Dendritic cells sample HIV-1 through an intestinal epithelial cell monolayer

The intestinal mucosa is a preferential portal of entry for HIV-1 during mother-to-child transmission. Oral infection is also a well documented route for transmission of HIV-1 in neonates. Neonates can acquire the disease by breast-feeding, moreover presence of blood in gastric aspirates of neonates born to HIV-1 infected mothers has also been incriminated as a risk factor in the transmission of HIV-1. Multiple mechanisms for mucosal HIV-1 transmission have been proposed, however the exact role played by dendritic cells in facilitating viral passage across intestinal epithelium have not been fully defined. We had hypothesized that sub-mucosal dendritic cells (DCs) can mediate mucosal transmission of HIV-1 through a process similar to bacterial sampling through gastrointestinal epithelium (Rescigno M., Nat.Immun.2001)

Dendritic cells sample HIV-1 through an intestinal epithelial cell monolayer

The intestinal mucosa is a preferential portal of entry for HIV-1 during mother-to-child transmission. Oral infection is also a well documented route for transmission of HIV-1 in neonates. Neonates can acquire the disease by breast-feeding, moreover presence of blood in gastric aspirates of neonates born to HIV-1 infected mothers has also been incriminated as a risk factor in the transmission of HIV-1. Multiple mechanisms for mucosal HIV-1 transmission have been proposed, however the exact role played by dendritic cells in facilitating viral passage across intestinal epithelium have not been fully defined. We had hypothesized that sub-mucosal dendritic cells (DCs) can mediate mucosal transmission of HIV-1 through a process similar to bacterial sampling through gastrointestinal epithelium (Rescigno M., Nat.Immun.2001)

Flexible use of CCR5 in the absence of CXCR4 use explains the immune deficiency in HIV-1 infected children

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Role of R5 phenotypic variation in mother-to-child transmission of HIV-1

chronic viral infections transmitted to infants: from mechanisms to prevention and care Meetin

Broad-Spectrum Inhibition of HIV-1 by a Monoclonal Antibody Directed against a gp120-Induced Epitope of CD4

To penetrate susceptible cells, HIV-1 sequentially interacts with two highly conserved cellular receptors, CD4 and a chemokine receptor like CCR5 or CXCR4. Monoclonal antibodies (MAbs) directed against such receptors are currently under clinical investigation as potential preventive or therapeutic agents. We immunized Balb/c mice with molecular complexes of the native, trimeric HIV-1 envelope (Env) bound to a soluble form of the human CD4 receptor. Sera from immunized mice were found to contain gp120-CD4 complex-enhanced antibodies and showed broad-spectrum HIV-1-inhibitory activity. A proportion of MAbs derived from these mice preferentially recognized complex-enhanced epitopes. In particular, a CD4-specific MAb designated DB81 (IgG1Κ) was found to preferentially bind to a complex-enhanced epitope on the D2 domain of human CD4. MAb DB81 also recognized chimpanzee CD4, but not baboon or macaque CD4, which exhibit sequence divergence in the D2 domain. Functionally, MAb DB81 displayed broad HIV-1-inhibitory activity, but it did not exert suppressive effects on T-cell activation in vitro. The variable regions of the heavy and light chains of MAb DB81 were sequenced. Due to its broad-spectrum anti-HIV-1 activity and lack of immunosuppressive effects, a humanized derivative of MAb DB81 could provide a useful complement to current preventive or therapeutic strategies against HIV-1

Superior efficacy of a human immunodeficiency virus vaccine combined with antiretroviral prevention in simian-human immunodeficiency virus-challenged nonhuman primates

International audienc

B-cell subset alterations and correlated factors in HIV-1 infection

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HIV-1 with Multiple CCR5/CXCR4 Chimeric Receptor Use Is Predictive of Immunological Failure in Infected Children

BACKGROUND: HIV-1 R5 viruses are characterized by a large phenotypic variation, that is reflected by the mode of coreceptor use. The ability of R5 HIV-1 to infect target cells expressing chimeric receptors between CCR5 and CXCR4 (R5(broad) viruses), was shown to correlate with disease stage in HIV-1 infected adults. Here, we ask the question whether phenotypic variation of R5 viruses could play a role also in mother-to-child transmission (MTCT) of HIV-1 and pediatric disease progression. METHODOLOGY/PRINCIPAL FINDINGS: Viral isolates obtained from a total of 59 HIV-1 seropositive women (24 transmitting and 35 non transmitting) and 28 infected newborn children, were used to infect U87.CD4 cells expressing wild type or six different CCR5/CXCR4 chimeric receptors. HIV-1 isolates obtained from newborn infants had predominantly R5(narrow) phenotype (n = 20), but R5(broad) and R5X4 viruses were also found in seven and one case, respectively. The presence of R5(broad) and R5X4 phenotypes correlated significantly with a severe decline of the CD4+ T cells (CDC stage 3) or death within 2 years of age. Forty-three percent of the maternal R5 isolates displayed an R5(broad) phenotype, however, the presence of the R5(broad) virus was not predictive for MTCT of HIV-1. Of interest, while only 1 of 5 mothers with an R5X4 virus transmitted the dualtropic virus, 5 of 6 mothers carrying R5(broad) viruses transmitted viruses with a similar broad chimeric coreceptor usage. Thus, the maternal R5(broad) phenotype was largely preserved during transmission and could be predictive of the phenotype of the newborn's viral variant. CONCLUSIONS/SIGNIFICANCE: Our results show that R5(broad) viruses are not hampered in transmission. When transmitted, immunological failure occurs earlier than in children infected with HIV-1 of R5(narrow) phenotype. We believe that this finding is of utmost relevance for therapeutic interventions in pediatric HIV-1 infectio

Characterization of humoral responses to soluble trimeric HIV gp140 from a clade A Ugandan field isolate

Trimeric soluble forms of HIV gp140 envelope glycoproteins represent one of the closest molecular structures compared to native spikes present on intact virus particles. Trimeric soluble gp140 have been generated by several groups and such molecules have been shown to induce antibodies with neutralizing activity against homologous and heterologous viruses. In the present study, we generated a recombinant trimeric soluble gp140, derived from a previously identified Ugandan A-clade HIV field isolate (gp140(94UG018)). Antibodies elicited in immunized rabbits show a broad binding pattern to HIV envelopes of different clades. An epitope mapping analysis reveals that, on average, the binding is mostly focused on the C1, C2, V3, V5 and C5 regions. Immune sera show neutralization activity to Tier 1 isolates of different clades, demonstrating cross clade neutralizing activity which needs to be further broadened by possible structural modifications of the clade A gp140(94UG018). Our results provide a rationale for the design and evaluation of immunogens and the clade A gp140(94UG018) shows promising characteristics for potential involvement in an effective HIV vaccine with broad activity