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In vitro evaluation of novel reverse transcriptase inhibitors TAF (tenofovir alafenamide) and OBP-601 (2,3-didehydro-3-deoxy-4-ethynylthymidine) against multi-drug resistant primary isolates of HIV-2

Publication . Bártolo, Inês; Borrego, Pedro; Gomes, Perpétua; Gonçalves, Fátima; Caixas, Umbelina; Pinto, Inês V.; Taveira, Nuno

New antiretroviral drugs are needed to treat HIV-2 infected patients failing therapy. Herein, we evaluate the activity of novel reverse transcriptase inhibitors tenofovir alafenamide (TAF) and OBP-601(2,3-didehydro-3-deoxy-4-ethynylthymidine) against primary isolates from HIV-2 infected patients experiencing virologic failure. TAF and OBP-601 were tested against twelve primary isolates obtained from nine drug-experienced patients failing therapy and three drug naïve patients using a single-round infectivity assay in TZM-bl cells. The RT-coding region of pol was sequenced and the GRADE algorithm was used to identify resistance profiles and mutations. TAF and OBP-601 inhibited the replication of almost all isolates at a median EC50 of 0.27 nM and 6.83 nM, respectively. Two isolates showed moderate-level resistance to OBP-601 or TAF and two other isolates showed high-level resistance to OBP-601 or to both drugs. With one exception, all resistant viruses had canonical nucleoside reverse transcriptase inhibitors (NRTIs)-associated resistance mutations (K65R, N69S, V111I, Y115F, Q151M and M184V). Our results show that TAF has potent activity against most multi-drug resistant HIV-2 isolates and should be considered for the treatment of HIV-2 infected patients failing therapy.

2019-01Journal article

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Donor-Recipient identification in para- and poly-phyletic trees under alternative HIV-1 transmission hypotheses using approximate Bayesian computation

Publication . Romero-Severson, Ethan O.; Bulla, Ingo; Hengartner, Nick; Bártolo, Inês; Abecasis, Ana; Azevedo-Pereira, José M.; Taveira, Nuno; Leitner, Thomas

Diversity of the founding population of Human Immunodeficiency Virus Type 1 (HIV-1) transmissions raises many important biological, clinical, and epidemiological issues. In up to 40% of sexual infections, there is clear evidence for multiple founding variants, which can influence the efficacy of putative prevention methods, and the reconstruction of epidemiologic histories. To infer who-infected-whom, and to compute the probability of alternative transmission scenarios while explicitly taking phylogenetic uncertainty into account, we created an approximate Bayesian computation (ABC) method based on a set of statistics measuring phylogenetic topology, branch lengths, and genetic diversity. We applied our method to a suspected heterosexual transmission case involving three individuals, showing a complex monophyletic-paraphyletic-polyphyletic phylogenetic topology. We detected that seven phylogenetic lineages had been transmitted between two of the individuals based on the available samples, implying that many more unsampled lineages had also been transmitted. Testing whether the lineages had been transmitted at one time or over some length of time suggested that an ongoing superinfection process over several years was most likely. While one individual was found unlinked to the other two, surprisingly, when evaluating two competing epidemiological priors, the donor of the two that did infect each other was not identified by the host root-label, and was also not the primary suspect in that transmission. This highlights that it is important to take epidemiological information into account when analyzing support for one transmission hypothesis over another, as results may be nonintuitive and sensitive to details about sampling dates relative to possible infection dates. Our study provides a formal inference framework to include information on infection and sampling times, and to investigate ancestral node-label states, transmission direction, transmitted genetic diversity, and frequency of transmission.

2017-11-01Journal article

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Development of synthetic light-chain antibodies as novel and potent HIV fusion inhibitors

Publication . Cunha-Santos, Catarina; Figueira, Tiago N.; Borrego, Pedro; Oliveira, Soraia S.; Rocha, Cheila; Couto, Andreia; Cantante, Cátia; Santos- Costa, Quirina; Azevedo-Pereira, José M.; Fontes, Carlos M. G. A.; Taveira, Nuno; Aires-Da-Silva, Frederico; Castanho, Miguel A. R. B.; Veiga, Ana Salomé; Gonçalves, João

"Objective: To develop a novel and potent fusion inhibitor of HIV infection based on a rational strategy for synthetic antibody library construction. Design: The reduced molecular weight of single-domain antibodies (sdAbs) allows targeting of cryptic epitopes, the most conserved and critical ones in the context of HIV entry. Heavy-chain sdAbs from camelids are particularly suited for this type of epitope recognition because of the presence of long and flexible antigen-binding regions [complementary-determining regions (CDRs)]."

2016-07Journal article

Open access

Evaluation of an in-house molecular HIV-1 test to assess mother-to-child HIV-1 transmission in Angola (the APEHC cohort)

Publication . Martin, F.; Palladino, C.; Mateus, R.; Clemente, S.; Gomes, P.; Taveira, N.

"Mother-to-child-transmission (MTCT) rate has decreased sharply in recent years in most of the sub-Saharan Africa, however 220,000 children acquired HIV-1 in 2014. PCR detection of proviral DNA is the most sensitive method for early infant diagnosis (EID) of HIV-1 infection. Commercial kits are available but they have poor sensitivity with divergent non-B subtypes and high costs (≈30€ per test) which limit their use in resource-limited settings. The HIV-1 epidemic in Angola is driven by highly divergent strains of all group M subtypes, except B, as well as multiple recombinant forms (CRFs and URFs) making EID a challenge in this setting. The aim of this study was to develop and validate a qualitative, inexpensive and sensitive “inhouse” HIV-1 EID assay on heel prick dried blood spots (DBS) from infants of the Hospital da Divina Providência (HDP) in Luanda, Angola and determine the current HIV-1 MTCT rate in the Angolan PErinatal HIV Cohort (APEHC)."

2015-09-27Conference object

Open access

Inhibition of HIV cell-to-cell fusion by antiretroviral drugs and neutralizing antibodies

Publication . Diniz, A. R.; Borrego, P.; Bártolo, I.; Taveira, N.

"Inhibition of HIV cell entry by antiretroviral drugs and neutralizing antibodies (NAbs) is typically measured in assays where cell-free virions enter reporter cell lines. However, direct Env-mediated cell-to-cell transmission is a major mechanism of HIV infection that also needs to be targeted. In this work we aimed to determine the ability of anti-HIV compounds in clinical or research use to inhibit HIV mediated cell-to-cell fusion (syncytia formation)."

2015-07-15Conference object

Open access