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Background People with human immunodeficiency virus (HIV) on antiretroviral therapy (ART) with good CD4 T-cell counts make effective immune responses following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are few data on longer term responses and the impact of a booster dose. Methods Adults with HIV were enrolled into a single arm open label study. Two doses of ChAdOx1 nCoV-19 were followed 12 months later by a third heterologous vaccine dose. Participants had undetectable viraemia on ART and CD4 counts >350 cells/µL. Immune responses to the ancestral strain and variants of concern were measured by anti-spike immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA), MesoScale Discovery (MSD) anti-spike platform, ACE-2 inhibition, activation induced marker (AIM) assay, and T-cell proliferation. Findings In total, 54 participants received 2 doses of ChAdOx1 nCoV-19. 43 received a third dose (42 with BNT162b2; 1 with mRNA-1273) 1 year after the first dose. After the third dose, total anti-SARS-CoV-2 spike IgG titers (MSD), ACE-2 inhibition, and IgG ELISA results were significantly higher compared to Day 182 titers (P < .0001 for all 3). SARS-CoV-2 specific CD4+ T-cell responses measured by AIM against SARS-CoV-2 S1 and S2 peptide pools were significantly increased after a third vaccine compared to 6 months after a first dose, with significant increases in proliferative CD4+ and CD8+ T-cell responses to SARS-CoV-2 S1 and S2 after boosting. Responses to Alpha, Beta, Gamma, and Delta variants were boosted, although to a lesser extent for Omicron. Conclusions In PWH receiving a third vaccine dose, there were significant increases in B- and T-cell immunity, including to known variants of concern (VOCs).

Background: data on vaccine immunogenicity against SARS-CoV-2 are needed for the 40 million people globally living with HIV who might have less functional immunity and more associated comorbidities than the general population. We aimed to explore safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in people with HIV. Methods: in this single-arm open-label vaccination substudy within the protocol of the larger phase 2/3 trial COV002, adults aged 18–55 years with HIV were enrolled at two HIV clinics in London, UK. Eligible participants were required to be on antiretroviral therapy (ART), with undetectable plasma HIV viral loads (0·05 for all analyses). Interpretation: in this study of people with HIV, ChAdOx1 nCoV-19 was safe and immunogenic, supporting vaccination for those well controlled on ART. Funding: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

We identified a novel HLA A*6801-restricted HIV-1 Tat-derived cytotoxic T lymphocyte (CTL) epitope using an adapted enzyme-linked immunospot assay that allows the rapid ex vivo identification of CTL epitopes together with their associated HLA Class I restriction elements. The optimal 11 amino acid residue Tat epitope efficiently stabilized the refolding of monomeric peptide-HLA A6801 complexes in vitro and fluorochrome-labelled, tetrameric peptide-HLA A6801 complexes stained CD8 T cells specific for this epitope directly ex vivo.

The use of peptide-human histocompatibility leukocyte antigen (HLA) class I tetrameric complexes to identify antigen-specific CD8(+) T cells has provided a major development in our understanding of their role in controlling viral infections. However, questions remain about the exact function of these cells, particularly in HIV infection. Virus-specific cytotoxic T lymphocytes exert much of their activity by secreting soluble factors such as cytokines and chemokines. We describe here a method that combines the use of tetramers and intracellular staining to examine the functional heterogeneity of antigen-specific CD8(+) T cells ex vivo. After stimulation by specific peptide antigen, secretion of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-1beta, and perforin is analyzed by FACS((R)) within the tetramer-positive population in peripheral blood. Using this method, we have assessed the functional phenotype of HIV-specific CD8(+) T cells compared with cytomegalovirus (CMV)-specific CD8(+) T cells in HIV chronic infection. We show that the majority of circulating CD8(+) T cells specific for CMV and HIV antigens are functionally active with regards to the secretion of antiviral cytokines in response to antigen, although a subset of tetramer-staining cells was identified that secretes IFN-gamma and MIP-1beta but not TNF-alpha. However, a striking finding is that HIV-specific CD8(+) T cells express significantly lower levels of perforin than CMV-specific CD8(+) T cells. This lack of perforin is linked with persistent CD27 expression on HIV-specific cells, suggesting impaired maturation, and specific lysis ex vivo is lower for HIV-specific compared with CMV-specific cells from the same donor. Thus, HIV-specific CD8(+) T cells are impaired in cytolytic activity.

To determine the prevalence and prognostic significance of intermittent viraemia (IV) in patients who attained an undetectable viral load (VL)400 copies/ml within 6 months on highly active antiretroviral therapy (HAART).Retrospective analysis of viral load reboundor = 400 copies/ml and CD4 cell counts rise for 765 patients followed foror = 12 months following initial VL undetectability, comparing the 226 (29.5%) who maintained an undetectable VL for1 year from initiation of HAART and 122 (15.9%) who had one or more episodes of IV. Genotypic resistance was evaluated at the time of the first episode of IVor = 2000 copies/ml.Patients with IV had a threefold higher rate of sustained virological rebound [hazards ratio (HR), 3.15; 95% confidence interval (CI), 1.72-5.77; P0.001). For patients with and without IV, the Kaplan-Meier estimates at 24 and 36 months after initiation of HAART were 19.3% (95% CI, 8.9-21.5) versus 7.7% (95% CI, 4.5-13.0) and 31.6% (95% CI, 21.8-44.2) versus 12.9% (95% CI, 7.5-21.5), respectively (P0.001). The median CD4 cell count rise at 18 and 24 months was significantly lower in those with IV than in those without: 138 [interquartile range (IQR), 58-221] versus 224 x 10(6) cells/l (IQR, 119-357) (P = 0.0001) and 200 (IQR, 89-294) versus 260 x 10(6) cells/l (IQR, 125-384) (P = 0.003), respectively. In a subgroup of 16 patients, genotypic resistance mutations were found in the reverse transcriptase gene for five (31%) and in the protease gene in one. A probable contributing factor/event was identified for most patients with IV, such as poor adherence (42.6%), intercurrent infection (26.2%) or drug interaction (6.8%).Patients with IV400 copies/ml are three times more likely to experience sustained viral rebound and to have an impaired CD4 cell rise relative to those who maintain undetectable VL. This supports the adoption of a more pro-active approach to treatment intensification and the need for caution with structured treatment interruptions.

We describe an unusual pathway of human immunodeficiency virus type 1 reverse transcriptase resistance during therapy with tenofovir-emtricitabine, characterized initially by the mutations K70E and M184V and later by K70G and M184V, with the two mutations coexisting on the same viral genome. Phenotypic resistance to lamivudine, emtricitabine, abacavir, didanosine, and tenofovir was observed, whereas susceptibility to zidovudine and stavudine was preserved.

The outcome of human immunodeficiency virus type 1 (HIV-1) infection is related to the set-point plasma virus load (pVL) that emerges after primary HIV-1 infection ( PHI). This set-point pVL generally remains stable but eventually increases with progression to disease. However, the events leading to loss of viremic control are poorly understood. Here, we describe an individual who presented with symptomatic PHI and subsequently progressed rapidly, after an initial period of 1 year during which viral replication was well controlled. Escalation of viral replication in this atypical case was preceded by the emergence of escape variants in many epitopes targeted by dominant CD8(+) T cell responses and a marked decrease in HIV-1-specific CD4(+) and CD8(+) T cell frequencies. There were no changes in viral tropism, replication kinetics, or neutralizing antibody titers. These findings demonstrate the temporal relationship between viral escape from CD8(+) T cell activity, decrease in HIV-1-specific T cell frequencies, and loss of control of viral replication.

Progress in the fight against the HIV/AIDS epidemic is hindered by our failure to elucidate the precise reasons for the onset of immunodeficiency in HIV-1 infection. Increasing evidence suggests that elevated immune activation is associated with poor outcome in HIV-1 pathogenesis. However, the basis of this association remains unclear. Through ex vivo analysis of virus-specific CD8(+) T-cells and the use of an in vitro model of naïve CD8(+) T-cell priming, we show that the activation level and the differentiation state of T-cells are closely related. Acute HIV-1 infection induces massive activation of CD8(+) T-cells, affecting many cell populations, not only those specific for HIV-1, which results in further differentiation of these cells. HIV disease progression correlates with increased proportions of highly differentiated CD8(+) T-cells, which exhibit characteristics of replicative senescence and probably indicate a decline in T-cell competence of the infected person. The differentiation of CD8(+) and CD4(+) T-cells towards a state of replicative senescence is a natural process. It can be driven by excessive levels of immune stimulation. This may be part of the mechanism through which HIV-1-mediated immune activation exhausts the capacity of the immune system., Journal Article, Research Support, N.I.H. Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Review, info:eu-repo/semantics/published

AIM To characterize HIV-1 Gag p24-specific CD4 cell responses in HIV-exposed-seronegative (ES) individuals. METHODOLOGY Twelve ES individuals, of diverse ethnicity and wild type for the CCR5 Delta-32 mutation, were identified. Controls were HIV-negative blood donors. Gag p24-specific and total Vbeta+ CD4 cells that expressed MIP-1beta, IFN-gamma and IL-2 were enumerated by intracytoplasmic cytokine staining. beta-Chemokine expression was correlated with susceptibility to R5 HIV-1 infection, as measured by polymerase chain reaction for integrated HIV-1 and by p24 enzyme-linked immunosorbent assay. RESULTS Similar numbers of mitogen-stimulated and Vbeta+ MIP-1beta+, IFN-gamma+ and IL-2+ T cells were found in ES and HIV-negative control subjects. However, all ES subjects tested had an HIV Gag p24-specific MIP-1beta+, IFN-gamma+ and IL-2+ CD4 T-cell response that was rare in controls. p24-Specific cells of all ES but no control subjects could be expanded by in-vitro Ag/IL-2 stimulation, and when re-stimulated with an overlapping peptide series showed evidence of a broad CD4 cell memory response directed against multiple regions of Gag p24. Mitogen-stimulated ES CD4 cells were as susceptible to HIV infection as those from control subjects, but p24-specific IFN-gamma+ CD4 cells of six out of seven ES subjects tested were less susceptible to R5 HIV-1 infection than the counterpart fraction depleted of p24-specific IFN-gamma+ cells. The addition of blocking anti-beta-chemokine antibodies did not promote R5 HIV-1 infection of p24-specific IFN-gamma+ cells. CONCLUSION Specific CD4 cell immunity, characterized by a broadly directed memory Gag-p24 CD4 cell response and reduced susceptibility of specific CD4 cells to R5 HIV-1 infection, is a likely correlate of non-transmission.

M Ramaswamy1, A Waters1,2, E Hainsworth1, C Smith1, G Hardy1, M Johnson1, JAinsworth2, A Phillips1, and Anna Maria GerettiAuthor Email1 1Royal Free and Univ Coll Med Sch, London, UK and 2North Middlesex Hosp, London,UK Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 786 February 5, 2006 BACKGROUND: Secretion of interferon-gamma (IFN-γ) by activated T cells has beenproposed as a key protective mechanism against herpes simplex virus (HSV) infection.We reported previously that the clinical expression of HSV infection declined in HIV-infected patients after the introduction of HAART, suggesting restoration ofimmunologic control. Our aim here was to study HSV-specific T-cell immunity inperipheral blood of HIV-infected persons at different disease stages.METHODS: We investigated 4 HIV-infected groups: A) long-term slow/non-progressors(LTSP/LTNP) with CD4 >450 cells/mm3 over ≥10 years, sampled at 3 time points; B)newly diagnosed patients; C) patients stable on HAART; D) patients starting HAARTsampled prospectively. Control groups: HSV IgG seropositive (HSV+) andseronegative (HSV-) healthy donors sampled at 3 time points and HSV- HIV-infectedpersons with CD4 >250. IFN-γ production of fresh peripheral blood mononuclear cells(PBMC) (triplicate wells) stimulated with HSV-1 and HSV-2 lysates (1, 5, and 10µg/mL) were assayed by ELISpot. The mean number of spot-forming cells (SFCn) per106 PBMC was determined by an automated reader. Responses were furthercharacterised by intracellular cytokine staining (ICS).RESULTS: SFCn was 320±90 in HSV+ healthy donors (n = 11) and 28±11 in HSV-donors (n = 9); responses were stable over 9 weeks. SFCn was 30±18 in HSV- HIV-infected persons (n = 10, median CD4 457). SFCn of HSV+ HIV-infected persons was:A) LTSP/LTNP (n = 3, median CD4 953): 334±82, stable over ≤43 weeks. B) newlydiagnosed patients (n = 9, median CD4 453): 186±51. C) patients on stable HAART (n= 33, median CD4 360, 91% with viral load