Percorrer por autor "Badura, Robert"
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- Antibody response against selected epitopes in the HIV-1 envelope gp41 ectodomain contributes to reduce viral burden in HIV-1 infected patientsPublication . Marcelino, Rute; Gramacho, Filipa; Martin, Francisco; Brogueira, Pedro; Janeiro, Nuno; Afonso, Cláudia; Badura, Robert; Valadas, Emília; Mansinho, Kamal; Caldeira, Luís; Taveira, Nuno; Marcelino, José M.The ectodomain of gp41 is the target of potent binding and neutralizing antibodies (NAbs) and is being explored in new strategies for antibody-based HIV vaccines. Previous studies have suggested that the W164A-3S (3S) and EC26-2A4 (EC26) peptides located in the gp41 ectodomain may be potential HIV vaccine candidates. We assessed 3S- and EC26-specific binding antibody responses and related neutralizing activity in a large panel of chronic HIV-1-infected Portuguese individuals on ART. A similar proportion of participants had antibodies binding to 3S (9.6%) and EC26 (9.9%) peptides but the level of reactivity against 3S was significantly higher compared to EC26, except in the rare patients with double peptide reactivity. The higher antigenicity of 3S was unrelated with disease stage, as assessed by CD4+ T cell counts, but it was directly related with plasma viral load. Most patients that were tested (89.9%, N = 268) showed tier 1 neutralizing activity, the potency being inversely associated with plasma viral load. In the subset of patients that were tested for neutralization of tier 2 isolates, neutralization breadth was inversely correlated with plasma viral load and directly correlated with CD4+ T cell counts. These results are consistent with a role for neutralizing antibodies in controlling viral replication and preventing the decline of CD4+ T lymphocytes. Importantly, in patients with 3S-specific antibodies, neutralizing titers were inversely correlated with viral RNA levels and proviral DNA levels. Moreover, patients with 3S and/or EC26-specific antibodies showed a 1.9-fold higher tier 2 neutralization score than patients without antibodies suggesting that 3S and/or EC26-specific antibodies contribute to neutralization breadth and potency in HIV-1 infected patients. Overall, these results suggest that antibodies targeting the S3 and EC26 epitopes may contribute to reduce viral burden and provide further support for the inclusion of 3S and EC26 epitopes in HIV-1 vaccine candidates.
- Early ART in Acute HIV-1 Infection: Impact on the B-Cell CompartmentPublication . Badura, Robert; Foxall, Russell B.; Ligeiro, Dario; Rocha, Miguel; Godinho-Santos, Ana; Trombetta, Amelia C.; Sousa, Ana E.HIV-1 infection induces B cell defects, not fully recovered upon antiretroviral therapy (ART). Acute infection and the early start of ART provide unique settings to address the impact of HIV on the B cell compartment. We took advantage of a cohort of 21 seroconverters, grouped according to the presence of severe manifestations likely mediated by antibodies or immune complexes, such as Guillain-Barré syndrome and autoimmune thrombocytopenic purpura, with a follow-up of 8 weeks upon effective ART. We combined B and T cell phenotyping with serum immunoglobulin level measurement and quantification of sj-KRECs and ΔB to estimate bone marrow output and peripheral proliferative history of B cells, respectively. We observed marked B cell disturbances, notably a significant expansion of cells expressing low levels of CD21, in parallel with markers of both impaired bone marrow output and increased peripheral B cell proliferation. This B cell dysregulation is likely to contribute to the severe immune-mediated conditions, as attested by the higher serum IgG and the reduced levels of sj-KRECs with increased ΔB in these individuals as compared to those patients with mild disease. Nevertheless, upon starting ART, the dynamic of B cell recovery was not distinct in the two groups, featuring both persistent alterations by week 8. Overall, we showed for the first time that acute HIV-1 infection is associated with decreased bone marrow B cell output assessed by sj-KRECs. Our study emphasizes the need to intervene in both bone marrow and peripheral responses to facilitate B cell recovery during acute HIV-1 infection.
- Lymph node remodelling underlies the attenuated form of HIV/AIDS in people with HIV-2Publication . Fernandes, Susana M.; Farias, Guilherme B.; Pires, Ana R.; Santos, Diana F.; Antão, Ana Vieira; Pires, André; Moura, Rita; Godinho-Santos, Ana; Marques, Rita T.; Gomes, André M. C.; Ferreira, Cristina; Nunes-Cabaço, Helena; Gomes, Perpétua; Poças, José; Vasconcelos, Carlos; Badura, Robert; Sousa, Ana E.HIV-2 infection is associated with low-to-undetectable plasma viral load, broad and sustained specific antibody and T cell responses, and a slow course of CD4 T cell decline, even in the absence of antiretroviral therapy (ART). Here, we investigated the secondary lymphoid organs of people with HIV-2 (PWH2) as compared to people with HIV-1 (PWH1) and seronegative subjects. We found active HIV-2 replication and major disruption of lymph node architecture in PWH2, also attested by the alterations that we demonstrated in the blood counterparts of follicular T and B cells. These findings were corroborated by in vitro infection assays using tonsil organ cultures and HIV-2 or HIV-1 primary isolates with distinct co-receptor usage, CCR5 or CXCR4, which showed significant HIV-2 cytopathogenicity associated with post-transcriptional control of HIV-2 replication, revealed by high titres of cell-associated viral DNA and mRNA transcripts but reduced HIV-2 protein production. Overall, our findings support a major impact of HIV-2 on secondary lymphoid tissue organisation throughout the disease course, stressing the relevance of this neglected infection to understand host-pathogen equilibrium in retroviral zoonoses and to identify strategies towards a functional HIV cure.
- Shaping the founders : naïve CD4 T cell heterogeneity in people with HIV-1 or HIV-2Publication . Badura, Robert; Martins, Nicole C.; Farias, Guilherme B.; Tendeiro, Rita; Foxall, Russell B.; Santos, Diana F.; Gomes, André M. C.; Marques, Rita T.; Moleirinho, Beatriz; Godinho-Santos, Ana C.; Valadas, Emília; Gomes, Perpétua; Almeida, Afonso R. M.; Sousa, Ana E.Naïve CD4 T cells harbour functional subsets that influence the quality of immune reconstitution and the persistent viral reservoirs in people with HIV (PWH) under antiretroviral therapy (ART). Here, we profiled the circulating naïve CD4 T cells from PWH under effective ART with distinct past histories of viral burden, namely starting treatment early in acute or late in chronic stage HIV-1 infection, and people with HIV-2 (PWH2), who feature low to undetectable viremia before ART and slow disease progression. Spectral flow cytometry enabled us to capture the heterogeneity of this overlooked T cell compartment. Early-treated PWH1 maintained a naïve CD4 T cell profile comparable to that of age-matched seronegative individuals. Late-treated PWH1 and PWH2 showed distinct imbalances in conventional and regulatory subpopulations, yet both exhibited a relative expansion of CD31-expressing naïve cells, consistent with an IL-7-mediated homeostatic response. The ability of purified naïve CD4 T cells to respond to IL-7 was evaluated in additional cohorts of untreated PWH, revealing reduced proliferation and increased p21 transcription in PWH1 elite controllers. Additionally, a significant decline in proviral DNA was found in PWH2, suggesting an impact of IL-7 on HIV-2-infected naïve CD4 T cells that was not observed in the case of HIV-1 infection. Unravelling the homeostatic pathways and functional implications of naïve CD4 T cell heterogeneity will help clarify viral reservoir dynamics and inflammation in PWH and define strategies to prevent immune senescence.