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HIV-1 has an antisense gene overlapping env that encodes the ASP protein. ASP functions are still unknown, but it has been associated with gp120 in the viral envelope and membrane of infected cells, making it a potential target for immune response. Despite this, immune response patterns against ASP are poorly described and can be influenced by the high genetic variability of the env gene. To explore this, we analyzed 100k HIV-1 ASP sequences from the Los Alamos HIV sequence database using phylogenetic, Shannon entropy (Hs), and logo tools to study ASP variability in worldwide and Brazilian sequences from the most prevalent HIV-1 subtypes in Brazil (B, C, and F1). Data obtained in silico guided the design and synthesis of 15-mer overlapping peptides through spot synthesis on cellulose membranes. Peptide arrays were screened to assess IgG and IgM responses in pooled plasma samples from HIV controllers and individuals with acute or recent HIV infection. Excluding regions with low alignment accuracy, several sites with higher variability (Hs > 1.5) were identified among the datasets (25 for worldwide sequences, 20 for Brazilian sequences). Among sites with Hs < 1.5, sequence logos allowed the identification of 23 other sites with subtype-specific signatures. Altogether, amino acid variations with frequencies > 20% in the 48 variable sites identified were included in 92 peptides, divided into 15 sets, representing near full-length ASP. During the immune screening, the strongest responses were observed in three sets, one in the middle and one at the C-terminus of the protein. While some sets presented variations potentially associated with epitope displacement between IgG and IgM targets and subtype-specific signatures appeared to impact the level of response for some peptides, signals of cross-reactivity were observed for some sets despite the presence of B/C/F1 signatures. Our data provides a map of ASP regions preferentially targeted by IgG and IgM responses. Despite B/C/F1 subtype signatures in ASP, the amino acid variation in some areas preferentially targeted by IgM and IgG did not negatively impact the response against regions with higher immunogenicity.

The yellow fever (YF) vaccine is one of the safest and most effective vaccines currently available. Still, its administration in people living with HIV (PLWH) is limited due to safety concerns and a lack of consensus regarding decreased immunogenicity and long-lasting protection for this population. The mechanisms associated with impaired YF vaccine immunogenicity in PLWH are not fully understood, but the general immune deregulation during HIV infection may play an important role. To assess if HIV infection impacts YF vaccine immunogenicity and if markers of immune deregulation could predict lower immunogenicity, we evaluated the association of YF neutralization antibody (NAb) titers with the pre-vaccination frequency of activated and exhausted T cells, levels of pro-inflammatory cytokines, and frequency of T cells, B cells, and monocyte subsets in PLWH and HIV-negative controls. We observed impaired YF vaccine immunogenicity in PLWH with lower titers of YF-NAbs 30 days after vaccination, mainly in individuals with CD4 count <350 cells/mm 3 . At the baseline, those individuals were characterized by having a higher frequency of activated and exhausted T cells and tissue-like memory B cells. Elevated levels of those markers were also observed in individuals with CD4 count between 500 and 350 cells/mm 3 . We observed a negative correlation between the pre-vaccination level of CD8 + T cell exhaustion and CD4 + T cell activation with YF-NAb titers at D365 and the pre-vaccination level of IP-10 with YF-NAb titers at D30 and D365. Our results emphasize the impact of immune activation, exhaustion, and inflammation in YF vaccine immunogenicity in PLWH.

Between 2016 and 2018, Brazil faced a yellow fever (YF) outbreak, which led to an expansion of vaccination coverage. The coexistence of the YF outbreak and the HIV-1 epidemic in Brazil raised concerns regarding the immune response and vaccine effectiveness in individuals living with HIV (PLWH). The aim of this study was to investigate the immune response to YF vaccination in PLWH and HIV-uninfected individuals as controls. Transcript levels of immunomodulatory molecules, including IL-6, IL-10, IL-21, TGF-β, CD19, CD163, miR-21, miR-146, and miR-155, were measured using RTqPCR. TCD4 + cells were evaluated by cytometry, and neutralizing antibody (Nab) titers were detected by a micro plaque-reduction neutralization test. The findings of our study revealed several noteworthy observations. First, there was a notable reduction in the circulation of TCD4 + cells postvaccination. Among people living with HIV (PLWH), we observed an increase in the expression of IL-10 following vaccination, while IL-6 expression was diminished in PLWH with lower TCD4 + counts. Furthermore, we identified the downregulation of CD19 and TGF-β, along with the upregulation of IL-21 and CD163. Notably, we observed positive correlations between the levels of IL-10/IL-21, IL-10/CD163, and IL-6/CD19. Additionally, there was a positive correlation between miRNAs 146 and 155. It is important to emphasize that all participants exhibited robust neutralizing antibody responses after receiving 17DD YF vaccination. In this context, the gene expression data presented can be useful for biomarker studies of protective antibodies induced by YF vaccination. This study sheds light on immune mechanisms in individuals living with HIV and YF vaccination., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

HIV controllers (HICs) are models of HIV functional cure, although some studies have shown persistent inflammation and increased rates of atherosclerosis in HICs. Since immune activation/inflammation contributes to the pathogenesis of cardiovascular diseases (CVD), we evaluated clinical data and inflammation markers in HIV-1 viremic controllers (VC), elite controllers (EC), and control groups (HIV positive individuals with virological suppression by antiretroviral therapy-cART; HIV negative individuals-HIVneg) to assess whether they presented elevated levels of inflammation markers also associated with CVD. We observed the highest frequencies of activated CD8 + T cells in VCs, while EC and cART groups presented similar but slightly altered frequencies of this marker when compared to the HIVneg group. Regarding platelet activation, both HICs groups presented higher expression of P-selectin in platelets when compared to control groups. Monocyte subset analyses revealed lower frequencies of classical monocytes and increased frequencies of non-classical and intermediate monocytes among cART individuals and in EC when compared to HIV negative individuals, but none of the differences were significant. For VC, however, significant decreases in frequencies of classical monocytes and increases in the frequency of intermediate monocytes were observed in comparison to HIV negative individuals. The frequency of monocytes expressing tissue factor was similar among the groups on all subsets. In terms of plasma markers, VC had higher levels of many inflammatory markers, while EC had higher levels of VCAM-1 and ICAM-1 compared to control groups. Our data showed that VCs display increased levels of inflammation markers that have been associated with CVD risk. Meanwhile, ECs show signals of lower but persistent inflammation, comparable to the cART group, indicating the potential benefits of alternative therapies to decrease inflammation in this group., (© 2022. The Author(s).)