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies

Broadly neutralizing antibodies (bnAbs) against HIV are believed to be a critical component of the protective responses elicited by an effective HIV vaccine. Neutralizing antibodies against the evolutionarily conserved CD4-binding site (CD4-BS) on the HIV envelope glycoprotein (Env) are capable of inhibiting infection of diverse HIV strains, and have been isolated from HIV-infected individuals. Despite the presence of anti–CD4-BS broadly neutralizing antibody (bnAb) epitopes on recombinant Env, Env immunization has so far failed to elicit such antibodies. Here, we show that Env immunogens fail to engage the germline-reverted forms of known bnAbs that target the CD4-BS. However, we found that the elimination of a conserved glycosylation site located in Loop D and two glycosylation sites located in variable region 5 of Env allows Env-binding to, and activation of, B cells expressing the germline-reverted BCRs of two potent broadly neutralizing antibodies, VRC01 and NIH45-46. Our results offer a possible explanation as to why Env immunogens have been ineffective in stimulating the production of such bNAbs. Importantly, they provide key information as to how such immunogens can be engineered to initiate the process of antibody-affinity maturation against one of the most conserved Env regions

Rapid progression is associated with lymphoid follicle dysfunction in SIV-infected infant rhesus macaques.

HIV-infected infants are at an increased risk of progressing rapidly to AIDS in the first weeks of life. Here, we evaluated immunological and virological parameters in 25 SIV-infected infant rhesus macaques to understand the factors influencing a rapid disease outcome. Infant macaques were infected with SIVmac251 and monitored for 10 to 17 weeks post-infection. SIV-infected infants were divided into either typical (TypP) or rapid (RP) progressor groups based on levels of plasma anti-SIV antibody and viral load, with RP infants having low SIV-specific antibodies and high viral loads. Following SIV infection, 11 out of 25 infant macaques exhibited an RP phenotype. Interestingly, TypP had lower levels of total CD4 T cells, similar reductions in CD4/CD8 ratios and elevated activation of CD8 T cells, as measured by the levels of HLA-DR, compared to RP. Differences between the two groups were identified in other immune cell populations, including a failure to expand activated memory (CD21-CD27+) B cells in peripheral blood in RP infant macaques, as well as reduced levels of germinal center (GC) B cells and T follicular helper (Tfh) cells in spleens (4- and 10-weeks post-SIV). Reduced B cell proliferation in splenic germinal GCs was associated with increased SIV+ cell density and follicular type 1 interferon (IFN)-induced immune activation. Further analyses determined that at 2-weeks post SIV infection TypP infants exhibited elevated levels of the GC-inducing chemokine CXCL13 in plasma, as well as significantly lower levels of viral envelope diversity compared to RP infants. Our findings provide evidence that early viral and immunologic events following SIV infection contributes to impairment of B cells, Tfh cells and germinal center formation, ultimately impeding the development of SIV-specific antibody responses in rapidly progressing infant macaques

Otosclerose infantil: relato de caso e revisão da literatura Pediatric otosclerosis: case report and literature review

A otospongiose é uma osteodistrofia do osso temporal caracterizada pela reabsorção e neoformação óssea desordenada. Clinicamente, caracteriza-se por disacusia condutiva, neurossensorial, e/ou mista, progressiva e zumbidos. O início dos sintomas ocorre entre 30 e 40 anos de idade sendo rara sua manifestação na infância. Descrevemos o caso de um paciente de 11 anos de idade, com quadro de hipoacusia unilateral progressiva há 5 anos. O exame otorrinolaringológico revelou mancha rubra de Schwartze em orelha esquerda. A audiometria, imitanciometria e a tomografia computadorizada demonstraram características sugestivas de otospongiose. Realizamos uma revisão dos aspectos clínicos, diagnósticos e da conduta terapêutica da otospongiose na infância.<br>Otospongiosis is an osteodystrophy of the temporal bone, characterized by disordered neoformation and deposition of bone, characterized by the presence of a progressive conductive, sensorineural or mixed hearing loss and tinnitus. Typically, otospongiosis presents as a slowly progressive conductive hearing loss in the third to fourth decade of life. Uncommonly children and adolescents may also have conductive or sensorineural hearing loss caused by otosclerosis. We describe a case of an 11-year-old patient, with progressive unilateral conductive hearing loss for 5 years. The otoscopic examination revealed a positive Schwartz's sign in the left ear. Audiometry, impedanciometry and CT scan showed characteristics that suggested otospongiosis. We reviewed clinical aspects, diagnosis and the therapeutic approach for otospongiosis in children