[Professor Jacques Fouad Acar, Africa and the "potluck"]. / Professeur Jacques Fouad Acar, l'Afrique et l'« auberge espagnole ¼.

The biography of Professor Jacques Fouad Acar (1931-2020) shows the exceptional trajectory of an atypical doctor, infectiologist-clinician and microbiologist, propelled by the international dynamics of integration and social progress originating in the Lebanese diaspora with his first founding experiences in Dakar, Senegal, in French West Africa, during the golden age of French colonial medicine. Jacques Acar's imprint will comprise three remarkable dimensions: on the one hand, the promotion of integrated multidisciplinary clinical-biological reasoning in infectious pathology; on the other hand, independence of thought in the field of action, which will become his leitmotiv during his university hospital career, allowing him to integrate "pastoral esprit de corps" into his fundamental research at the Pasteur Institute in Paris on the molecular mechanisms of antibiotic resistance and to participate in the explosion of world medicine; lastly, his unique emotional intelligence potentiated by his instinctive sense of networking, with students of all origins and disciplines.

HIV self-testing in adolescents living in Sub-Saharan Africa.

Less than 20% of African adolescents aged 10-19 years are aware of their HIV status, whereas HIV screening remains the gateway to care and while AIDS has become the leading cause of death among adolescents in Sub-Saharan Africa. According to the UNAIDS target, scalable HIV testing strategies specific to various age groups, populations, and geographical areas must be implemented to end the AIDS epidemic by 2030. Many African countries have implemented policies supporting HIV self-testing (HIVST). Evidence of practicability and efficiency of HIVST in Sub-Saharan Africa settings has been reported, including HIVST data among adolescents. Adapted strategies of HIVST are urgently needed to promote HIV testing among adolescents living in sub-Saharan Africa.

HIV self-testing in Africa: stakes and challenges.

HIV self-testing constitutes a new complementary strategy for HIV testing for general populations as well as "key" populations such as sex workers and their clients, men who have sex with men, and young people; it may help to reach the UNAIDS 90-90-90 objectives by 2020. In Africa, many pilot studies have been conducted, mainly in English-speaking countries, and they have demonstrated the high acceptability, practicability and clinical performance of HIV self-testing. Innovative strategies, including the translation of HIV self-test instructions for use into vernacular languages in association with educational pictograms, should be developed and evaluated in sub-Saharan Africa to implement HIV self-testing.

Cervical cancer in sub-Saharan Africa: an emerging and preventable disease associated with oncogenic human papillomavirus.

Highly oncogenic human papillomavirus (HPV) infections are responsible for 7.7 % of cancers in developing countries, mainly cervical cancer. The incidence of this emerging cancer is steadily increasing in sub-Saharan Africa, with more than 75,000 new cases and close to 50,000 deaths a year, a toll further increased by HIV infection. According to the World Health Organization, cervical cancer will kill more than 443,000 women per year worldwide by 2030, nearly 90 % of them in sub-Saharan Africa. This increase in cervical cancer incidence in Africa is now counteracting the progress made by African women in reducing maternal mortality and increasing longevity. Nevertheless, cervical cancer is a potentially preventable noncommunicable disease that can be averted or halted by primary (vaccination), secondary (early diagnosis of situations at risk), and tertiary (early diagnosis of proven cases of cervical neoplasia) prevention. The close links between HIV and HPV justify linking cervical cancer prevention, screening, and management programs with AIDS programs as part of the "90-90-90" initiative of the UNAIDS, both nationally and regionally. Innovative strategies based on effective, rapid, inexpensive, and mobile screening tools, including at best molecular biology as well as vaccination and awareness programs, should be rapidly implemented and evaluated in sub-Saharan Africa.

Evaluation of the Upgraded Version 2.0 of the Roche COBAS® AmpliPrep/COBAS® TaqMan HIV-1 Qualitative Assay in Central African Children.

BACKGROUND: Several commercially available molecular techniques were developed based on subtype B of HIV-1, which represents only 10% of HIV strains worldwide. Indeed, in sub-Saharan Africa, non-B subtypes of HIV-1 are predominant. The aim of this study was to evaluate the performances of the COBAS® AmpliPrep/COBAS® (CAP/CTM) HIV-1 Qualitative assays to detect the broad range of HIV-1 variants circulating in Central Africa and compare to the outgoing CAP/CTM HIV-1 Quantitative test v2.0 (Roche Molecular Systems), chosen as reference gold standard molecular assay. METHODS: The CAP/CTM HIV-1 Qualitative tests versions 1.0 and 2.0 (Roche Molecular Systems, Inc., Branchburg, NJ, USA) were evaluated compared to CAP/CTM TaqMan HIV-1 Quantitative test v2.0 (Roche Molecular Systems) on 239 dried plasma spot (DPS) from 133 HIV-1-infected (with detectable plasma HIV RNA load) and 106 uninfected children, followed-up at Complexe Pédiatrique, Bangui, Central African Republic. RESULTS: The version 1.0 showed low sensitivity (93.2%), with 9 (6.8%) false negative results, demonstrating under-detection of non-B HIV-1 subtypes. In contrast, the upgraded version 2.0 showed 100%-sensitivity, 100%-specificity and perfect agreement (κ coefficient, 1.0). CONCLUSION: Our evaluation in the Central African Republic demonstrates the clinical implications of the accuracy and reliability of the CAP/CTM HIV-1 Qualitative assay for early diagnosis of HIV-1 in Central African children.

Variability of human immunodeficiency virus-1 in the female genital reservoir during genital reactivation of herpes simplex virus type 2.

Clinical and subclinical genital herpes simplex virus type 2 (HSV-2) reactivations have been associated with increases in human immunodeficiency virus (HIV)-1 genital shedding. Whether HSV-2 shedding contributes to the selection of specific genital HIV-1 variants remains unknown. We evaluated the genetic diversity of genital and blood HIV-1 RNA and DNA in 14 HIV-1/HSV-2-co-infected women, including seven with HSV-2 genital reactivation, and seven without as controls. HIV-1 DNA and HIV-1 RNA env V1-V3 sequences in paired blood and genital samples were compared. The HSV-2 selection pressure on HIV was estimated according to the number of synonymous substitutions (dS), the number of non-synonymous substitutions (dN) and the dS/dN ratio within HIV quasi-species. HIV-1 RNA levels in cervicovaginal secretions were higher in women with HSV-2 replication than in controls (p0.02). Plasma HIV-1 RNA and genital HIV-1 RNA and DNA were genetically compartmentalized. No differences in dS, dN and the dS/dN ratio were observed between the study groups for either genital HIV-1 RNA or plasma HIV-1 RNA. In contrast, dS and dN in genital HIV-1 DNA were significantly higher in patients with HSV-2 genital reactivation (p <0.01 and p <0.05, respectively). The mean of the dS/dN ratio in genital HIV-1 DNA was slightly higher in patients with HSV-2 genital replication, indicating a trend for purifying selection (p 0.056). HSV-2 increased the genetic diversity of genital HIV-1 DNA. These observations confirm molecular interactions between HSV-2 and HIV-1 at the genital tract level.

[Alain Georges: in the footsteps of Louis Pasteur and Eugène Jamot]. / Alain Georges : sur les traces de Louis Pasteur et d'Eugène Jamot.

The biography of the physician general Alain Jean Georges (1946-2012) shows the exceptional career of a military physician-clinical pathologist specialized in tropical medicine and educated at the Navy Health School in Bordeaux and the Pharo School in Marseille. He completed his education at the Institut Pasteur de Paris in courses still conducted in the spirit of those taught by Louis Pasteur. In 1979, he became director of the Pasteur Institute of Bangui, following in the steps of Eugène Jamot, in the long tradition of military doctors from the Institut Pasteur overseas network committed to a career in Africa. For more than 12 years, Alain Georges directed the Pasteur Institute of Bangui, one of the last citadels of French postcolonial military medicine, in a very personal and charismatic style. He was thus a pioneer in research about both AIDS in Africa and hemorrhagic fevers. His methods were widely misunderstood later as the traditional networks of French biomedical research in its former African colonies modernized and opened internationally, including to national elites. Alain Georges was probably one of the last important figures of the golden age of French colonial medicine.

[The challenges of training in medical laboratories in Africa]. / Le défi de la formation dans le domaine du laboratoire de biologie clinique en Afrique.

Sub-Saharan Africa has a considerable deficit in laboratory facilities. For a decade, international and national public and private initiatives have multiplied to expand both the supply and quality of medical laboratories in Africa. By 2020, the World Health Organization, with as its main operator the African Society for Laboratory Medicine, will have provided training for 30,000 laboratory personnel and encouraged 2,500 laboratories to begin the accreditation process. In addition, the World Health Organization recommendations for treatment and care of HIV-infected individuals in resource-limited settings, revised in 2013, emphasize the need for laboratory monitoring to guide antiretroviral therapy. The University Diploma in Biological Retrovirology at the Cheikh Anta Diop University in Dakar, Senegal, offers multidisciplinary training in French at the postgraduate level in the complex and diverse field of biological monitoring of HIV infection in Africa. In nearly 10 years, more than 200 African biologists have been trained.

Dynamics of HIV-1 DNA level in highly antiretroviral-experienced patients receiving raltegravir-based therapy.

To assess dynamics of HIV-1 DNA in highly antiretroviral (ARV)-experienced HIV-infected patients successfully treated with raltegravir (RAL)-containing therapy. Nineteen patients with virological failure whose ARV treatment was switched to a RAL-based salvage regimen with virological success were included (Group I). Ten patients in virological failure and responding to ARV salvage therapy not containing RAL were also included (Group II). The HIV-1 DNA level in peripheral blood mononuclear cells (PBMC) was assessed by real-time PCR at baseline, W12, W24, W36 or W48. In group I, a marked decrease in the HIV-1 DNA level was observed at W12 both in PBMC (median decrease = 0.38 log(10)copies/10(6)PBMC; P < 0.001) and in CD4 T cells (0.85 log(10)copies/10(6)CD4 T cells; P < 0.001). Plasma HIV-1 RNA decrease was correlated with HIV-1 DNA decrease expressed as copies/10(6)CD4 T cells (r = 0.55, P = 0.03). HIV-1 DNA level reached a steady state by W24. Thus, RAL-containing treatment in highly ARV-experienced patients was associated with a rapid HIV-1 DNA decrease, mainly in the circulating CD4 T cells compartment. Group II patients showed an early decrease in the HIV-1 DNA load until W12, which was 2.5-fold less pronounced in the CD4 T cells compartment than in the RAL-treated patients. The potent action of RAL-containing treatment observed in the CD4 T cells compartment may suggest a pronounced reduced inhibition in the pool of regenerating CD4 T cells on a RAL-based therapy.

Concentrated and linked epidemics of both HSV-2 and HIV-1/HIV-2 infections in Senegal: public health impacts of the spread of HIV.

The objective of this article is to report seroprevalences on HIV and herpes simplex virus 2 (HSV-2) in female sex workers (FSW) and in two sentinel populations of pregnant women living in Senegal. Serosurveys of HIV and HSV-2 were conducted in two unselected sentinel populations from Dakar, Senegal, and its provinces, including in 2003 only pregnant women and 2006 pregnant women and FSW. The population study involved 888 pregnant women and 604 FSW. In pregnant women, HIV and HSV-2 seroprevalences were, respectively, 1.01% and 15.65%. There was no association between HSV-2 and HIV infection, whatever the age. In contrast, the seroprevalence of HIV infection in the group of FSW was high, reaching 22.9% in women over 30 years old. FSW above 20 years of age harboured much higher HSV-2 seroprevalences that those found in pregnant women of similar age groups. In FSW, strong associations between HSV-2 and age, and among HSV-2 and HIV-1 as well HIV-2, were evidenced. In conclusion, HIV epidemic remains concentrated in high-risk groups of the Senegalese population, such as the FSW population in which the seroprevalence of HSV-2 infection is very high. Intervention against STI including HSV-2 is urgently needed to prevent the spreading of HIV epidemic.

Drug resistance profiles for the HIV integrase gene in patients failing raltegravir salvage therapy.

OBJECTIVES: Recent data showed the selection of mutations in the integrase gene, mainly involving position 148 or 155, in patients displaying virological failure (VF) on raltegravir (RAL) therapy. Here, we describe the development of RAL resistance, in both plasmatic and cellular compartments, in three heavily pretreated HIV-infected patients failing RAL-containing regimens. METHODS: Three of 17 patients receiving RAL displayed VF. The entire integrase gene, isolated from plasma and peripheral blood mononuclear cells (PBMC), was sequenced. A clonal analysis was performed in one patient at the time of VF. RESULTS: At the time of VF, RAL-resistance mutations were selected: (i) Q148R in patients 1 and 3; (ii) T66A and E92Q in patient 2. A gradual accumulation of new mutations was observed in all patients, including G140S, Q148H and N155H in patient 1, L74I in patient 2, and G140S in patient 3. Clonal analysis showed the coexistence, in patient 1, of the two common resistance pathways (mutations Q148R/H and N155H) found in distinct quasi-species. In addition, RAL-resistance mutations were detected in HIV DNA in all patients. CONCLUSIONS: Having rapidly established, resistance to RAL evolves and diversifies, and is likely to impact the efficacy of subsequently used second-generation integrase inhibitors. Moreover, RAL-resistance mutations can be archived early in PBMC.

Interactions between human immunodeficiency virus and herpes viruses within the oral mucosa.

There is evidence from clinical case reports and epidemiological studies that human immunodeficiency virus (HIV) can be transmitted through oral sex. Herpes viruses that appear in the oral mucosa might influence the oral replication of HIV. A review of data suggesting that interactions occur between HIV and herpes viruses indicates that such interactions might operate in the oral mucosa. Defining the mechanisms by which herpes viruses interact with HIV in the oral mucosa should permit intervention measures to be targeted more precisely.

Herpes simplex virus type 2 and heterosexual spread of human immunodeficiency virus infection in developing countries: hypotheses and research priorities.

Herpes simplex virus type 2 (HSV-2) infection is almost always sexually transmitted, and causes genital ulceration. Significant progress in our understanding of HSV infection has occurred over the last decade, in part related to the development of accurate and sensitive laboratory tests to study HSV-2. The application of PCR and type-specific serology to individual cases and in population-based studies has enabled the identification of a potentially important role for HSV-2 infection as a cofactor in the sexual transmission of HIV. This is a particular issue in developing countries. This review describes the epidemiology of HSV-2 infection in the HIV era, the hypotheses regarding HSV-HIV interactions, and research priorities for the developing world.

Detection of genomic viral RNA in nerve and muscle of patients with HCV neuropathy.

BACKGROUND: Hepatitis C virus (HCV)-associated neuropathy is usually associated with mixed cryoglobulinemia (MC) and vasculitis. MC may contain viral RNA, and tissues showing vasculitis may contain intracellular HCV. Local HCV replication remains to be evidenced. OBJECTIVE: To delineate the spectrum of HCV-associated neuropathy and to assess the presence of HCV in nerve and muscle tissues. METHODS: Thirty consecutive HCV-infected patients with peripheral neuropathy were included. Genomic and replicative strands of HCV RNA were detected in both nerve and muscle biopsy samples using distinctive reverse transcription nested PCR. RESULTS: Neuropathy was consistent with distal axonal polyneuropathy (DPN) in 25 of 30 patients, mononeuropathy multiplex (MM) in 3 of 30, and demyelinating polyneuropathy in 2 of 30. Pain was present in 18 of 30 patients and MC in 16 of 30. Biopsy showed inflammatory vascular lesions in 26 of 30 patients (87%), including necrotizing arteritis (6/30), small-vessel vasculitis (12/30) of either the lymphocytic (9/12) or the leukocytoclastic (3/12) type, and perivascular inflammatory infiltrates (8/30). All patients with necrotizing arteritis had DPN and positive MC detection. Both pain (p < 0.03) and positive MC detection (p < 0.01) were associated with the presence of vasculitis. Positive-strand genomic HCV RNA was detected in tissues of 10 of 30 patients (muscle 9, nerve 3). In contrast, negative-strand replicative RNA was never detected. Genomic RNA was found in nerve tissue samples showing vasculitis (necrotizing arteritis 2, small-vessel lymphocytic vasculitis 1). CONCLUSION: Painful DPN associated with MC and neuromuscular vasculitis is the most frequent type of HCV neuropathy. The usual detection of MC and the lack of local HCV replication indicate that HCV neuropathy results from virus-triggered immune-mediated mechanisms rather than direct nerve infection and in situ replication.

Do retroviruses preferentially integrate within highly plastic regions of the human genome?

Whether retroviral integration is a phenomenon specific to properties of the surrounding genomic region is a widely debated question. In this paper we attempt to enlight the involvement of genomic regions prone to DNA double strand breaks in such process, as well as the more general concept of genome plasticity concerning repair, recombination, transposition events. While performing a differential display analysis of the promonocytic cell line U937 and clone U42 HIV infected counterpart, we found, out of about 15 highly dysregulated genes, expected according to our previous proteomic analysis, two dysregulated cellular transcripts that are shown in the present study to colocalize on band 22q11. The LB14 transcript maps within the DiGeorge critical region. Whereas the AG46 transcript encodes the immunoglobulin-lambda like polypeptide 1 (IGLL1) 4.7Mb apart from LB14. The 22q11 band is remarkable for its high plasticity involving DNA double strand breaks, that may lead to translocations, large deletions, and immunoglobulin rearrangements, frequently observed in this region. We suggest that provirus integration preferentially occurs in such genomic regions and that the subsequent insertional mutagenesis leads to the present observations. Finally, we stress out the possibility that the small size of chromosome 22 is associated with this physical property of the genome.

[Defenses of the female genital tract against infection]. / Défenses non immunes, pré-immunes et immunes du tractus génital féminin contre les infections.

The female genital tract possesses various systems of defenses against the infectious risk, which appear complementary, additive and even synergistic. These defenses comprise first non immune strategies, passive (synthesis of protective mucus; pH; epithelial barrier) or active (inflammatory reaction; secretion of humoral soluble factors such as lactoferrin), which are likely very efficient to limit the infectious inoculum. Pre-immune defense strategies, both humoral and cellular, yet not well understood, are also possibly involved in rapid protection pre-existing before antigenic stimulation. When these initial lines of defenses have failed, a third strategy, acquired and specific of the pathogen, occurs progressively. This latter associates humoral immune response, with secretory IgA (S-IgA) and IgM (S-IgM), and locally produced IgG (s-IgG), and cellular immune response. The very high amount of IgG in the female genital secretions, at levels more than 10-fold those of IgA, and originating in part from plasma by transudation, is remarkable for a corporeal fluid, the mucosal secretions being most often characterized by the predominance of immunoglobulins of the IgA isotype. The defenses of the female genital tract are largely under the influence of female hormones (menstrual cycle or pregnancy) and of paracrine production of various cytokines. Note that the genital defenses against infectious agents must not decrease the efficiency of the reproduction; indeed, spermatozoa act as potential exo-antigens for the female genital tract, and the inductive capabilities of the genital immunocompetent tissue have to be limited when the epithelial barrier has not been crossed. Systemic immunity acts in a second step to reinforce or substitute the acquired mucosal immunity of the genital tract.

Cervicovaginal secretory antibodies to human immunodeficiency virus type 1 (HIV-1) that block viral transcytosis through tight epithelial barriers in highly exposed HIV-1-seronegative African women.

Antibodies to human immunodeficiency virus (HIV) of the IgA, IgG, and IgM isotypes and high levels of the HIV suppressive beta-chemokine RANTES (regulated on activation, normally T cell expressed and secreted) were found in the cervicovaginal secretions (CVSs) of 7.5% of 342 multiply and repeatedly exposed African HIV-seronegative female sex workers. The antibodies are part of a local compartmentalized secretory immune response to HIV, since they are present in vaginal fluids that are free of contaminating semen. Cervicovaginal antibodies showed a reproducible pattern of reactivity restricted to gp160 and p24. Locally produced anti-env antibodies exhibit reactivity toward the neutralizing ELDKWA epitope of gp41. Study results show that antibodies purified from CVSs block the transcytosis of cell-associated HIV through a tight epithelial monolayer in vitro. These findings suggest that genital resistance to HIV may involve HIV-specific cervicovaginal antibody responses in a minority of highly exposed HIV-seronegative women in association with other protecting factors, such as local production of HIV-suppressive chemokines.