Differences in neuroinflammation in people who started antiretroviral treatment during primary versus chronic HIV infection: an 18kDa Translocator protein (TSPO) positron emission tomography (PET) study.

Persistent inflammation is described in people with HIV (PWH) on antiretroviral treatment (ART). Early ART initiation is associated with reduced inflammation. We aimed to evaluate neuroinflammation, using translocator protein (TSPO) [11C]PBR28 PET neuroimaging in PWH who initiated ART during acute HIV (aPWH) versus chronic HIV infection (cPWH) versus a control population. This was a cross-sectional, observational study. All participants underwent [11C]PBR28 PET-CT neuroimaging. Using a two-tissue compartment model, total volume of distribution (VT) and distribution volume ratios (DVR) using cortical grey matter as a pseudo-reference region at 20 regions of interest (ROIs) were calculated. Differences in VT and DVR were compared between groups using the Kruskall-Wallis test. Seventeen neuro-asymptomatic male PWH on ART (9 aPWH, 8 cPWH) and 8 male control participants (CPs) were included. Median (interquartile range, IQR) age was 40 (30, 46), 44 (41, 47) and 21 (20, 25) years in aPWH, cPWH and CPs, respectively. Median (IQR) CD4 (cells/µL) and CD4:CD8 were 687 (652, 1014) and 1.37 (1.24, 1.42), and 700 (500, 720) and 0.67 (0.64, 0.82) in aPWH and cPWH, respectively. Overall, no significant difference in VT and DVR were observed between the three groups at any ROIs. cPWH demonstrated a trend towards higher mean VT compared with aPWH and CPs at most ROIs. No significant differences in neuroinflammation, using [11C]PBR28 binding as a proxy, were identified between cPWH, aPWH and CPs. A trend towards lower absolute [11C]PBR28 binding was seen amongst aPWH and CPs, suggesting early ART may mitigate neuroinflammation.

Experiences of initiating rapid antiretroviral therapy among people newly diagnosed with HIV in East London: a qualitative study.

OBJECTIVES: We aimed to explore the experiences of people who initiated rapid antiretroviral therapy (ART) within 7 days of HIV diagnosis, as part of routine care in London. METHODS: Using purposive sampling, 18 in-depth, semistructured interviews were conducted between December 2020 and September 2021 with people who started rapid ART at Barts Health NHS Trust. Participants aged 22-69 years included 15 cisgender men and three cisgender women. Five identified as heterosexual and 13 as gay and bisexual and other men who have sex with men. Ethnic identities: six White Non-UK, five White UK, three Black Caribbean, two South Asian and two East Asian. Interviews explored feelings about the new HIV diagnosis, attitudes to rapid ART including barriers to and facilitators of starting. Thematic analysis of transcribed interviews was undertaken. RESULTS: Four themes were identified: (1) being offered rapid ART is acceptable; (2) it is a way of taking control of their health; (3) the need for information and support and (4) an individualised approach to care. Reasons for starting included getting well, staying well and reducing the likelihood of passing on HIV. Facilitators included being given comprehensive information about treatment and managing potential side-effects and a supportive clinical team. Support specified included a non-judgemental attitude, approachability, reassurance, encouragement and information about peer support. Most participants expressed they could not understand why people would not begin treatment, but suggested needing more time to decide and denial of diagnosis as possible barriers. CONCLUSIONS: To our knowledge, this is the first qualitative study exploring the experiences of people initiating rapid ART in the UK. It was deemed acceptable to an ethnically diverse, predominantly male sample of people newly diagnosed with HIV. Future research should include strategies to recruit a more gender diverse sample and those who declined or stopped rapid ART.

Human monkeypox virus infection in women and non-binary individuals during the 2022 outbreaks: a global case series.

BACKGROUND: Between May and November, 2022, global outbreaks of human monkeypox virus infection have been reported in more than 78 000 people worldwide, predominantly in men who have sex with men. We describe the epidemiological and clinical characteristics of monkeypox virus infection in cisgender (cis) and transgender (trans) women and non-binary individuals assigned female sex at birth to improve identification and understanding of risk factors. METHODS: International collaborators in geographical locations with high numbers of diagnoses of monkeypox virus infection were approached and invited to contribute data on women and non-binary individuals with confirmed monkeypox virus infection. Contributing centres completed deidentified structured case-report spreadsheets, adapted and developed by participating clinicians, to include variables of interest relevant to women and non-binary individuals assigned female at birth. We describe the epidemiology and clinical course observed in the reported infections. FINDINGS: Collaborators reported data for a total of 136 individuals with monkeypox virus infection who presented between May 11 and Oct 4, 2022, across 15 countries. Overall median age was 34 years (IQR 28-40; range 19-84). The cohort comprised 62 trans women, 69 cis women, and five non-binary individuals (who were, because of small numbers, grouped with cis women to form a category of people assigned female at birth for the purpose of comparison). 121 (89%) of 136 individuals reported sex with men. 37 (27%) of all individuals were living with HIV, with a higher proportion among trans women (31 [50%] of 62) than among cis women and non-binary individuals (six [8%] of 74). Sexual transmission was suspected in 55 (89%) trans women (with the remainder having an unknown route of transmission) and 45 (61%) cis women and non-binary individuals; non-sexual routes of transmission (including household and occupational exposures) were reported only in cis women and non-binary individuals. 25 (34%) of 74 cis women and non-binary individuals submitted to the case series were initially misdiagnosed. Overall, among individuals with available data, rash was described in 124 (93%) of 134 individuals and described as anogenital in 95 (74%) of 129 and as vesiculopustular in 105 (87%) of 121. Median number of lesions was ten (IQR 5-24; range 1-200). Mucosal lesions involving the vagina, anus, or oropharynx or eye occurred in 65 (55%) of 119 individuals with available data. Vaginal and anal sex were associated with lesions at those sites. Monkeypox virus DNA was detected by PCR from vaginal swab samples in all 14 samples tested. 17 (13%) individuals were hospitalised, predominantly for bacterial superinfection of lesions and pain management. 33 (24%) individuals were treated with tecovirimat and six (4%) received post-exposure vaccinations. No deaths were reported. INTERPRETATION: The clinical features of monkeypox in women and non-binary individuals were similar to those described in men, including the presence of anal and genital lesions with prominent mucosal involvement. Anatomically, anogenital lesions were reflective of sexual practices: vulvovaginal lesions predominated in cis women and non-binary individuals and anorectal features predominated in trans women. The prevalence of HIV co-infection in the cohort was high. FUNDING: None.

Impact of antiretroviral therapy in primary HIV infection on natural killer cell function and the association with viral rebound and HIV DNA following treatment interruption.

Natural Killer (NK) cells play a key role in controlling HIV replication, with potential downstream impact on the size of the HIV reservoir and likelihood of viral rebound after antiretroviral therapy (ART) cessation. It is therefore important to understand how primary HIV infection (PHI) disrupts NK cell function, and how these functions are restored by early ART. We examined the impact of commencing ART during PHI on phenotypic and functional NK cell markers at treatment initiation (baseline), 3 months, 1 year, and 2 years in seven well-characterised participants in comparison to HIV seronegative volunteers. We then examined how those NK cell properties differentially impacted by ART related to time to viral rebound and HIV DNA levels in 44 individuals from the SPARTAC trial who stopped ART after 48 weeks treatment, started during PHI. NK cell markers that were significantly different between the seven people with HIV (PWH) treated for 2 years and HIV uninfected individuals included NKG2C levels in CD56dim NK cells, Tim-3 expression in CD56bright NK cells, IFN-γ expressed by CD56dim NK cells after IL-12/IL-18 stimulation and the fraction of Eomes-/T-bet+ in CD56dim and CD56bright NK cells. When exploring time to viral rebound after stopping ART among the 44 SPARTAC participants, no single NK phenotypic marker correlated with control. Higher levels of IL-12/IL-18 mediated NK cell degranulation at baseline were associated with longer times to viral rebound after treatment interruption (P=0.028). Additionally, we found higher fractions of CD56dim NK cells in individuals with lower levels of HIV DNA (P=0.048). NKG2A and NKp30 levels in CD56neg NK cells were higher in patients with lower HIV DNA levels (p=0.00174, r=-0.49 and p=0.03, r= -0.327, respectively) while CD27 levels were higher in those with higher levels of HIV DNA (p=0.026). These data show NK cell functions are heterogeneously impacted by HIV infection with a mixed picture of resolution on ART, and that while NK cells may affect HIV DNA levels and time to viral rebound, no single NK cell marker defined delayed viral rebound.

Monkeypox Virus Infection in Humans across 16 Countries - April-June 2022.

BACKGROUND: Before April 2022, monkeypox virus infection in humans was seldom reported outside African regions where it is endemic. Currently, cases are occurring worldwide. Transmission, risk factors, clinical presentation, and outcomes of infection are poorly defined. METHODS: We formed an international collaborative group of clinicians who contributed to an international case series to describe the presentation, clinical course, and outcomes of polymerase-chain-reaction-confirmed monkeypox virus infections. RESULTS: We report 528 infections diagnosed between April 27 and June 24, 2022, at 43 sites in 16 countries. Overall, 98% of the persons with infection were gay or bisexual men, 75% were White, and 41% had human immunodeficiency virus infection; the median age was 38 years. Transmission was suspected to have occurred through sexual activity in 95% of the persons with infection. In this case series, 95% of the persons presented with a rash (with 64% having ≤10 lesions), 73% had anogenital lesions, and 41% had mucosal lesions (with 54 having a single genital lesion). Common systemic features preceding the rash included fever (62%), lethargy (41%), myalgia (31%), and headache (27%); lymphadenopathy was also common (reported in 56%). Concomitant sexually transmitted infections were reported in 109 of 377 persons (29%) who were tested. Among the 23 persons with a clear exposure history, the median incubation period was 7 days (range, 3 to 20). Monkeypox virus DNA was detected in 29 of the 32 persons in whom seminal fluid was analyzed. Antiviral treatment was given to 5% of the persons overall, and 70 (13%) were hospitalized; the reasons for hospitalization were pain management, mostly for severe anorectal pain (21 persons); soft-tissue superinfection (18); pharyngitis limiting oral intake (5); eye lesions (2); acute kidney injury (2); myocarditis (2); and infection-control purposes (13). No deaths were reported. CONCLUSIONS: In this case series, monkeypox manifested with a variety of dermatologic and systemic clinical findings. The simultaneous identification of cases outside areas where monkeypox has traditionally been endemic highlights the need for rapid identification and diagnosis of cases to contain further community spread.

HIV-1 Vpr drives a tissue residency-like phenotype during selective infection of resting memory T cells.

HIV-1 replicates in CD4+ T cells, leading to AIDS. Determining how HIV-1 shapes its niche to create a permissive environment is central to informing efforts to limit pathogenesis, disturb reservoirs, and achieve a cure. A key roadblock in understanding HIV-T cell interactions is the requirement to activate T cells in vitro to make them permissive to infection. This dramatically alters T cell biology and virus-host interactions. Here we show that HIV-1 cell-to-cell spread permits efficient, productive infection of resting memory T cells without prior activation. Strikingly, we find that HIV-1 infection primes resting T cells to gain characteristics of tissue-resident memory T cells (TRM), including upregulating key surface markers and the transcription factor Blimp-1 and inducing a transcriptional program overlapping the core TRM transcriptional signature. This reprogramming is driven by Vpr and requires Vpr packaging into virions and manipulation of STAT5. Thus, HIV-1 reprograms resting T cells, with implications for viral replication and persistence.

Epigenetic Features of HIV-Induced T-Cell Exhaustion Persist Despite Early Antiretroviral Therapy.

T cell dysfunction occurs early following HIV infection, impacting the emergence of non-AIDS morbidities and limiting curative efforts. ART initiated during primary HIV infection (PHI) can reverse this dysfunction, but the extent of recovery is unknown. We studied 66 HIV-infected individuals treated from early PHI with up to three years of ART. Compared with HIV-uninfected controls, CD4 and CD8 T cells from early HIV infection were characterised by T cell activation and increased expression of the immune checkpoint receptors (ICRs) PD1, Tim-3 and TIGIT. Three years of ART lead to partial - but not complete - normalisation of ICR expression, the dynamics of which varied for individual ICRs. For HIV-specific cells, epigenetic profiling of tetramer-sorted CD8 T cells revealed that epigenetic features of exhaustion typically seen in chronic HIV infection were already present early in PHI, and that ART initiation during PHI resulted in only a partial shift of the epigenome to one with more favourable memory characteristics. These findings suggest that although ART initiation during PHI results in significant immune reconstitution, there may be only partial resolution of HIV-related phenotypic and epigenetic changes.

Levels of Human Immunodeficiency Virus DNA Are Determined Before ART Initiation and Linked to CD8 T-Cell Activation and Memory Expansion.

Initiation of antiretroviral therapy (ART) in early compared with chronic human immunodeficiency virus (HIV) infection is associated with a smaller HIV reservoir. This longitudinal analysis of 60 individuals who began ART during primary HIV infection (PHI) investigates which pre- and posttherapy factors best predict HIV DNA levels (a correlate of reservoir size) after treatment initiation during PHI. The best predictor of HIV DNA at 1 year was pre-ART HIV DNA, which was in turn significantly associated with CD8 memory T-cell differentiation (effector memory, naive, and T-bet-Eomes- subsets), CD8 T-cell activation (CD38 expression) and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3) expression on memory T cells. No associations were found for any immunological variables after 1 year of ART. Levels of HIV DNA are determined around the time of ART initiation in individuals treated during PHI. CD8 T-cell activation and memory expansion are linked to HIV DNA levels, suggesting the importance of the initial host-viral interplay in eventual reservoir size.

CD32 expressing doublets in HIV-infected gut-associated lymphoid tissue are associated with a T follicular helper cell phenotype.

Gut-associated lymphoid tissue (GALT) is a key location for the HIV reservoir. The observation that B-cell-T-cell doublets are enriched for CD32a (a low-affinity IgG receptor) in peripheral blood raises interesting questions, especially as these cells have been associated with HIV DNA in some studies. We sought to determine if similar doublets were present in GALT, the significance of these doublets, and their implications for the HIV reservoir. Given the importance of GALT as a reservoir for HIV, we looked for expression of CD32 on gut CD4 T cells and for evidence of doublets, and any relationship with HIV DNA in HIV + individuals initiated on antiretroviral therapy (ART) during primary HIV infection (PHI). Tonsil tissue was also available for one individual. As previously shown for blood, CD32high CD4 cells were mainly doublets of CD4 T cells and B cells, with T-cell expression of ICOS in tonsil and gut tissue. CD4 T cells associated with CD32 (compared with 'CD32-' CD4 cells) had higher expression of follicular markers CXCR5, PD-1, ICOS, and Bcl-6 consistent with a T follicular helper (TFH) phenotype. There was a significant correlation between rectal HIV DNA levels and CD32 expression on TFH cells. Together, these data suggest that CD32high doublets are primarily composed of TFH cells, a subset known to be preferentially infected by HIV.

CD32-Expressing CD4 T Cells Are Phenotypically Diverse and Can Contain Proviral HIV DNA.

Efforts to both characterize and eradicate the HIV reservoir have been limited by the rarity of latently infected cells and the absence of a specific denoting biomarker. CD32a (FcγRIIa) has been proposed to be a marker for an enriched CD4 T cell HIV reservoir, but this finding remains controversial. Here, we explore the expression of CD32 on CD3+CD4+ cells in participants from two primary HIV infection studies and identify at least three distinct phenotypes (CD32low, CD32+CD14+, and CD32high). Of note, CD4 negative enrichment kits remove the majority of CD4+CD32+ T cells, potentially skewing subsequent analyses if used. CD32high CD4 T cells had higher levels of HLA-DR and HIV co-receptor expression than other subsets, compatible with their being more susceptible to infection. Surprisingly, they also expressed high levels of CD20, TCRαß, IgD, and IgM (but not IgG), markers for both T cells and naïve B cells. Compared with other populations, CD32low cells had a more differentiated memory phenotype and high levels of immune checkpoint receptors, programmed death receptor-1 (PD-1), Tim-3, and TIGIT. Within all three CD3+CD4+CD32+ phenotypes, cells could be identified in infected participants, which contained HIV DNA. CD32 expression on CD4 T cells did not correlate with HIV DNA or cell-associated HIV RNA (both surrogate measures of overall reservoir size) or predict time to rebound viremia following treatment interruption, suggesting that it is not a dominant biomarker for HIV persistence. Our data suggest that while CD32+ T cells can be infected with HIV, CD32 is not a specific marker of the reservoir although it might identify a population of HIV enriched cells in certain situations.