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Research Project
DESENVOLVIMENTO DE NOVOS MICROBICIDAS PARA PREVENIR A INFECÇÃO POR VIH
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Publications
Rare HIV-1 subtype J genomes and a new H/U/CRF02-AG recombinant genome suggests an ancient origin of HIV-1 in Angola
Publication . Bártolo, Inês; Calado, Rita; Borrego, Pedro; Leitner, Thomas; Taveira, Nuno
Angola has an extremely diverse HIV-1 epidemic fueled in part by the frequent interchange of people with the Democratic Republic of Congo (DRC) and Republic of Congo (RC). Characterization of HIV-1 strains circulating in Angola should help to better understand the origin of HIV-1 subtypes and recombinant forms and their transmission dynamics. In this study we characterize the first near full-length HIV-1 genomic sequences from HIV-1 infected individuals from Angola. Samples were obtained in 1993 from three HIV-1 infected patients living in Cabinda, Angola. Near full-length genomic sequences were obtained from virus isolates. Maximum likelihood phylogenetic tree inference and analyses of potential recombination patterns were performed to evaluate the sequence classifications and origins. Phylogenetic and recombination analyses revealed that one virus was a pure subtype J, another mostly subtype J with a small uncertain region, and the final virus was classified as a H/U/CRF02_AG recombinant. Consistent with their epidemiological data, the subtype J sequences were more closely related to each other than to other J sequences previously published. Based on the env gene, taxa from Angola occur throughout the global subtype J phylogeny. HIV-1 subtypes J and H are present in Angola at low levels since at least 1993. Low transmission efficiency and/or high recombination potential may explain their limited epidemic success in Angola and worldwide. The high diversity of rare subtypes in Angola suggests that Angola was part of the early establishment of the HIV-1 pandemic.
A prime-boost immunization strategy with vaccinia virus expressing novel gp120 envelope glycoprotein from a CRF02_AG isolate elicits cross-clade Tier 2 HIV-1 neutralizing antibodies
Publication . Calado, Rita; Duarte, Joana; Borrego, Pedro; Marcelino, José Maria; Bartolo, Inês; Martin, Francisco; Figueiredo, Inês; Almeida, Silvia; Graça, Luis; Carrapiço, Belmira
Development of new immunogens eliciting broadly neutralizing antibodies (bNAbs) is a
main priority for the HIV-1 vaccine field. Envelope glycoproteins from non-B-non-C HIV-1clades
have not been fully explored as components of a vaccine. We produced Vaccinia viruses expressing a
truncated version of gp120 (gp120t) from HIV-1 clades CRF02_AG, H, J, B, and C and examined their
immunogenicity in mice and rabbits. Mice primed with the recombinant Vaccinia viruses and boosted
with the homologous gp120t or C2V3C3 polypeptides developed antibodies that bind potently to
homologous and heterologous envelope glycoproteins. Notably, a subset of mice immunized with the
CRF02_AG-based envelope immunogens developed a cross-reactive neutralizing response against
tier 2 HIV-1 Env-pseudoviruses and primary isolates. Rabbits vaccinated with the CRF02_AG-based
envelope immunogens also generated potent binding antibodies, and one animal elicited antibodies
that neutralized almost all (13 of 16, 81.3%) tier 2 HIV-1 isolates tested. Overall, the results suggest
that the novel CRF02_AG-based envelope immunogens and prime-boost immunization strategy elicit
the type of immune responses required for a preventive HIV-1 vaccine.
A Prime-Boost Immunization Strategy with Vaccinia Virus Expressing Novel gp120 Envelope Glycoprotein from a CRF02_AG Isolate Elicits Cross-Clade Tier 2 HIV-1 Neutralizing Antibodies
Publication . Calado, Rita; Duarte, Joana; Borrego, Pedro; Marcelino, José Maria; Bártolo, Inês; Martin, Francisco; Figueiredo, Inês; Almeida, Sílvia; Graça, Luis; Vítor, Jorge M. B.; Silva, Frederico Aires da; Dias, Inês; Carrapiço, Belmira; Taveira, Nuno
Development of new immunogens eliciting broadly neutralizing antibodies (bNAbs) is a main priority for the HIV-1 vaccine field. Envelope glycoproteins from non-B-non-C HIV-1clades have not been fully explored as components of a vaccine. We produced Vaccinia viruses expressing a truncated version of gp120 (gp120t) from HIV-1 clades CRF02_AG, H, J, B, and C and examined their immunogenicity in mice and rabbits. Mice primed with the recombinant Vaccinia viruses and boosted with the homologous gp120t or C2V3C3 polypeptides developed antibodies that bind potently to homologous and heterologous envelope glycoproteins. Notably, a subset of mice immunized with the CRF02_AG-based envelope immunogens developed a cross-reactive neutralizing response against tier 2 HIV-1 Env-pseudoviruses and primary isolates. Rabbits vaccinated with the CRF02_AG-based envelope immunogens also generated potent binding antibodies, and one animal elicited antibodies that neutralized almost all (13 of 16, 81.3%) tier 2 HIV-1 isolates tested. Overall, the results suggest that the novel CRF02_AG-based envelope immunogens and prime-boost immunization strategy elicit the type of immune responses required for a preventive HIV-1 vaccine.
Predictors of attrition and immunological failure in HIV-1 patients on highly active antiretroviral therapy from different healthcare settings in mozambique
Publication . Palladino, Claudia; Briz, Veronica; Bellón, José María; Bártolo, Inês; Carvalho, Patrícia; Camacho, Ricardo; Muñoz-Fernández, M. Ángeles; Bastos, Rui; Manuel, Rolanda; Casanovas, José; Taveira, Nuno
In Mozambique, the evaluation of retention in HIV care and ART programmes is limited. To assess rate and predictors of attrition (no retention in care) and HAART effectiveness in HIV-1 infected patients who pay for medication and laboratory testing in Mozambique, we conducted a multicenter survey of HIV-1-infected patients who started HAART during 2002–2006. Cox proportional hazard models were used to assess risk of attrition and of therapy failure. Overall, 142 patients from 16 healthcare centers located in the capital city Maputo were followed-up for 22.2 months (12.1–46.7). The retention rate was 75%, 48% and 37% after one, two and three years, respectively. Risk of attrition was lower in patients with higher baseline CD4 count (P = 0.022) and attending healthcare center 1 (HCC1) (P = 0.013). The proportion of individuals with CD4 count ≤200 cells/µL was 55% (78/142) at baseline and decreased to 6% (3/52) at 36 months. Among the patients with available VL, 86% (64/74) achieved undetectable VL levels. The rate of immunologic failure was 17.2% (95% CI: 12.6–22.9) per 100 person-years. Risk of failure was associated to higher baseline CD4 count (P = 0.002), likely reflecting low adherence levels, and decreased with baseline VL ≥10,000 copies/mL (P = 0.033). These results suggest that HAART can be effective in HIV-1 infected patients from Mozambique that pay for their medication and laboratory testing. Further studies are required to identify the causes for low retention rates in patients with low CD4 counts and to better understand the association between healthcare setting and attrition rate.
Spiro-ß-lactam BSS-730A Displays Potent Activity against HIV and Plasmodium
Publication . Bártolo, Inês; Santos, Bruna S.; Fontinha, Diana; Machado, Marta; Francisco, Denise; Sepodes, Bruno; Rocha, Joao; Mota-Filipe, Hélder; Pinto, Rui; Figueira, Maria-Eduardo; Barroso, Helena; Nascimento, Teresa; Matos, António P. Alves de; Alves, Américo; Alves, Nuno G.; Simões, Carlos J. V.; Prudêncio, Miguel; Melo, Teresa M. V. D. Pinho E; Taveira, Nuno
The high burden of malaria and HIV/AIDS prevents economic and social progress in developing countries. A continuing need exists for development of novel drugs and treatment regimens for both diseases in order to address the tolerability and long-term safety concerns associated with current treatment options and the emergence of drug resistance. We describe new spiro-β-lactam derivatives with potent (nM) activity against HIV and Plasmodium and no activity against bacteria and yeast. The best performing molecule of the series, BSS-730A, inhibited both HIV-1 and HIV-2 replication with an IC50 of 13 ± 9.59 nM and P. berghei hepatic infection with an IC50 of 0.55 ± 0.14 μM with a clear impact on parasite development. BSS-730A was also active against the erythrocytic stages of P. falciparum, with an estimated IC50 of 0.43 ± 0.04 μM. Time-of-addition studies showed that BSS-730A potentially affects all stages of the HIV replicative cycle, suggesting a complex mechanism of action. BSS-730A was active against multidrug-resistant HIV isolates, with a median 2.4-fold higher IC50 relative to control isolates. BSS-730A was equally active against R5 and X4 HIV isolates and displayed strong synergism with the entry inhibitor AMD3100. BSS-730A is a promising candidate for development as a potential therapeutic and/or prophylactic agent against HIV and Plasmodium.
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Funding agency
Fundação para a Ciência e a Tecnologia
Funding programme
Funding Award Number
SFRH/BPD/76225/2011