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Background Hepatitis C virus (HCV) coinfection among people with human immunodeficiency virus (HIV) might perturb immune function and HIV persistence. We aimed to evaluate the impact of HCV clearance with direct-acting antivirals (DAAs) on immune activation and HIV persistence in HIV/HCV-coinfected individuals on antiretroviral therapy (ART). Methods In a prospective observational study, ART-treated participants with HIV/HCV coinfection received sofosbuvir/daclatasvir ± ribavirin (n = 19). Blood samples were collected before DAA therapy, at the end of treatment, and 12 months after DAA termination (12MPT). T- and natural killer (NK)-cell phenotype, soluble plasma factors, cell-associated (CA)-HIV deoxyribonucleic acid (DNA) forms (total, integrated, 2LTR), CA-unspliced (US) and multiple-spliced ribonucleic acid (RNA), and plasma HIV RNA were evaluated. Results Hepatitis C virus clearance was associated with (1) a downmodulation of activation and exhaustion markers in CD4+, CD8+ T, and NK cells together with (2) decreased plasma levels of Interferon gamma-induced protein 10 (IP10), interleukin-8 (IL-8), soluble (s)CD163 and soluble intercellular adhesion molecule (sICAM). Cell-associated US HIV RNA was significantly higher at 12MPT compared to baseline, with no change in HIV DNA or plasma RNA. Conclusions Elimination of HCV in HIV/HCV-coinfected individuals alters immune function and the transcriptional activity of latently infected cells. This report provides insights into the effects of HCV coinfection in HIV persistence and regards coinfected subjects as a population in which HIV remission might prove to be more challenging.

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Background SARS-CoV-2-specific immune response features in people with HIV infection (PWH) remain to be fully elucidated. We aimed to evaluate the impact of HIV over humoral and cellular responses in COVID-19 convalescent PWH. Methods Blood samples from 29 PWH with preserved CD4+T-cell counts on ART and 29 HIV-negative (HIVneg) donors were included. SARS-CoV-2-specific IgG levels and IgG titers were determined by ELISA. Antibody neutralization capacity was evaluated against the reference B1 strain SARS-CoV-2. IFN-γ-secreting cells were detected by ELISpot using SARS-CoV-2 Spike, RBD, or Nucleocapsid protein or overlapping peptide pools. Frequency and phenotype of T, B and NK cells and levels of soluble cytokines and chemokines were assessed by flow cytometry. Results SARS-CoV-2-specific antibodies were detected on 65.5% of PWH and 79.3% of HIVneg individuals, with no differences in serum IgG levels and anti-SARS-CoV-2 neutralizing antibodies. All donors exhibited SARS-CoV-2-specific cellular immunity, including those with undetectable antibody responses. PWH showed diminished percentages of antibody-secreting cells compared to HIVneg cohort, with similar B cell proportions between groups. PWH presented an increment in T follicular helper (Tfh, CD4+CXCR5+) percentage, which negatively correlated with IgG titers. Additionally, CD4+PD1+ and CD8+HLA-DR+ cell frequencies were augmented in PWH. Moreover, PWH presented a high proportion of CD95+, CD25+, NKp46+, HLA-DR+, and CD38+/HLA-DR+ NK cells. Both groups displayed similar Tregs frequency, effector/memory, and T-helper profile for CD4TL, exhaustion and memory phenotypes for CD8TL and subtle differences in classical monocytes. Profile of circulating cytokines and chemokines was significantly different between both groups. Magnitude of IFN-γ responses to S or N proteins, and RBD was lower in PWH compared to HIVneg donors. Correlation analysis of immune and clinical parameters showed a distinct immune landscape in the PWH group. Conclusions PWH showed a distinctive immune profile although severity of COVID-19 was not exacerbated. PWH with conserved CD4+T-cell counts exerted both humoral and cellular responses against SARS-CoV-2. Even though cellular response was lower compared to HIVneg individuals, PWH achieved similar antibody responses with a high neutralization capacity. These data reinforce the impact of ART, not only in controlling HIV but also other infections.

Antiretroviral therapy has led to a dramatic reduction in HIV-related morbidity and mortality. However, cART does not eradicate the virus, which persists in resting CD4 + T cells as the main viral reservoir, consequently requiring lifelong treatment.

Background: Combined antiretroviral treatment (cART) for HIV infection is highly effective in controlling viral replication. However, it cannot achieve a sterilizing cure.  Several strategies have been proposed to achieve a functional cure, some of them based on immune-mediated clearing of persistently infected cells. Here, we aimed at identifying factors related to CD8TC and CD4TC quality before cART initiation that associate with the persistence of CD8TC antiviral response after cART, inflammation levels, and the size of the viral reservoir. Methods: Samples from 25 persons living with HIV were obtained before and after (15 months) cART initiation. Phenotype and functionality of bulk and HIV-specific T cells were assayed by flow cytometry ex vivo or after expansion in pre-cART or post-cART samples, respectively. Cell-Associated (CA) HIV DNA (total and integrated) and RNA (unspliced [US] and multiple spliced [MS]) were quantitated by real-time PCR on post-cART samples. Post-cART plasma levels of CXCL10 (IP-10), soluble CD14 (sCD14) and soluble CD163 (sCD163) were measured by ELISA.  Results: Pre-cART phenotype of CD8TCs and magnitude and phenotype of HIV-specific response correlated with the phenotype and functionality of CD8TCs post-cART. Moreover, the phenotype of the CD8TCs pre-cART correlated with markers of HIV persistence and inflammation post-cART. Finally, exhaustion and differentiation of CD4TCs pre-cART were associated with the composition of the HIV reservoir post-cART and the level of inflammation. Conclusions: Overall, this work provides data to help understand and identify parameters that could be used as markers in the development of immune-based functional HIV cure strategies.

In this study, we evaluate the role of the MIF/CD74 axis in the functionality of CD4+ T lymphocytes (CD4TL) during HIV infection. MDMs from healthy donors were infected with a R5-tropic or Transmitted/Founder (T/F) HIV strain. At day 11 post-MDM infection, allogeneic co-cultures with uninfected CD4TLs plus MIF stimulus were performed. Cytokine production was evaluated by ELISA. MIF plasma levels of people with HIV (PWH) were evaluated by ELISA. The phenotype and infection rate of CD4TLs from PWH were analyzed after MIF stimulus. Intracellular cytokines and transcription factors were evaluated by flow cytometry. Data were analyzed by parametric or non-parametric methods. The MIF stimulation of HIV-infected MDMs induced an increased expression of IL-6, IL-1β and IL-8. In CD4TL/MDM co-cultures, the MIF treatment increased IL-17A/RORγt-expressing CD4TLs. Higher concentrations of IL-17A in supernatants were also observed. These results were recapitulated using transmitted/founder (T/F) HIV-1 strains. The MIF treatment appeared to affect memory CD4TLs more than naïve CD4TLs. MIF blocking showed a negative impact on IL17A+CD4TL proportions. Higher MIF concentrations in PWH-derived plasma were correlated with higher IL-17A+CD4TL percentages. Finally, MIF stimulation in PWH-derived PBMCs led to an increase in Th17-like population. MIF may contribute to viral pathogenesis by generating a microenvironment enriched in activating mediators and Th17-like CD4TLs, which are known to be highly susceptible to HIV-1 infection and relevant to viral persistence. These observations establish a basis for considering MIF as a possible therapeutic target.

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