[French research organization on emerging infectious diseases: From REACTing to ANRS emerging infectious diseases]. / La recherche française face aux maladies infectieuses émergentes : de REACTing à l'ANRS- maladies infectieuses émergentes.

Emerging infectious diseases (EIDs) can be responsible for epidemics or even pandemics that disrupt societies and cause national and international crises. In our globalized world, anarchic urbanization, ecosystem disruptions (deforestation, creation of dams…), changes in crop and livestock farming conditions, the increasing availability of air transport, population displacement and climate change are all factors that favor the occurrence and spread of emerging or re-emerging pathogens such as SARS-Cov, MERS-CoV, Ebola, Zika, influenza, or more recently SARS-CoV-2 and Monkeypox. States, regional and international organizations, health and research agencies, non-governmental organizations and the pharmaceutical industry are today challenged by the repetition of these crises and their consequences on health, social, economic and political balances. For the past fifteen years, we have clearly been in a new regime of infectious emergence and re-emergence. This new regime calls for new responses, to meet in the urgency the challenges of emergency epidemic crises and to better respond to the issues of crisis management in a context of "One Health". Research is an essential pillar in the response to these epidemics with a double challenge: (i) to improve knowledge on the disease, its prevention, treatment, diagnosis, impact on society. and (ii) to prepare for and understand future emergencies, "anticipate". As epidemics have occurred over the last fifteen years, French research has been organized and has evolved to respond to these crises, from the genesis of REACTing in 2011, to the creation of the ANRS Emerging Infectious Diseases in 2021.

HIV-1 subtype influences susceptibility and response to monotherapy with the protease inhibitor lopinavir/ritonavir.

OBJECTIVE: PI susceptibility results from a complex interplay between protease and Gag proteins, with Gag showing wide variation across HIV-1 subtypes. We explored the impact of pre-treatment susceptibility on the outcome of lopinavir/ritonavir monotherapy. METHODS: Treatment-naive individuals who experienced lopinavir/ritonavir monotherapy failure from the MONARK study were matched (by subtype, viral load and baseline CD4 count) with those who achieved virological response ('successes'). Successes were defined by viral load <400 copies/mL after week 24 and <50 copies/mL from week 48 to week 96. Full-length Gag-protease was amplified from patient samples for in vitro phenotypic susceptibility testing, with susceptibility expressed as fold change (FC) relative to a subtype B reference strain. RESULTS: Baseline lopinavir susceptibility was lower in viral failures compared with viral successes, but the differences were not statistically significant (median lopinavir susceptibility: 4.4 versus 8.5, respectively, P = 0.17). Among CRF02_AG/G patients, there was a significant difference in lopinavir susceptibility between the two groups (7.1 versus 10.4, P = 0.047), while in subtype B the difference was not significant (2.7 versus 3.4, P = 0.13). Subtype CRF02_AG/G viruses had a median lopinavir FC of 8.7 compared with 3.1 for subtype B (P = 0.001). CONCLUSIONS: We report an association between reduced PI susceptibility (using full-length Gag-protease sequences) at baseline and subsequent virological failure on lopinavir/ritonavir monotherapy in antiretroviral-naive patients harbouring subtype CRF02_AG/G viruses. We speculate that this may be important in the context of suboptimal adherence in determining viral failure.

Single-nucleotide polymorphism-defined class I and class III major histocompatibility complex genetic subregions contribute to natural long-term nonprogression in HIV infection.

We performed a genome-wide association study comparing a cohort of 144 human immunodeficiency virus (HIV type 1-infected, untreated white long-term nonprogressors (LTNPs) with a cohort of 605 HIV-1-infected white seroconverters. Forty-seven single-nucleotide polymorphisms (SNPs), located from class I to class III major histocompatibility complex (MHC) subregions, show statistical association (false discovery rate, <0.05) with the LTNP condition, among which 5 reached genome-wide significance after Bonferonni correction. The MHC LTNP-associated SNPs are ordered in ≥4 linkage disequilibrium blocks; interestingly, an MHC class III linkage disequilibrium block (defined by the rs9368699 SNP) seems specific to the LTNP phenotype.

Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo-controlled, multicenter study.

BACKGROUND: The immune deficiency of human immunodeficiency virus (HIV) infection is not fully corrected with ARV therapy. Interleukin-7 (IL-7) can boost CD4 T-cell counts, but optimal dosing and mechanisms of cellular increases need to be defined. METHODS: We performed a randomized placebo-controlled dose escalation (10, 20 and 30 µg/kg) trial of 3 weekly doses of recombinant human IL-7 (rhIL-7) in ARV-treated HIV-infected persons with CD4 T-cell counts between 101 and 400 cells/µL and plasma HIV levels <50 copies/mL. Toxicity, activity and the impact of rhIL-7 on immune reconstitution were monitored. RESULTS: Doses of rhIL-7 up to 20 µg/kg were well tolerated. CD4 increases of predominantly naive and central memory T cells were brisk (averaging 323 cells/µL at 12 weeks) and durable (up to 1 year). Increased cell cycling and transient increased bcl-2 expression were noted. Expanded cells did not have the characteristics of regulatory or activated T cells. Transient low-level HIV viremia was seen in 6 of 26 treated patients; modest increases in total levels of intracellular HIV DNA were proportional to CD4 T-cell expansions. IL-7 seemed to increase thymic output and tended to improve the T-cell receptor (TCR) repertoire in persons with low TCR diversity. CONCLUSIONS: Three weekly doses of rhIL-7 at 20 µg/kg are well tolerated and lead to a dose-dependent CD4 T-cell increase and the broadening of TCR diversity in some subjects. These data suggest that this rhIL-7 dose could be advanced in future rhIL-7 clinical studies. CLINICAL TRIALS REGISTRATION: NCT0047732.

Long-term (96-week) follow-up of antiretroviral-naïve HIV-infected patients treated with first-line lopinavir/ritonavir monotherapy in the MONARK trial.

BACKGROUND: The toxicities, cost and complexity of triple combinations warrant the search for other treatment options, such as boosted protease inhibitor (PI) monotherapy. MONotherapy AntiRetroviral Kaletra (MONARK) is the first randomized trial comparing lopinavir/ritonavir monotherapy to triple combination therapy with zidovudine/lamivudine and lopinavir/ritonavir in antiretroviral-naïve patients. METHODS: A total of 136 antiretroviral-naïve patients, with a CD4 cell count above 100 cells/microL and a plasma HIV RNA below 100,000 HIV-1 RNA copies/mL, were randomized and dosed with either lopinavir/ritonavir monotherapy (n = 83) or lopinavir/ritonavir + zidovudine/lamivudine (n = 53). We focus here on patients in the lopinavir/ritonavir monotherapy arm followed to week 96. The intent-to-treat (ITT) analysis initially involved all patients randomized to lopinavir/ritonavir monotherapy (n = 83), and then focused on patients who had an HIV RNA < 50 copies/mL at week 48 (n = 56). RESULTS: At week 96, 39 of 83 patients (47%) had HIV RNA < 50 copies/mL, five of 83 had HIV RNA between 50 and 400 copies/mL, and three of 83 had HIV RNA > 400 copies/mL. Focusing on the 56 patients with an HIV RNA < 50 copies/mL at week 48, 38 of 56 patients (68%) had a sustained HIV RNA < 50 copies/mL to week 96. To week 96, a total of 28 patients (34%) had discontinued the study treatment. In addition, the allocated treatment was changed for seven patients. PI-associated resistance mutations were evident in five of 83 patients in the monotherapy arm from baseline to week 96. CONCLUSION: By ITT analysis, 39 of the 83 patients initially randomized to lopinavir/ritonavir monotherapy had HIV RNA < 50 copies/mL at week 96. The occurrence in some patients of low-level viraemia (50-500 copies/mL) may increase the risk of drug resistance. First-line lopinavir/ritonavir monotherapy cannot be systematically recommended.

Breast enlargement in an HIV-infected man on combined antiretroviral therapy: what if it was carcinoma?

We describe a case of an HIV-infected man on effective combined antiretroviral therapy, presenting with bilateral gynaecomastia revealing breast carcinoma. Gynaecomastia was first considered to be related to efavirenz and/or didanosine. Although breast carcinoma is rare among HIV-infected men, it should be considered as a potential cause of breast enlargement.

Rapid progression to AIDS in HIV+ individuals with a structural variant of the chemokine receptor CX3CR1.

Human immunodeficiency virus (HIV) enters cells in vitro via CD4 and a coreceptor. Which of 15 known coreceptors are important in vivo is poorly defined but may be inferred from disease-modifying mutations, as for CCR5. Here two single nucleotide polymorphisms are described in Caucasians in CX3CR1, an HIV coreceptor and leukocyte chemotactic/adhesion receptor for the chemokine fractalkine. HIV-infected patients homozygous for CX3CR1-I249 M280, a variant haplotype affecting two amino acids (isoleucine-249 and methionine-280), progressed to AIDS more rapidly than those with other haplotypes. Functional CX3CR1 analysis showed that fractalkine binding is reduced among patients homozygous for this particular haplotype. Thus, CX3CR1-I249 M280 is a recessive genetic risk factor in HIV/AIDS.

[Autoimmune myelofibrosis with dermatomyositis]. / Myélofibrose auto-immune secondaire à une dermatomyosite.

We report a second observation of autoimmune myelofibrosis associated with an inflammatory myositis in a 30-year-old female. The links between myelofibrosis and autoimmunity are discussed.

Depressed primary in vitro antibody response in untreated systemic lupus erythematosus. T helper cell defect and lack of defective suppressor cell function.

The in vitro antibody response of peripheral blood lymphocytes (PBL) from 19 patients with untreated systemic lupus erythematosus (SLE) was compared with that of 20 control patients and 44 normal subjects. Trinitrophenyl polyacrylamide beads (TNP-PAA) were used to induce IgM anti-TNP plaque-forming cells. SLE patients displayed a markedly depressed, and in most instances virtually absent, response. This was not due to an unusual kinetics of the response; nor could it be induced by preincubation of SLE patients' PBL. In co-cultures of SLE patients and normal PBL, the former, with few exceptions, did not exert a suppressive effect. In four patients the anti-TNP response of either unfractionated or T-depleted SLE PBL could be restored by T cells from a normal individual. Conversely in three of these patients, SLE T cells could not support the response of normal B cells, suggesting a T helper cell defect in SLE PBL. Concanavalin A (Con A)-induced suppressor cells of the antibody response could be assayed by two approaches: (a) in responder SLE patients, by the direct addition of Con A to TNP-PAA-stimulated cultures; (b) in seven patients by transfer of Con A-activated cells to the responding culture of a normal allogeneic donor. In both cases SLE PBL were able to exert a suppressive effect to the same extent as normal PBL.

Production of interleukins in human immunodeficiency virus-1-replicating lymph nodes.

To document the in vivo interactions occurring between the immune system and HIV replicating cells, we analyzed using in situ hybridization the production of IL-1 beta, IL-6, IL-2, and INF-gamma in eight hyperplastic lymph nodes from HIV-1 infected patients. Numerous IL-1 beta- and IL-6-producing cells associated in clusters were detected in sinuses. Few individual IL-1 beta- and IL-6-producing cells were present in interfollicular and follicular areas. IL-2- and INF-gamma-producing cells were observed in all lymph node compartments, with a selective enrichment in germinal centers. The amount and distribution of IL-1 beta, IL-6-, and IL-2-producing cells in HIV lymph nodes were not different from those found in six HIV unrelated hyperplastic lymph nodes. In contrast, a higher level of INF-gamma production was observed in HIV-1 lymph nodes. The CD8+ cells that accumulate in germinal centers of HIV lymph nodes (and not in non-HIV germinal centers) were actively involved in this INF-gamma production. INF-gamma synthesizing cells were in direct contact with cells containing HIV core antigens and HIV RNA. Thus a high INF-gamma production may characterize anti-HIV T cell immune response, potentially contributing to control of viral spreading as well as to the development of follicle lysis.

Weak anti-HIV CD8(+) T-cell effector activity in HIV primary infection.

HIV-specific CD8(+) T cells play a major role in the control of virus during HIV primary infection (PI) but do not completely prevent viral replication. We used IFN-gamma enzyme-linked immunospot assay and intracellular staining to characterize the ex vivo CD8(+) T-cell responses to a large variety of HIV epitopic peptides in 24 subjects with early HIV PI. We observed HIV-specific responses in 71% of subjects. Gag and Nef peptides were more frequently recognized than Env and Pol peptides. The number of peptides recognized was low (median 2, range 0-6). In contrast, a much broader response was observed in 30 asymptomatic subjects with chronic infection: all were responders with a median of 5 peptides recognized (range 1-13). The frequency of HIV-specific CD8(+) T cells among PBMC for a given peptide was of the same order of magnitude in both groups. The proportion of HIV-specific CD8(+)CD28(-) terminally differentiated T cells was much lower in PI than at the chronic stage of infection. The weakness of the immune response during HIV PI could partially account for the failure to control HIV. These findings have potential importance for defining immunotherapeutic strategies and establishing the goals for effective vaccination.

[Actinomyces odontolyticus isolation during prosthetic aortic graft infection with paraprosthetic duodenal fistula]. / Isolement d'Actinomyces odontolyticus au cours d'une infection de prothèse aortique avec fistule duodénoparaprothétique.

INTRODUCTION: Prosthetic vascular graft infection is a rare complication of vascular surgery. We report a case with graft enteric fistula and Actinomyces odontolyticus bacteremia. EXEGESIS: A 73 year-old man with a prosthetic aortic graft and who had a parodontal disease, has been hospitalised for fever of unknown origin. Blood cultures grew with Escherichia coli and Actinomyces odontolyticus. The imaging studies indicated graft infection. Laparotomy has confirmed the diagnosis and highlighted a polymicrobial infection and a paraprosthetic duodenal fistula. A review of the literature's data concerning prosthetic vascular graft infections is made. The role of Actinomyces odontolyticus in that case is discussed. CONCLUSION: Prosthetic aortic graft infection due to graft enteric fistula is usually a polymicrobial infection and is a late complication of aortic surgery. Imaging is essential for the diagnosis of prosthetic aortic graft infection. It is possible that Actinomyces odontolyticus has contributed to prosthesis infection in this case.

[Risk factors for incident cervical intraepithelial neoplasia (CIN) among HIV-infected women: a prospective study]. / Facteurs de risque d'acquisition de lésions du col utérin dans une population de femmes infectées par le VIH: étude prospective.

OBJECTIVES: To study risk factors for incident cervical intraepithelial neoplasia (CIN) among HIV-infected women. PATIENTS AND METHODS: Prospective study of a population of 97 HIV-infected women with normal Pap smear at inclusion. RESULTS: Fourteen CIN (diagnosed by colposcopy and confirmed with biopsy) were observed within a median follow-up of 38 months (13 CIN 1, one CIN 2). The incidence of cervical lesions was estimated to be 2%, 7% and 10% respectively at one year, two and three years after inclusion, The time to occurrence was very variable (ranging from 7 months to 6 years) among our patients. No known risk factors, in particular neither the CD4 cell count nor antiretroviral treatment, were identified to be associated with occurrence of CIN in our study population. CONCLUSION: Regardless of their immune status and HIV treatments, extensive and prolonged gynaecological follow up of HIV-infected women remains necessary.

Beneficial effect of highly active antiretroviral therapy on the prognosis of AIDS-related systemic non-Hodgkin lymphomas.

The influence of HAART on the survival of patients with AIDS-related lymphoma (ARL) was evaluated. A retrospective analysis of 73 HIV-1-infected patients with proven ARL diagnosed between 1992 and 2000 was conducted. Patients received uniformly the same chemotherapy regimen according to CD4 cell counts at NHL diagnosis:, patients with CD4 cells below or above 100 cells x 10(6)/liter received CHOP or ACVBP regimens, respectively. Event-free survival (EFS) and survival were estimated by the Kaplan-Meir method and a Cox model was used to evaluate the effect of different variables on survival. At diagnosis of ARL, the median age was 37 years and 22 patients (30%) had prior AIDS-defining events. Median CD4 cell count was 99 x 10(6)/liter. The median follow-up was 60 months. Ann Arbor stage 3-4 was noted in 60 patients (82%) and bone marrow or meningeal involvement was present in 13 (17%) and 12 (16%) patients, respectively. Two groups were identified: group 1 (n = 38) included patients who had never received HAART and group 2 (n = 35) included those who received HAART either before the diagnosis or following ARL. There was no statistical significant differences in lymphoma extensive stage, presence of B symptoms, meningeal involvement, CD4 cell count at diagnosis, prior AIDS events, or chemotherapy regimens between the two groups. Median survival (MS) of the whole cohort of patients was 8 months. Estimated EFS was significantly higher (30 months) in group 2 compared to group 1 (6.1 months) (p = 0.03). In the multivariate Cox model HAART has an independent significant effect on EFS (p = 0.0085). No influence on outcome was found for other variables except for prior AIDS and bone marrow involvement. HAART has significantly improved the survival and EFS in patients with ARL, independently of chemotherapy regimen.

Lack of evidence of HTLV-I/II infection in T CD8 malignant or reactive lymphoproliferative disorders in France: a serological and/or molecular study of 169 cases.

Human T lymphotropic virus type II (HTLV-II), originally isolated in 1982 from a patient with a "T hairy cell leukemia", has not yet been proven to be the causative agent of any specific hematological disease. In order to screen for such an event, and because HTLV-II has a preferential tropism for OKT8 (CD8) T cells (both in vivo and in vitro), we searched for the presence of HTLV-II in lymphoproliferative diseases (LP) of CD8+ T cells. We report a serological and/or molecular study of 169 patients with a T CD8 LP, including 76 patients with malignant or reactive T CD8 LP (34 lymphomas, 27 large granular leukemias, three prolymphocytic leukemias, one hairy cell leukemia, 11 reactive T CD8 LP) and 93 HIV-1+ patients with a T CD8 peripheral lymphocytosis ( > 1500/mm3) from a prospective HIV cohort involving 1264 individuals. In the first series, the 40 sera available were all HTLV-I/II negative, except a 67-year-old French Guyanan man, with a cutaneous large T CD8 cell lymphoma, HTLV-I+. Furthermore, the molecular analysis of the 69 available DNA samples by PCR failed to detect any proviral HTLV-I/II sequences, except for the HTLV-I+ patient. The serological study of the 93 HIV-1+ individuals with CD8 lymphocytosis, showed that three patients were HTLV-I+, but none was HTLV-II+. Thus, in contrast to HTLV-I, whose etiological role in adult T cell leukemia is now well established, there is neither epidemiological nor molecular evidence that prototypic HTLV-II may be etiologically associated specifically with any of the CD8+ T cell LP investigated in this report.

Failure of rituximab to treat a lupus flare-up with nephritis.

The autoantibodies secreted by B lymphocytes have recently been shown to play an important role in autoimmune disease. B lymphocyte depletion by rituximab, a monoclonal anti-CD20 antibody, has been introduced for the treatment of several autoimmune disorders. Few reports have underlined its potential use for the treatment of systemic lupus erythematosus (SLE). We report here the occurrence of extracapillary glomerulonephritis associated with a thrombotic event shortly after rituximab treatment for a lupus flare-up in a patient with anticardiolipin antibodies. This observation suggests that rituximab alone may be insufficient to control severe SLE with glomerulonephritis and should therefore be used with caution in patients with this condition.

Staphylococcal superantigens activate HIV-1 replication in naturally infected monocytes.

OBJECTIVES: To study the effects of microbial superantigens, Staphylococcal exotoxins (SE), on HIV replication in monocytes following binding to and signalling through major histocompatibility complex (MHC) class II molecules. METHODS: We investigated the effects of SE on HIV replication and monokine production in three different in vitro models of monocyte culture: chronically infected monocytic cell line U1, acute infection of normal monocytes by different HIV-1 strains, and naturally-infected monocytes from seropositive patients. p24 antigen, interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha production was measured by specific enzyme-linked immunosorbent assay (ELISA). RESULTS: Staphylococcal enterotoxin B and toxic shock syndrome toxin-1 (1-1000 ng/ml) are powerful inducers of HIV-1 expression in U1 cells pretreated with granulocyte macrophage colony stimulating factor. SE induce viral replication in short-term cultures (days 6-21) of monocytes infected in vitro by HIVBa-L, HIVLAI, or naturally infected in vivo. Induction of HIV expression requires direct interactions of SE with MHC class II molecules but not T-cell receptor binding and T-cell-monocyte contact. Anti-TNF-alpha and anti-IL-6 neutralizing monoclonal antibodies inhibit by over 61% SE-induced HIV replication. CONCLUSIONS: Using SE we have linked two important pathways for the regulation of HIV replication in monocytes, namely signalling through MHC class II molecules and monokine production potentially mediated by induction of the pleiotropic cellular transcription factor NF-kappa B. In HIV-infected patients bacterial infections are common and could be an important cofactor in the immunopathogenesis of AIDS by inducing HIV replication in latently infected monocytes. Their prevention might emerge as beneficial in these patients.

HIV-associated endometritis.

Using immunohistochemical staining, in situ hybridization and a combination of both, we demonstrate here the replication of HIV in the endometrial stroma. Infected cells do not belong to the T-lymphocyte lineage but rather to a monocyte-macrophage cell type. This report suggests a possible relationship between HIV infection and endometritis. Moreover, HIV replication in endometrial tissues could play a role in heterosexual and materno-fetal transmission.

HIV-induced, HIV-specific in vitro antibody response by B-cells from HIV-seropositive individuals.

OBJECTIVE: Recent studies have shown that B-cells from HIV-infected patients can secrete anti-HIV antibodies in vitro and that they represent 20-40% of immunoglobulin (Ig)-secreting B-cells in vivo. This study was designed to investigate the precise role of HIV in this in vitro antibody production. DESIGN AND METHODS: B-cells from HIV-infected patients [asymptomatic, n = 28; symptomatic (AIDS), n = 14], from seronegative adult volunteers (n = 22) and subjects at high risk for HIV infection (n = 15) were cultured in vitro in the presence of pokeweed mitogen, Staphylococcus aureus cowan or HIV, and T-cells or interleukins (IL). Non-specific Ig production and specific anti-HIV antibody (Ab) production were measured by enzyme-linked immunosorbent and Western blot assays. RESULTS: We found that HIV induced a specific response in cultured B-cells from seropositive patients, in contrast with cultured B-cells from uninfected normal individuals. The characteristics of the HIV-induced response differed from those of a spontaneous or a mitogen-induced response. Anti-HIV Ab production was optimal on day 8-10, when B-cells were cultured with recombinant IL-2 and recombinant interferon-alpha in the presence of infectious virus or recombinant gp160 Env protein. The anti-HIV Ab were mainly directed against Env proteins. Interaction of HIV with B-cells involved surface IgG but not CD4 antigen. Autologous CD8+ T-cells had a non-specific inhibitory effect. Both CD5+ and CD5- B-cells produced anti-HIV Ab. No anti-HIV Ab production was observed in B-cells from high-risk HIV-seronegative individuals. CONCLUSION: HIV (infectious virus or gp160) can induce B-cells from infected patients to secrete specific anti-HIV Ab in vitro.

Pregnancy and progression to AIDS: results of the French prospective cohorts. SEROGEST and SEROCO Study Groups.

OBJECTIVE: To investigate whether pregnancy accelerates HIV-1 disease progression. METHOD: In two large French SEROCO and SEROGEST prospective cohorts of HIV infected patients, the progression to AIDS in 365 women with a known date of HIV-1 seroconversion was examined by comparing those who delivered after HIV infection (n = 241) with those who did not become pregnant while HIV-infected (n = 124). RESULTS: The crude relative risk of developing AIDS associated with pregnancy was 0.7 [95% confidence interval (CI), 0.4-1.2]. Adjustment for age at seroconversion, the CD4+ cell percentage at entry, and the method used to date seroconversion did not modify the results (adjusted relative risk, 0.7; 95% CI 0.4-1.2). CONCLUSIONS: No deleterious effect of pregnancy on progression from seroconversion to AIDS was found. This result has important implications for the counselling of HIV-infected women of child-bearing age.