[SARS-CoV-2 variants in relation to screening and vaccines]. / Les variants du SARS-CoV-2 face au dépistage et aux vaccins.

As of today, September 2021, it is very difficult to predict how the SARS-CoV-2 pandemic will develop in France and around the world. The objective of this review is to analyze recent studies concerning SARS-CoV-2, especially those looking for its origin, particularly in viruses from various bat populations. The ability of variants to escape vaccine responses is a real concern, as these variants show increased pathogenicity. Screening of infected subjects and large-scale sequencing are essential tools to be strengthened, for monitoring the risk of emergence of possible new variants and for the development of the second generation vaccines.

Comparative performance of the Biocentric Generic Viral Load, Roche CAP/CTM v1.5, Roche CAP/CTM v2.0 and m2000 Abbott assays for quantifying HIV-1 B and non-B strains: Underestimation of some CRF02 strains.

BACKGROUND: HIV-1 viral load testing is now recommended by the World Health Organization for every patient receiving antiretroviral therapy (ART). OBJECTIVES: The objective of this study is to evaluate the performance of commercial assays for their ability to quantify HIV-1 strains currently circulating in France. STUDY DESIGN: The performances of the Generic HIV-RNA assay from Biocentric were compared to those of the Roche CAP/CTM v1.5, Roche CAP/CTM v2.0 and Abbott m2000 RealTime HIV-1 assays. A total of 1885 HIV-1 plasma samples were tested, including 684 samples from patients included in the ANRS-Primo Cohort. RESULTS: We found a good concordance of quantification between the Roche v2.0 and the Biocentric assays, both of which were superior to the Roche v1.5 assay. We show moderate agreement between techniques; however, CRF02_AG strains and undetermined viruses were underestimated when quantified with the Roche CAP/CTM v2.0. In contrast, a comparison of the Biocentric and Abbott assay results showed strong agreement between assays, indicating that both are well suited for quantification of CRF02_AG strains. Moreover, a 2% underestimation of the B subtypes was observed with the Biocentric assay. CONCLUSIONS: These results have implications for viral load monitoring in Western Africa, where CRF02_AG strains are highly prevalent. Closer epidemiological surveillance and evaluation of commercial assays are still necessary to better evaluate the impact of the genetic evolution of circulating viruses on HIV-RNA quantification in the regions most affected by the HIV-1 epidemic.

What Is the most Important for Elite Control: Genetic Background of Patient, Genetic Background of Partner, both or neither? Description of Complete Natural History within a Couple of MSM.

BACKGROUND: We describe a homosexual man who strongly controlled HIV-1 for ten years despite lack of protective genetic background. METHODS: HIV-1 DNA was measured in blood and other tissues. Cell susceptibility was evaluated with various strains. HIV-1-specific (CD4 and CD8 activation markers and immune check points) and NK cells responses were assessed; KIRs haplotypes and HLA alleles were determined. FINDINGS: Two HIV-1 RNA copies/mL of plasma were detected in 2009, using an ultra-sensitive assay. HIV-DNA was detected at 1.1 and 2 copies/106 PBMCs in 2009 and 2015 respectively, at 1.2 copies/106 cells in rectal cells in 2011. WBs showed weak reactivity with antibodies to gp160, p55 and p25 from 2007 to 2014, remaining incomplete in 2017. CD4 T cells were susceptible to various strains including HIVKON, a primary isolate of his own CRF02_AG variant. CD8 T cells showed a strong poly-functional response against HIV-Gag, producing mainly IFN-γ; a robust capacity of antibody-dependant cell cytotoxicity (ADCC) was observed in NK cells. Case patient was group B KIR haplotype. Neutralizing antibodies were not detected. CD4 and CD8 blood T cells showed normal proportions without increased activation markers. Phylogenetic analyses identified the same CRF02_AG variant in his partner. The patient and his partner were heterozygous for the CCR5ΔD32 deletion and shared HLA-B*07, C*07 non-protective alleles. INTERPRETATION: This thorough description of the natural history of an individual controlling HIV-1 in various compartments for ten years despite lack of protective alleles, and of his partner, may have implications for strategies to cure HIV-1 infection.

[Reproductive options for people living with HIV: 2013 guidelines from the French expert working group]. / Désir d'enfant chez les personnes vivant avec le VIH : nouvelles recommandations 2013 du groupe d'experts français.

The desire for children is a legitimate aspiration that should be part of multidisciplinary care for all men, women or couples living with HIV. The use of effective antiretroviral therapy has revolutionized the prevention of sexual, as well as mother-to-child HIV transmission. When the HIV plasma viral load is undetectable on long-term antiretroviral therapy, the risk of mother-to-child transmission is <1% and the risk of heterosexual HIV transmission without condom use in a stable relationship is very low (estimated at less than 1/10,000) in the absence of inflammation of the genital tract. In a man with a long-term undetectable viral load, viral shedding in semen is uncommon, but may occur persistently or intermittently. The same appears true of viral shedding in the vaginal tract of women. Reproductive options are: natural conception, self-insemination when the woman is HIV-infected, assisted reproduction. Natural conception is now considered to be an acceptable option when the conditions are met, after exploring four aspects: (1) virological (viral load undetectable sustained for at least 6 months on therapy), (2) genital (absence of genital infections or lesions), (3) fertility (after appropriate evaluation) and (4) detecting the ovulation period to limit intercourse without condoms. Assisted reproduction has two objectives in the context of HIV, to allow the couple to conceive without abandoning condom use and/or to treat infertility.

[HIV and pregnancy: 2013 guidelines from the French expert working group]. / Infection par le VIH et grossesse: nouvelles recommandations 2013 du groupe d'experts français.

With effective antiretroviral therapy, the risk of mother to child transmission (MTCT) is now under 1%. The 2013 French guidelines emphasize early antiretroviral lifelong antiretroviral therapy. Thus, the current trend for women living with HIV is to take antiretroviral therapy before, during and after their pregnancies. A major issue today is the choice of antiretroviral drugs, to maximize the benefits and minimize the risks of fetal exposure. This requires interdisciplinary care. The use of effective therapies permits gradual but profound changes in obstetric practice. When maternal plasma viral load is controlled (<50 copies/ml), obstetrical care can be more similar to standards in HIV-negative women. Prophylactic cesarean section is recommended when the viral load in late pregnancy is above 400 copies/mL. Intravenous zidovudine during labor is recommended only if the last maternal viral load is>400 copies/mL or in case of complications such as preterm delivery, bleeding or chorio-amnionitis during labor. In case of premature rupture of membranes before 34 weeks, a multidisciplinary decision should be made, based on gestational age and control of maternal viral load; if the woman is under antiretroviral therapy and especially if her viral load is undetectable, steroids and antibiotics should be offered and pregnancy can be continued except in case of signs or symptoms of chorio-amnionitis. Breastfeeding is not recommended in women living with HIV in France, as in industrialized countries. Prophylaxis in the newborn is usually zidovudine for 1 month. In case of significant exposure to HIV perinatally, in particular when, maternal viral load is>1000 copies/mL, prophylactic combination therapy is recommended. Monitoring of the child is necessary to determine whether or not it is free of HIV infection and to monitor possible adverse effects of perinatal exposure to antiretroviral drugs.

[Pediatric aids, 30 years later]. / Le sida pédiatrique, 30ans plus tard.

Thirty years after the first descriptions of AIDS in children in May 1983, the risk of viral transmission from mother to child has been reduced to almost zero and the disease in infected children has become an asymptomatic condition, stable in the long-term, thanks to antiretroviral drugs. Unbelievable though it may have seemed until the mid-1990s, children infected during the perinatal period are now growing up to be adults in a chronic, stable, asymptomatic medical condition with often satisfactory personal, family, and social lives. The French perinatal epidemiological cohort, which was set up in 1984 and has included more than 18,000 mother-child pairs to date, traces the steps in this extraordinary revolution in the prevention and treatment of HIV-1 infection in children.

Prevalence of CXCR4-tropic viruses in clustered transmission chains at the time of primary HIV-1 infection.

During 2003-2010, 555 strains isolated from sexually-infected patients at the time of primary HIV-1 infection (PHI) were characterized. Tree topology revealed that 11.7% of PHIs segregated into transmission clusters. CXCR4-usage was identified in 27 strains (4.9%) and was significantly associated with subtype B (p 0.003) and low CD4 cell count (p 0.01). In clustered and unique PHIs, the prevalence of CXCR4-tropic strains was 1.5% and 5.3%, respectively (p 0.35). Our results are in line with the hypothesis of a mucosal bottleneck contributing to the high prevalence of CCR5 variants during PHI.

Non-disclosure of a pregnant woman's HIV status to her partner is associated with non-optimal prevention of mother-to-child transmission.

Our objective was to study relations between non-disclosure of HIV to partner, socio demographics and prevention of HIV mother-to-child transmission (PMTCT), among HIV-infected pregnant women enrolled in the French Perinatal Cohort (ANRS-EPF-CO1) from 2005 to 2009 (N = 2,952). Fifteen percent of the women did not disclose their HIV status to their partner. Non-disclosure was more frequent in women diagnosed with HIV infection late in pregnancy, originating from Sub-Saharan Africa or living alone, as well as when the partner was not tested for HIV. Non-disclosure was independently associated with non optimal PMTCT: late initiation of antiretroviral therapy, detectable viral load at delivery and lack of neonatal prophylaxis. Nonetheless, the rate of transmission did not differ according to disclosure status. Factors associated with non-disclosure reflect vulnerability and its association with non optimal PMTCT is a cause for concern although the impact on transmission was limited in this context of universal free access to care.

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.

Blood Epstein-Barr virus DNA load and risk of progression to AIDS-related systemic B lymphoma.

BACKGROUND: AIDS-related lymphoma (ARL) remains the main cause of AIDS-related deaths in the combined antiretroviral therapy (cART) era. Although most ARLs are associated with the Epstein-Barr virus (EBV), whether patients with high EBV burden are more at risk of developing ARL is unknown. This study investigated the relationship between high blood EBV DNA loads and subsequent progression to ARL. METHODS: We identified 43 cases of ARL diagnosed between 1988 and 2007 within two cohorts (ANRS SEROCO/HEMOCO and PRIMO) and for which stored serum and peripheral blood mononuclear cell (PBMC) samples were available within 3 years before ARL diagnosis. For each case, two controls matched for the cohort and CD4 cell count in the year of ARL diagnosis were selected. EBV DNA was measured in PBMCs and serum samples with a commercial kit. RESULTS: High levels of EBV DNA in PBMCs collected a median of 10 months before diagnosis were associated with an increased risk of developing systemic B lymphoma (adjusted odds ratio 2.47; 95% confidence interval 1.15; 5.32 for each 1 log copies/10(6) PBMC increase in EBV load) but not with primary brain lymphoma. CONCLUSION: In this study, HIV-infected patients with undetectable EBV DNA in PBMCs did not develop ARL in the following 3 years, while high levels of EBV DNA in PBMCs predicted subsequent progression to systemic B lymphoma. Clinicians should be aware of the increased risk of developing systemic B lymphoma in HIV-infected patients with a high blood EBV DNA load.

Mother-to-child transmission of HIV-2 infection from 1986 to 2007 in the ANRS French Perinatal Cohort EPF-CO1.

BACKGROUND: Management of pregnant women with human immunodeficiency virus (HIV) type 2 infection remains unclear because of its low prevalence and important differences from HIV-1. METHODS: Pregnant women monoinfected with HIV-2 or HIV-1 and their infants enrolled in the prospective, national, multicenter French Perinatal Cohort between 1986 and 2007. RESULTS: Overall, 2.6% (223/8660) of mothers were infected with HIV-2, and they accounted for 3.1% (367/ 11841) of the total births. Most were born in sub-Saharan Africa. A higher proportion of HIV-2-infected mothers than HIV-1-infected mothers had no symptoms, had received no antiretroviral therapy at conception (85.9% vs 66.7%), and had received no antiretroviral therapy during pregnancy (42.8% vs 19.9%), particularly highly active antiretroviral therapy (HAART) (79.7% vs 46.1%), and they had higher CD4 cell counts near delivery (median, 574 vs 452 cells/mm3; P < .01). If antiretroviral therapy was used, it was started at a later gestational age for HIV- 2-infected mothers (median, 28 vs 25 weeks; P < .01). HIV-2-infected mothers were more likely to deliver vaginally (67.9% vs 49.3%) and to breastfeed (3.6% vs 0.6%; P < .01), and their infants less frequently received postexposure prophylaxis. In the period 2000-2007, the proportion with viral load <100 copies/mL at delivery was 90.5% of HIV-2-infected mothers, compared with 76.2% of HIV-1-infected mothers (P=.1). There were 2 cases of transmission: 1 case in 1993 occurred following maternal primary infection, and the other case occurred postnatally in 2002 and involved a mother with severe immune deficiency. The mother-to-child transmission rate for HIV-2 was 0.6% (95% confidence interval, 0.07%-2.2%). CONCLUSIONS: Care for HIV-2-infected pregnant women rests on expert opinion. The mother-to-child transmission residual rate (0.07%-2.2%) argues for systematic treatment: protease inhibitor-based HAART for women requiring antiretrov

Long-term outcomes in adolescents perinatally infected with HIV-1 and followed up since birth in the French perinatal cohort (EPF/ANRS CO10).

BACKGROUND. Increasing numbers of children perinatally infected with human immunodeficiency virus (HIV) are reaching adolescence, largely because of advances in treatment over the past 10 years, but little is known about their current health status. We describe here the living conditions and clinical and immunovirologic outcomes at last evaluation among this pioneering generation of adolescents who were born before the introduction of prophylaxis for vertical transmission and whose infections were diagnosed at a time when treatment options were limited. METHODS. The eligible population consisted of HIV-1-infected children who were born before December 1993 and who were included at birth in the prospective national French Perinatal Cohort (EPF/ANRS CO10). RESULTS. Of the 348 eligible children, 210 (60%; median age, 15 years) were still alive and regularly followed up. Current treatment was highly active antiretroviral therapy (HAART) in 77% and 2 nucleoside analogues in 5.0%; 16% had stopped treatment, and 2% had never been treated. The median CD4 cell count was 557 cells/microL, and 200 cells/microL was exceeded in 94% of patients. The median viral load was 200 copies/mL. Viral load was undetectable in 43% of the adolescents and in 54.5% of those receiving HAART. Median height, weight, and body mass index were similar to French reference values for age, and school achievement was similar to nationwide statistics. Better immunologic status was associated with being younger and with having begun HAART earlier. Undetectable viral load was associated with maternal geographic origin and current HAART. CONCLUSIONS. Given the limited therapeutic options available during the early years of these patients' lives and the challenge presented by treatment adherence during adolescence, the long-term outcomes among this population are encouraging.

Evaluation of an upgraded version of the Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 test for HIV-1 load quantification.

We evaluated the performance of the prototype Cobas AmpliPrep/Cobas TaqMan HIV-1 test, version 2.0, using prospective and archived clinical samples initially underquantitated by the Cobas AmpliPrep/Cobas TaqMan HIV-1 test. The performance of the new test was significantly improved, and the majority of the underquantitation observed with the first-version test was eliminated.

[HIV infection: Which therapeutical challenges remain in 2009?]. / L'infection à VIH : quels enjeux thérapeutiques en 2009 ? Quel a été l'impact sur la virologie médicale en France ?

More than 25 years after the first description of HIV, a large number of antiretroviral drugs are now available, allowing a major reduction of morbidity and mortality in most developed countries; HIV disease may be now considered as a chronic infection. However, because of the presence of provirus within infected cells totally inaccessible to drugs, treatments need to be maintained for life inducing progressively long terms secondary effects. Researches on reservoirs are a new challenge for the development of new therapeutical approaches. In resource-limited countries, where the epidemics is still going on, with the prevalence of infection that may rise 30 % in some countries such as Swaziland, access to treatments are still very limited. The development of structure including medical laboratories with trained technicians is a large challenge to transfer molecular techniques and diagnostics necessary for therapeutical follow-up of infected adults and children, as well as for the diagnosis of HIV infection in babies born to seropositive mother. French laboratories for medical virology have largely developed many molecular diagnoses for viral infections based on their experience for HIV. H1N1 is now the new challenge.

Improved virological response to highly active antiretroviral therapy in HIV-1-infected patients carrying the CCR5 Delta32 deletion.

BACKGROUND: Patients heterozygous for the C-C chemokine receptor 5 (CCR5) Delta32 deletion spontaneously progress less rapidly to AIDS and death than do wild-type patients. We investigated whether the CCR5 Delta32 deletion has an impact on immunological, virological and clinical responses to highly active antiretroviral therapy (HAART) in HIV-1-infected patients. PATIENTS AND METHODS: We included in the study 565 HIV-1-infected patients from the French HIV-1 infected cohort with documented date of seroconversion (SEROCO)/haemophiliacs HIV-1 infected (HEMOCO) cohorts, who started HAART after 1996. We investigated virological responses to HAART at 6 months (defined as a plasma HIV-1 RNA measurement below the threshold of detection or a 2 log HIV-1 RNA decrease) and at 12 months (defined as a plasma HIV-1 RNA measurement below the threshold of detection) and clinical response to HAART by Kaplan-Meier survival curves, with AIDS and death as outcomes. RESULTS: The Delta32 heterozygous patients (n=83; 15%) had a better virological response to HAART than wild-type patients (73 vs 53% at 6 months, P=0.01; and 60 vs 44% at 12 months, P=0.01). This better virological response was still observed after adjustment for antiretroviral status (whether or not patients were naïve to antiretroviral therapy), year of HAART initiation, number of new antiretroviral drugs and baseline viral load. There was no statistical difference between heterozygous patients and wild-type patients in terms of survival and AIDS-free survival. CONCLUSIONS: CCR5 Delta32 heterozygous patients were more likely to have a virological response to HAART than wild-type patients at 6 and 12 months. However, this virological response did not produce better immunological and clinical responses. The long-term impact of the Delta32 deletion on survival in HIV-1-infected treated patients should be investigated in a meta-analysis.

[HIV-1 drug resistance in French infected-children: from newborn to adolescent]. / La résistance du VIH-1 aux antirétroviraux chez les enfants infectés : du nouveau-né à l'adolescent.

Limit of antiretroviral treatment success is the emergence of drug-resistant virus. As reported in adult population, prevalence of resistance was high in treated HIV-infected children with detectable HIV viral load. Resistance increased with number of prior antiretroviral treatments, particularly with protease inhibitors. Adolescent boys seem at greater risk to harbor multi-classes resistant virus. In HIV-infected newborns, prevalence of resistance was 20%. Most of resistance mutations detected were in accord to perinatal antiretroviral exposition. Principal mechanism of resistance acquisition in newborns was transmission of resistant viruses from mother to child with early archive in cellular reservoir and long term persistence with or without treatment. Consequences of long term therapeutic strategies in children are major.

Examination of real-time PCR for HIV-1 RNA and DNA quantitation in patients infected with HIV-1 BF intersubtype recombinant variants.

The impact of HIV-1 genetic diversity on the performance of laboratory testing is an issue that has to be monitored continuously. An "in-house" real-time PCR assay was developed by the Agence Nationale de Recherche sur le SIDA (ANRS) in France for viral load (VL) quantitation based on the amplification of the HIV-1 long terminal repeat (LTR) region. This technology has not been used in Argentina yet and considering the HIV-1 diversity in the country, a comparative analysis of this assay was undertaken versus the Versant HIV-1 RNA 3.0 Assay (b-DNA). The performance was assessed on 30 drug-naïve HIV-1 infected patients who were characterized previously by phylogenetic analysis of the pol and vpu gene. The results showed that there is a significant linear correlation between values of transformed viral load logarithms measured by both, bDNA and real-time PCR assay and that this assay can be used to quantify viral load in samples from BF-infected patients with the same accuracy and reliability as for B subtype samples. The use of "in-house" real-time PCR to measure DNA in PBMCs correlated strongly with the HIV-1 RNA levels in all specimens.

Impact of highly active antiretroviral therapy on the maturation of anti-HIV-1 antibodies during primary HIV-1 infection.

OBJECTIVES: To study the impact of highly active antiretroviral therapy (HAART) on isotype switching and avidity maturation of HIV-1-specific immunoglobulin G (IgG) in patients with primary HIV-1 infection (PHI). METHODS: We studied the emergence and the evolution of anti-HIV IgG antibodies by quantitative immunoblotting to analyse IgG subclasses and IgG avidity. Serum samples were obtained from 16 PHI patients from the French PRIMO Cohort Study at various points in the first year of infection: eight patients received no treatment (group I), and eight patients received efficient HAART (group II) during the study period. RESULTS: Early initiation of HAART in PHI patients partially prevented an increase in anti-HIV-1 IgG levels. Within IgG subclasses, the amount of anti-HIV-1 IgG1 gradually increased with time in both groups, although levels remained lower in treated patients. The anti-p24 IgG2 level was always lower in group II. We observed a decrease in anti-p24 IgG3 over time in both groups. Treatment did not affect the maturation of HIV-1 IgG avidity, which increased in both groups until month 3 and then remained high until the end of the 12-month follow-up period. CONCLUSIONS: HAART in PHI partially prevents the emergence of HIV-1 IgG antibodies, but does not affect the quality of these antibodies, as reflected in their isotype and avidity.

Increase in hepatitis C virus incidence in HIV-1-infected patients followed up since primary infection.

BACKGROUND: An increase in the incidence of sexually transmitted infections and hepatitis C virus (HCV) infections in HIV-infected men who have sex with men (MSM) has recently been reported. OBJECTIVE: To estimate HCV incidence and risk factors among HIV-1-infected patients followed up since primary HIV infection in the French PRIMO Cohort between 1996 and 2005. PATIENTS AND METHODS: All patients with at least 18 months of follow-up were studied. HCV antibody tests were performed on baseline plasma samples and repeated on the latest available sample when negative at baseline. RESULTS: In total, 402 patients with a median follow-up of 36 (range 18-104) months were eligible. HCV seroconversion was observed in 6 patients (4 men and 2 women), corresponding to an HCV incidence rate of 4.3 per 1000 person-years. Incidence rates in men and women were 3.5 and 7.8 per 1000 person-years, respectively. The incidence rate was 1.2 per 1000 person-years before January 2003 and 8.3 per 1000 person-years after January 2003 (p = 0.06). The classic risk factors for HCV infection were found in women (intravenous drug use, and body piercing), whereas the only identified risk factor for HCV acquisition was unsafe sex in the four men. CONCLUSIONS: Increase in the incidence of acute HCV infection in recently HIV-infected patients confirms the shift in sexual behaviour in the recent years, especially in HIV-infected MSM. Repeated testing for HCV antibodies should be carried out in HCV-negative HIV-infected patients and specific recommendations about protected sex should be clearly provided.