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1.
PLoS One ; 14(8): e0219142, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31393868

RESUMO

BACKGROUND: Additional forms of pre-exposure prophylaxis are needed to prevent HIV-1 infection. 3BNC117 and 10-1074 are broadly neutralizing anti-HIV-1 antibodies that target non-overlapping epitopes on the HIV-1 envelope. We investigated the safety, tolerability, pharmacokinetics, and immunogenicity of the intravenous administration of the combination of 3BNC117 and 10-1074 in healthy adults. METHODS: This randomized, double-blind, placebo-controlled, single center, phase 1 study enrolled healthy adults aged 18-65 years to receive one infusion of 3BNC117 immediately followed by 10-1074 at 10 mg/kg, three infusions of 3BNC117 followed by 10-1074 at 3 mg/kg or 10 mg/kg every 8 weeks, or placebo infusions. The primary outcomes were safety and pharmacokinetics. This trial is registered with ClinicalTrials.gov, number NCT02824536. FINDINGS: Twenty-four participants were enrolled in a 3:1 ratio to receive the study products or placebo. The combination of 3BNC117 and 10-1074 was safe and generally well tolerated. There were no serious adverse events considered related to the infusions. The mean elimination half-lives of 3BNC117 and 10-1074 were 16.4 ± 4.6 days and 23.0 ± 5.4 days, respectively, similar to what was observed in previous studies in which each antibody was administered alone. Anti-drug antibody responses were rare and without evidence of related adverse events or impact on elimination kinetics. INTERPRETATION: Single and repeated doses of the combination of 3BNC117 and 10-1074 were well tolerated in healthy adults. These data support the further development of the combination of 3BNC117 and 10-1074 as a long-acting injectable form of pre-exposure prophylaxis for the prevention of HIV-1 infection.

2.
J Virol ; 93(8)2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30700598

RESUMO

The role of lymphoid tissue as a potential source of HIV-1 rebound following interruption of antiretroviral therapy (ART) is uncertain. To address this issue, we compared the latent viruses obtained from CD4+ T cells in peripheral blood and lymph nodes to viruses emerging during treatment interruption. Latent viruses were characterized by sequencing near-full-length (NFL) proviral DNA and env from viral outgrowth assays (VOAs). Five HIV-1-infected individuals on ART were studied, four of whom participated in a clinical trial of a TLR9 agonist that included an analytical treatment interruption. We found that 98% of intact or replication-competent clonal sequences overlapped between blood and lymph node. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the four individuals who underwent treatment interruption. However, rebound viruses could be accounted for by recombination. The data suggest that CD4+ T cells carrying latent viruses circulate between blood and lymphoid tissues in individuals on ART and support the idea that recombination may play a role in the emergence of rebound viremia.IMPORTANCE HIV-1 persists as a latent infection in CD4+ T cells that can be found in lymphoid tissues in infected individuals during ART. However, the importance of this tissue reservoir and its contribution to viral rebound upon ART interruption are not clear. In this study, we sought to compare latent HIV-1 from blood and lymph node CD4+ T cells from five HIV-1-infected individuals. Further, we analyzed the contribution of lymph node viruses to viral rebound. We observed that the frequencies of intact proviruses were the same in blood and lymph node. Moreover, expanded clones of T cells bearing identical proviruses were found in blood and lymph node. These latent reservoir sequences did not appear to be the direct origin of rebound virus. Instead, latent proviruses were found to contribute to the rebound compartment by recombination.

3.
Proc Natl Acad Sci U S A ; 115(48): E11341-E11348, 2018 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-30420517

RESUMO

Combination antiretroviral therapy controls but does not cure HIV-1 infection because a small fraction of cells harbor latent viruses that can produce rebound viremia when therapy is interrupted. The circulating latent virus reservoir has been documented by a variety of methods, most prominently by viral outgrowth assays (VOAs) in which CD4+ T cells are activated to produce virus in vitro, or more recently by amplifying proviral near full-length (NFL) sequences from DNA. Analysis of samples obtained in clinical studies in which individuals underwent analytical treatment interruption (ATI), showed little if any overlap between circulating latent viruses obtained from outgrowth cultures and rebound viruses from plasma. To determine whether intact proviruses amplified from DNA are more closely related to rebound viruses than those obtained from VOAs, we assayed 12 individuals who underwent ATI after infusion of a combination of two monoclonal anti-HIV-1 antibodies. A total of 435 intact proviruses obtained by NFL sequencing were compared with 650 latent viruses from VOAs and 246 plasma rebound viruses. Although, intact NFL and outgrowth culture sequences showed similar levels of stability and diversity with 39% overlap, the size of the reservoir estimated from NFL sequencing was larger than and did not correlate with VOAs. Finally, intact proviruses documented by NFL sequencing showed no sequence overlap with rebound viruses; however, they appear to contribute to recombinant viruses found in plasma during rebound.

4.
Nature ; 561(7724): 479-484, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30258136

RESUMO

Individuals infected with HIV-1 require lifelong antiretroviral therapy, because interruption of treatment leads to rapid rebound viraemia. Here we report on a phase 1b clinical trial in which a combination of 3BNC117 and 10-1074, two potent monoclonal anti-HIV-1 broadly neutralizing antibodies that target independent sites on the HIV-1 envelope spike, was administered during analytical treatment interruption. Participants received three infusions of 30 mg kg-1 of each antibody at 0, 3 and 6 weeks. Infusions of the two antibodies were generally well-tolerated. The nine enrolled individuals with antibody-sensitive latent viral reservoirs maintained suppression for between 15 and more than 30 weeks (median of 21 weeks), and none developed viruses that were resistant to both antibodies. We conclude that the combination of the anti-HIV-1 monoclonal antibodies 3BNC117 and 10-1074 can maintain long-term suppression in the absence of antiretroviral therapy in individuals with antibody-sensitive viral reservoirs.

5.
Nat Med ; 24(11): 1701-1707, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30258217

RESUMO

Monotherapy of HIV-1 infection with single antiretroviral agents is ineffective because error-prone HIV-1 replication leads to the production of drug-resistant viral variants1,2. Combinations of drugs can establish long-term control, however, antiretroviral therapy (ART) requires daily dosing, can cause side effects and does not eradicate the infection3,4. Although anti-HIV-1 antibodies constitute a potential alternative to ART5,6, treatment of viremic individuals with a single antibody also results in emergence of resistant viral variants7-9. Moreover, combinations of first-generation anti-HIV-1 broadly neutralizing antibodies (bNAbs) had little measurable effect on the infection10-12. Here we report on a phase 1b clinical trial ( NCT02825797 ) in which two potent bNAbs, 3BNC11713 and 10-107414, were administered in combination to seven HIV-1 viremic individuals. Infusions of 30 mg kg-1 of each of the antibodies were well-tolerated. In the four individuals with dual antibody-sensitive viruses, immunotherapy resulted in an average reduction in HIV-1 viral load of 2.05 log10 copies per ml that remained significantly reduced for three months following the first of up to three infusions. In addition, none of these individuals developed resistance to both antibodies. Larger studies will be necessary to confirm the efficacy of antibody combinations in reducing HIV-1 viremia and limiting the emergence of resistant viral variants.

6.
J Exp Med ; 215(9): 2311-2324, 2018 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-30072495

RESUMO

A clinical trial was performed to evaluate 3BNC117, a potent anti-HIV-1 antibody, in infected individuals during suppressive antiretroviral therapy and subsequent analytical treatment interruption (ATI). The circulating reservoir was evaluated by quantitative and qualitative viral outgrowth assay (Q2VOA) at entry and after 6 mo. There were no significant quantitative changes in the size of the reservoir before ATI, and the composition of circulating reservoir clones varied in a manner that did not correlate with 3BNC117 sensitivity. 3BNC117 binding site amino acid variants found in rebound viruses preexisted in the latent reservoir. However, only 3 of 217 rebound viruses were identical to 868 latent viruses isolated by Q2VOA and near full-length sequencing. Instead, 63% of the rebound viruses appeared to be recombinants, even in individuals with 3BNC117-resistant reservoir viruses. In conclusion, viruses emerging during ATI in individuals treated with 3BNC117 are not the dominant species found in the circulating latent reservoir, but frequently appear to represent recombinants of latent viruses.

7.
Nat Med ; 24(5): 604-609, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29686423

RESUMO

Despite suppressive combination antiretroviral therapy (ART), latent HIV-1 proviruses persist in patients. This latent reservoir is established within 48-72 h after infection, has a long half-life1,2, enables viral rebound when ART is interrupted, and is the major barrier to a cure for HIV-1 3 . Latent cells are exceedingly rare in blood (∼1 per 1 × 106 CD4+ T cells) and are typically enumerated by indirect means, such as viral outgrowth assays4,5. We report a new strategy to purify and characterize single reactivated latent cells from HIV-1-infected individuals on suppressive ART. Surface expression of viral envelope protein was used to enrich reactivated latent T cells producing HIV RNA, and single-cell analysis was performed to identify intact virus. Reactivated latent cells produce full-length viruses that are identical to those found in viral outgrowth cultures and represent clones of in vivo expanded T cells, as determined by their T cell receptor sequence. Gene-expression analysis revealed that these cells share a transcriptional profile that includes expression of genes implicated in silencing the virus. We conclude that reactivated latent T cells isolated from blood can share a gene-expression program that allows for cell division without activation of the cell death pathways that are normally triggered by HIV-1 replication.

8.
Curr Opin HIV AIDS ; 13(4): 366-373, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29697469

RESUMO

PURPOSE OF REVIEW: Several anti-HIV-1 broadly neutralizing antibodies (bNAbs) with exceptional breadth and potency that target different HIV-1 envelope epitopes have been identified. bNAbs are an attractive new strategy for HIV-1 prevention and therapy, and potentially, for long-term remission or cure. Here, we discuss findings from early clinical studies that have evaluated these novel bNAbs. RECENT FINDINGS: Phase 1 studies of bNAbs targeting two distinct HIV-1 envelope epitopes have demonstrated their favorable safety and pharmacokinetic profile. Single bNAb infusions led to significant, but transient, decline in viremia with selection of escape variants. A single bNAb also delayed viral rebound in ART-treated participants who discontinued ART. Importantly, in-vivo efficacy was related to antibody potency and to the level of preexisting resistance. Studies in animal models showed that bNAbs can clear HIV-infected cells and modulate host immune responses. These findings suggest that bNAbs may target the latent HIV reservoir in humans and could contribute to long-term remission of HIV-1 infection. SUMMARY: bNAbs may offer advantages over traditional ART for both the prevention and treatment of HIV-1 infection. In addition, bNAbs may target the latent viral reservoir. bNAb combinations and bNAbs engineered for prolonged half-life and increased potency are currently undergoing clinical evaluation.

9.
J Infect Dis ; 218(4): 633-644, 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-29669026

RESUMO

Background: Mosaic immunogens are bioinformatically engineered human immunodeficiency virus type 1 (HIV-1) sequences designed to elicit clade-independent coverage against globally circulating HIV-1 strains. Methods: This phase 1, double-blinded, randomized, placebo-controlled trial enrolled healthy HIV-uninfected adults who received 2 doses of a modified vaccinia Ankara (MVA)-vectored HIV-1 bivalent mosaic immunogen vaccine or placebo on days 0 and 84. Two groups were enrolled: those who were HIV-1 vaccine naive (n = 15) and those who had received an HIV-1 vaccine (Ad26.ENVA.01) 4-6 years earlier (n = 10). We performed prespecified blinded cellular and humoral immunogenicity analyses at days 0, 14, 28, 84, 98, 112, 168, 270, and 365. Results: All 50 planned vaccinations were administered. Vaccination was safe and generally well tolerated. No vaccine-related serious adverse events occurred. Both cellular and humoral cross-clade immune responses were elicited after 1 or 2 vaccinations in all participants in the HIV-1 vaccine-naive group. Env-specific responses were induced after a single immunization in nearly all subjects who had previously received the prototype Ad26.ENVA.01 vaccine. Conclusions: No safety concerns were identified, and multiclade HIV-1-specific immune responses were elicited. Clinical Trials Registration: NCT02218125.

10.
J Virol ; 92(5)2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29237833

RESUMO

Recently discovered broadly neutralizing antibodies (bNAbs) against HIV-1 demonstrate extensive breadth and potency against diverse HIV-1 strains and represent a promising approach for the treatment and prevention of HIV-1 infection. The breadth and potency of these antibodies have primarily been evaluated by using panels of HIV-1 Env-pseudotyped viruses produced in 293T cells expressing molecularly cloned Env proteins. Here we report on the ability of five bNAbs currently in clinical development to neutralize circulating primary HIV-1 isolates derived from peripheral blood mononuclear cells (PBMCs) and compare the results to those obtained with the pseudovirus panels used to characterize the bNAbs. The five bNAbs demonstrated significantly less breadth and potency against clinical isolates produced in PBMCs than against Env-pseudotyped viruses. The magnitude of this difference in neutralizing activity varied, depending on the antibody epitope. Glycan-targeting antibodies showed differences of only 3- to 4-fold, while antibody 10E8, which targets the membrane-proximal external region, showed a nearly 100-fold decrease in activity between published Env-pseudotyped virus panels and PBMC-derived primary isolates. Utilizing clonal PBMC-derived primary isolates and molecular clones, we determined that the observed discrepancy in bNAb performance is due to the increased sensitivity to neutralization exhibited by 293T-produced Env-pseudotyped viruses. We also found that while full-length molecularly cloned viruses produced in 293T cells exhibit greater sensitivity to neutralization than PBMC-derived viruses do, Env-pseudotyped viruses produced in 293T cells generally exhibit even greater sensitivity to neutralization. As the clinical development of bNAbs progresses, it will be critical to determine the relevance of each of these in vitro neutralization assays to in vivo antibody performance.IMPORTANCE Novel therapeutic and preventive strategies are needed to contain the HIV-1 epidemic. Antibodies with exceptional neutralizing activity against HIV-1 may provide several advantages to traditional HIV drugs, including an improved side-effect profile, a reduced dosing frequency, and immune enhancement. The activity of these antibodies has been established in vitro by utilizing HIV-1 Env-pseudotyped viruses derived from circulating viruses but produced in 293T cells by pairing Env proteins with a backbone vector. We tested PBMC-produced circulating viruses against five anti-HIV-1 antibodies currently in clinical development. We found that the activity of these antibodies against PBMC isolates is significantly less than that against 293T Env-pseudotyped viruses. This decline varied among the antibodies tested, with some demonstrating moderate reductions in activity and others showing an almost 100-fold reduction. As the development of these antibodies progresses, it will be critical to determine how the results of different in vitro tests correspond to performance in the clinic.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Leucócitos Mononucleares/imunologia , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/imunologia , Epitopos/imunologia , Feminino , Células HEK293 , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/genética , Humanos , Concentração Inibidora 50 , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , New York , Adulto Jovem , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia
11.
Nat Med ; 23(2): 185-191, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28092665

RESUMO

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.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Viremia/tratamento farmacológico , Adulto , Animais , Anticorpos Monoclonais/farmacocinética , Anticorpos Neutralizantes/farmacologia , Contagem de Linfócito CD4 , Células CHO , Cricetulus , Feminino , Anticorpos Anti-HIV/farmacologia , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/sangue , HIV-1/genética , HIV-1/imunologia , Humanos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/farmacologia , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/imunologia , RNA Viral/sangue , Proteínas Recombinantes , Carga Viral , Viremia/sangue , Adulto Jovem , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética
12.
Proc Natl Acad Sci U S A ; 113(49): E7908-E7916, 2016 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-27872306

RESUMO

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.

13.
Nature ; 535(7613): 556-60, 2016 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-27338952

RESUMO

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.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/crescimento & desenvolvimento , HIV-1/imunologia , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/uso terapêutico , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/imunologia , Antígenos CD4/metabolismo , Reservatórios de Doenças/virologia , Esquema de Medicação , Feminino , Anticorpos Anti-HIV/administração & dosagem , Anticorpos Anti-HIV/uso terapêutico , Proteína gp160 do Envelope de HIV/antagonistas & inibidores , Proteína gp160 do Envelope de HIV/química , Proteína gp160 do Envelope de HIV/imunologia , Proteína gp160 do Envelope de HIV/metabolismo , Infecções por HIV/imunologia , HIV-1/efeitos dos fármacos , Estudo Historicamente Controlado , Humanos , Masculino , Pessoa de Meia-Idade , Provírus/efeitos dos fármacos , Provírus/crescimento & desenvolvimento , Provírus/imunologia , Fatores de Tempo , Distribuição Tecidual , Carga Viral/efeitos dos fármacos , Carga Viral/imunologia , Adulto Jovem
14.
Ann Intern Med ; 164(5): 313-22, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26833336

RESUMO

BACKGROUND: A prophylactic HIV-1 vaccine is a global health priority. OBJECTIVE: To assess a novel vaccine platform as a prophylactic HIV-1 regimen. DESIGN: Randomized, double-blind, placebo-controlled trial. Both participants and study personnel were blinded to treatment allocation. (ClinicalTrials.gov: NCT01215149). SETTING: United States, East Africa, and South Africa. PATIENTS: Healthy adults without HIV infection. INTERVENTION: 2 HIV-1 vaccines (adenovirus serotype 26 with an HIV-1 envelope A insert [Ad26.EnvA] and adenovirus serotype 35 with an HIV-1 envelope A insert [Ad35.Env], both administered at a dose of 5 × 1010 viral particles) in homologous and heterologous combinations. MEASUREMENTS: Safety and immunogenicity and the effect of baseline vector immunity. RESULTS: 217 participants received at least 1 vaccination, and 210 (>96%) completed follow-up. No vaccine-associated serious adverse events occurred. All regimens were generally well-tolerated. All regimens elicited humoral and cellular immune responses in nearly all participants. Preexisting Ad26- or Ad35-neutralizing antibody titers had no effect on vaccine safety and little effect on immunogenicity. In both homologous and heterologous regimens, the second vaccination significantly increased EnvA antibody titers (approximately 20-fold from the median enzyme-linked immunosorbent assay titers of 30-300 to 3000). The heterologous regimen of Ad26-Ad35 elicited significantly higher EnvA antibody titers than Ad35-Ad26. T-cell responses were modest and lower in East Africa than in South Africa and the United States. LIMITATIONS: Because the 2 envelope inserts were not identical, the boosting responses were complex to interpret. Durability of the immune responses elicited beyond 1 year is unknown. CONCLUSION: Both vaccines elicited significant immune responses in all populations. Baseline vector immunity did not significantly affect responses. Second vaccinations in all regimens significantly boosted EnvA antibody titers, although vaccine order in the heterologous regimen had a modest effect on the immune response. PRIMARY FUNDING SOURCE: International AIDS Vaccine Initiative, National Institutes of Health, Ragon Institute, Crucell Holland.


Assuntos
Vacinas contra a AIDS/efeitos adversos , Vacinas contra a AIDS/imunologia , Infecções por HIV/prevenção & controle , HIV-1 , Adenoviridae , Adolescente , Adulto , África Oriental , Formação de Anticorpos , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , Feminino , Vetores Genéticos , HIV-1/imunologia , Humanos , Imunidade Celular , Imunidade Humoral , Masculino , Pessoa de Meia-Idade , África do Sul , Estados Unidos , Adulto Jovem
15.
Ann Intern Med ; 163(1): W129-34, 2015 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-26148293
16.
AIDS Res Hum Retroviruses ; 31(11): 1192-201, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26149894

RESUMO

A number of potent broadly neutralizing antibodies against HIV-1 have recently been identified that target epitopes on the viral envelope that contain N-linked glycans. It remains unknown how frequently glycan-dependent neutralizing antibodies generally arise during the course of natural infection or whether particular glycosylation sites are preferentially targeted. We tested sera with a broad range of neutralization activity from individuals infected with HIV-1 clades B or C against panels of HIV-1 Env pseudoviruses that lacked specific glycans in the outer domain glycan cluster (ODGC) or inner domain glycan cluster (IDGC) to determine the presence of glycan-dependent neutralizing antibodies. Overall, 54% of individuals were observed to have neutralizing antibodies targeting these glycan regions. Glycan-specific neutralizing antibodies were readily detected in sera that were selected for having broad, moderate, or weak neutralization potency and breadth. Our results demonstrate that glycan-specific neutralizing antibodies arise with appreciable frequency in individuals chronically infected with HIV-1 clades B and C. Antibody responses that commonly occur during natural infection may be more feasible to induce by vaccination; thus glycan-specific neutralizing antibodies may be desirable responses to elicit with candidate HIV-1 vaccines.


Assuntos
Anticorpos Neutralizantes/sangue , Genótipo , Anticorpos Anti-HIV/sangue , Infecções por HIV/imunologia , HIV-1/química , HIV-1/imunologia , Polissacarídeos/imunologia , Infecções por HIV/virologia , HIV-1/classificação
17.
Case Rep Infect Dis ; 2015: 821049, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26075119

RESUMO

Exophiala species are black, yeast-like molds that can cause subcutaneous cysts as well as disseminated disease. Isolated pneumonia due to Exophiala species is extremely uncommon. We report a case of isolated Exophiala pneumonia in a patient with bronchiectasis who presented with worsening dyspnea and a cough productive of black sputum. The production of black sputum, known as melanoptysis, is an uncommon physical finding with a limited differential diagnosis. To our knowledge, this is the first reported case of Exophiala pneumonia presenting with a cough productive of black sputum.

18.
J Clin Neurosci ; 21(6): 1056-8, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24355206

RESUMO

We report a patient with primary leptomeningeal melanocytosis presenting as chronic meningitis. A previously healthy 27-year-old man presented with 2 months of severe headaches and photophobia. A lumbar puncture was notable for a highly elevated cerebrospinal fluid (CSF) protein level without pleocytosis. Imaging at the time of admission suggested only meningitis without the presence of parenchymal lesions. On the basis of the CSF findings, early meningeal biopsy was performed, leading to the diagnosis of a meningeal melanocytic neoplasm. Early meningeal biopsy should be considered in patients with meningitis when the CSF profile suggests the possibility of a central nervous system neoplasm.


Assuntos
Neoplasias Encefálicas/diagnóstico , Melanócitos/patologia , Neoplasias Meníngeas/diagnóstico , Meningite/diagnóstico , Adulto , Neoplasias Encefálicas/complicações , Doença Crônica , Diagnóstico Diferencial , Evolução Fatal , Humanos , Masculino , Neoplasias Meníngeas/complicações , Meningite/complicações
19.
Ther Adv Vaccines ; 1(3): 99-112, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24757518

RESUMO

A human immunodeficiency virus (HIV) vaccine remains a central component in the quest to control the worldwide epidemic. To examine the status of the development of HIV vaccines, we review the results of the efficacy trials carried out to date and the immunologic principles that guided them. Four vaccine concepts have been evaluated in HIV-1 vaccine efficacy trials, and the results of these trials have provided significant information for future vaccine development. While one of these trials demonstrated that a safe and effective HIV vaccine is possible, many questions remain regarding the basis for the observed protection and the most efficient way to stimulate it. Novel HIV vaccine strategies including induction of highly potent broadly neutralizing antibodies, use of novel homologous and heterologous vector systems, and vectored immunoprophylaxis seek to expand and build upon the knowledge gained from these trials.

20.
Heart Lung ; 37(6): 481-4, 2008 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18992633

RESUMO

Fevers of unknown origin (FUOs) are defined as prolonged fevers of 101 degrees F or greater lasting 3 or more weeks that remain undiagnosed after comprehensive inpatient/outpatient laboratory testing. Tick-borne infections are uncommon causes of FUOs. Any infectious disease accompanied by prolonged fevers can present as an FUO if the diagnosis is not suspected or if specific laboratory testing is not done to confirm the diagnosis. Babesiosis is transmitted by the Ixodes scapularis ticks endemic to areas in the northeastern United States. We present the case of a 73-year-old, non-human immunodeficiency virus, male from Long Island who presented with FUO for 6 weeks. As with malaria, there are usually few or no localizing signs in babesiosis. During the patient's hospitalization, babesiosis was suspected on the basis of nonspecific laboratory findings, that is, relative lymphopenia, thrombocytopenia, thrombocytopenia, and an elevated lactate dehydrogenase. When babesiosis was considered in the differential diagnosis, stained blood smears demonstrated the red blood cell inclusions of babesiosis. In the hospital, the patient developed noncardiac pulmonary edema, which rapidly resolved which has been described as a rare complication of babesiosis. He also had an elevated immunoglobulin-M Lyme titer indicating coinfection with Lyme disease. Although his hemolytic anemia persisted for weeks, he only had 3% parasitemia and intact splenic function. We believe this to be the first case of babesiosis presenting as an FUO in a normal host.


Assuntos
Babesia/isolamento & purificação , Babesiose/complicações , Febre de Causa Desconhecida/etiologia , Imunocompetência , Idoso , Animais , Antibacterianos/uso terapêutico , Atovaquona/uso terapêutico , Babesiose/diagnóstico , Babesiose/tratamento farmacológico , Quimioterapia Combinada , Febre de Causa Desconhecida/fisiopatologia , Seguimentos , Humanos , Unidades de Terapia Intensiva , Masculino , Radiografia Torácica , Doenças Raras , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento
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