Monocyte phenotype and extracellular vesicles in HIV-1, HIV-2, and HIV-1/2 dual infection.

OBJECTIVE: AIDS-defining illness develops at higher CD4 + T-cell counts in individuals infected with HIV-2 compared with HIV-1-infected, which suggests that the two types of HIV may have different effects on other compartments of the immune system. We here investigate monocyte phenotype, activation and macrophage-derived extracellular vesicles in individuals with different HIV types. DESIGN: Cross-sectional. METHODS: ART-naive HIV-1 ( n  = 83), HIV-2 ( n  = 63), and HIV-1/2 dually positive ( n  = 27) participants were recruited in Bissau, Guinea-Bissau, together with HIV-negative controls ( n  = 26). Peripheral blood mononuclear cells (PBMCs) were isolated and analyzed by flow cytometry for monocyte phenotype and activation, and plasma was analyzed for extracellular vesicle forms of CD163 and CD206. RESULTS: Compared with HIV-negative controls, all groups of HIV-positive participants had a skewed monocyte phenotype with a higher proportion of intermediate monocytes, increased CD163 expression and elevated serum levels of the inflammatory biomarkers soluble (s)CD163 and sCD206. HIV-2-positive participants had lower CD163 monocyte expression than HIV-1-positive participants, regardless of HIV RNA or CD4 + cell count. Levels of sCD206 extracellular vesicles were increased in all HIV groups, and higher in HIV-1 compared with HIV-2-positive participants. CONCLUSION: The monocyte phenotype of HIV-2-positive participants deviated less from healthy controls than did HIV-1 participants. HIV-2-positive participants also had a lower concentration of extracellular CD206 vesicles compared with HIV-1-positive participants. This does not explain the difference in AIDS development.

Acceptance and Feasibility of Partner Notification to HIV Infected Individuals in Guinea-Bissau.

As partner notification (PN) has shown effective in increasing the number of partners of HIV infected patients being tested we aimed to evaluate the feasibility of implementing PN in the West-African country Guinea-Bissau. Patients enrolled were offered the choice of three different PN methods. Acceptance, successful referrals and HIV status of partners were evaluated. Of 697 patients offered PN, 495 (71.0%) accepted and listed 547 partners. At end of follow-up 118 (21.5%) partners had been tested of which 44 (37.3%) were HIV infected. HIV infected partners had a higher median CD4 count at diagnosis compared with index patients; 401 cells/mm3 versus 240 cells/mm3, p < 0.001. The results indicate that implementation of PN is feasible, effective in identifying HIV infected partners and enables initiation of earlier treatment, yet there are major barriers to bringing partners in for testing which should be addressed in order to exploit the full potential of PN.

HIV-2 as a model to identify a functional HIV cure.

Two HIV virus types exist: HIV-1 is pandemic and aggressive, whereas HIV-2 is confined mainly to West Africa and less pathogenic. Despite the fact that it has been almost 40 years since the discovery of AIDS, there is still no cure or vaccine against HIV. Consequently, the concepts of functional vaccines and cures that aim to limit HIV disease progression and spread by persistent control of viral replication without life-long treatment have been suggested as more feasible options to control the HIV pandemic. To identify virus-host mechanisms that could be targeted for functional cure development, researchers have focused on a small fraction of HIV-1 infected individuals that control their infection spontaneously, so-called elite controllers. However, these efforts have not been able to unravel the key mechanisms of the infection control. This is partly due to lack in statistical power since only 0.15% of HIV-1 infected individuals are natural elite controllers. The proportion of long-term viral control is larger in HIV-2 infection compared with HIV-1 infection. We therefore present the idea of using HIV-2 as a model for finding a functional cure against HIV. Understanding the key differences between HIV-1 and HIV-2 infections, and the cross-reactive effects in HIV-1/HIV-2 dual-infection could provide novel insights in developing functional HIV cures and vaccines.

T-cell and B-cell perturbations are similar in ART-naive HIV-1 and HIV-1/2 dually infected patients.

BACKGROUND: HIV-2 may slow progression of a subsequently acquired HIV-1 infection through cross-neutralizing antibodies and polyfunctional CD8 T cells. We hypothesized that HIV-1/2 dually infected patients compared with HIV-1-infected patients had more preserved immune maturation subsets and less immune activation of T and B cells. METHODS: ART-naive patients with HIV-1 (n = 83) or HIV-1/2 dual (n = 27) infections were included in this cross-sectional study at an HIV clinic in Guinea-Bissau. Peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry according to T-cell maturation and activation, regulatory T-cell fraction, and B-cell maturation and activation. RESULTS: HIV-1/2 dually infected patients had lower levels of HIV-1 RNA compared with patients with HIV-1 infection, but the levels of total HIV RNA (HIV-1 and HIV-2) were similar in the two patient groups. T-cell maturation, and proportions of regulatory T cells (FoxP3+) were also similar in the two groups. HIV-1/2 dually infected patients had higher proportions of CD4 and CD8 T cells positive for the activation marker CD38, but there was no difference in other T-cell activation markers (CD28, CTLA-4, PD-1). HIV-1/2 dually infected patients also had higher proportions of IgM-only B cells and plasmablasts. CONCLUSION: HIV-1/2 was not associated with less immune perturbations than for HIV-1 infection.

T-cell and B-cell perturbations identify distinct differences in HIV-2 compared with HIV-1-induced immunodeficiency.

BACKGROUND: For unknown reasons, HIV-2 is less pathogenic than HIV-1, and HIV-2-induced immunodeficiency may be different from that caused by HIV-1. Previous immunological studies have hinted at possible shifts in both T-cell and B-cell subsets, which we aimed to characterize further. METHODS: From an HIV clinic in Guinea-Bissau, 63 HIV-2, 83 HIV-1, and 26 HIV-negative participants were included. All HIV-infected participants were ART-naive. The following cell subsets were analysed by flow cytometry; T cells (maturation and activation), regulatory T cells, and B cells (maturation and activation). RESULTS: After standardizing for sex, age, and CD4 T-cell count HIV-2 had 0.938 log10 copies/ml lower HIV RNA levels than the HIV-1-infected patients. Whereas T-cell maturation and regulatory T-cell profiles were similar between patients, HIV-2-infected patients had higher proportions of CD8CD28 and lower proportions of CD8PD-1+ T cells than HIV-1-infected patients. This finding was independent of HIV RNA levels. HIV-2 was also associated with a more preserved proportion of naive B cells. CONCLUSION: HIV-2 is characterized by lower viral load, and lower T-cell activation, which may account for the slower disease progression.

HLA-DQB1*06:276, a novel HLA allele fund in a patient from Guinea-Bissau.

DQB1*06:276 differs from DQB1*06:03:01:01 by amino acid substitutions p.T71A, p.G74S, and p.L75V in exon 2.

Two novel HLA-B alleles, HLA-B*53:01:17 and -B*58:83, found in patients from Guinea-Bissau.

Novel HLA-B alleles HLA-B*53:01:17 and HLA-B*58:83 are described in two patients from Guinea-Bissau.

Prevalence and clinical characteristics of CMV coinfection among HIV infected individuals in Guinea-Bissau: a cross-sectional study.

OBJECTIVES: To describe the prevalence of CMV in a cohort of HIV infected individuals in Guinea-Bissau, West Africa and to evaluate differences in patients' clinical characteristics associated with their CMV status. METHODS: Newly diagnosed HIV infected adults were invited to participate in this cross-sectional study, from May until December 2015. Enrolled patients were interviewed and underwent a full physical examination focusing on CMV disease manifestations. Blood samples were analysed for CMV serology, QuantiFERON-CMV response and CMV DNA. Mortality follow-up were registered for one year after inclusion. RESULTS: In total, 180 patients were enrolled. Anti-CMV IgG positivity was found in 100% (138/138) and 2.8% (4/138) were anti-CMV IgM positive. A positive QuantiFERON-CMV response was found in 85.7% (60/70) of the patients and 60.6% (83/137) had CMV viraemia. QuantiFERON-CMV response and detectable CMV DNA were associated with lower CD4 cell count, older age and upper gastrointestinal complaints. During one year of follow-up, the IRR for death among CMV DNA positive patients was 1.5 (P = 0.5). CONCLUSIONS: CMV coinfection was detected among all enrolled patients and CMV viraemia was highly prevalent. Only age and upper gastrointestinal complaints were associated with the patients' CMV status.

Soluble Macrophage Mannose Receptor (sCD206/sMR) as a Biomarker in Human Immunodeficiency Virus Infection.

Macrophages play important roles during human immunodeficiency virus (HIV) infection, reflected by changes in macrophage-activation biomarker soluble CD163 (sCD163). Here, we present data on the novel macrophage-activation biomarker soluble mannose receptor/CD206 (sCD206) in HIV infection. We investigated sCD206 blood levels at baseline and follow-up with/without antiretroviral therapy (ART), in 212 patients with HIV type 1 (HIV-1), HIV type 2 (HIV-2), or dual infection. At baseline, there was no difference in sCD206 level between HIV types, and sCD206 was unchanged at follow-up without ART. However, in contrast to sCD163, sCD206 levels decreased significantly for both HIV-1 and HIV-2, but not for HIV-1/2 patients, during ART. Further investigations are needed to establish sCD206 as a biomarker in HIV infection.

HIV-2 continues to decrease, whereas HIV-1 is stabilizing in Guinea-Bissau.

OBJECTIVE: Although Guinea-Bissau has the world's highest prevalence of HIV-2, it has been decreasing since 1987. Meanwhile, the prevalence of HIV-1 has been increasing. We describe both the prevalence and changes in incidence of HIV-2 and HIV-1 during the last 30 years of observation in the capital Bissau in Guinea-Bissau. METHODS: A total of 3125 adults living in 412 houses in Bissau were eligible for inclusion in the present cross-sectional survey conducted from November 2014 to February 2016. All participants had a questionnaire filled out and a blood sample taken. Results were compared with previous surveys. RESULTS: Of the 3125 eligible adults, 2601 (83.2%) individuals participated. The overall prevalence of HIV decreased from 8.6% (218/2548) in 2006 to 6.7% (173/2601) in 2016 with an age-adjusted and sex-adjusted prevalence ratio (aPR) of 0.71 [95% confidence interval (CI) = 0.59-0.85]. Including HIV-1/2 dual infections, a decrease in the overall prevalence of HIV-2 from 4.4% (112/2548) to 2.8% (72/2601) was observed with an aPR of 0.55 (95% CI = 0.41-0.73). The overall prevalence of HIV-1 decreased from 4.6% (118/2548) to 4% (104/2601) with an aPR of 0.81 (95% CI = 0.63-1.05). Incidence rates for HIV-2 and HIV-1, estimated for 815 individuals, decreased from 0.24 to 0.09 and from 0.50 to 0.40 per 100 person-years of observation, respectively, in the periods between 1996-2006 and 2006-2016. CONCLUSION: The prevalence of HIV-2 continues to decrease, whereas the prevalence of HIV-1 showed sign of stabilization. The results observed may be explained by a lower pathogenicity of HIV-2 and changes in risk behavior.

Effect of sex and age on outcomes among HIV-2-infected patients starting antiretroviral therapy in West Africa.

OBJECTIVES: HIV-2-infected individuals usually initiate antiretroviral therapy (ART) at an advanced age compared with HIV-1 patients, with a potential impact on treatment outcomes. This study aimed to investigate the effect of sex and age on mortality and loss to follow-up (LTFU) among HIV-2-infected individuals initiating ART. METHODS: Analyses were conducted using the database of the International Epidemiological Databases to Evaluate AIDS's collaboration in West Africa. LTFU was considered if the interval between the last visit and the closing date for this analysis was more than 180 days. Probability of death and LTFU were estimated with Kaplan-Meier methods. A Cox regression model was used to identify factors associated with death and LTFU over the first 24 months on ART. RESULTS: A total of 1825 HIV-2-infected individuals, including 60% women were considered for this analysis. The median age, baseline CD4 cell count, and follow-up duration were 45 years [interquartile range (IQR; 38-52)], 185 cells/µl [IQR (95-297)], and 28.8 months [IQR (9.8-58.9)], respectively. Over the first 24 months, the mortality rate was 5.2/100 person-years of observation [95% confidence interval (CI; 4.4-6.1)] and 469 (25.7%) were LTFU. Male sex [hazard ratio (HR) = 1.9; 95% CI (1.4; 2.8)], baseline CD4 cell count less than 100 cell/µl [HR = 4.4 95% CI (1.7; 11.1); ref at least 350 cell/µl], haemoglobin 7.5-10 g/dl [HR = 2.4 95% CI (1.3; 4.4); ref at least 12 g/dl], and BMI less than 18 kg/m [HR = 2.1 95% CI (1.3; 3.4); ref = 18-25 kg/m] were associated with higher mortality over the first 24 months. Similar associations were found for LTFU. CONCLUSION: Mortality and LTFU are high among ART-receiving HIV-2-infected individuals and higher in men than in women. There is a critical need to further determine the causes of poor retention and implement sex-specific solutions that improve outcomes in HIV-2 ART programmes.

Brief Report: Macrophage Activation in HIV-2-Infected Patients Is Less Affected by Antiretroviral Treatment-sCD163 in HIV-1, HIV-2, and HIV-1/2 Dually Infected Patients.

The course of disease among HIV-2, HIV-1, and HIV-1/2 dually infected patients is different. We investigated the macrophage activation marker soluble CD163 (sCD163) dynamics in 212 HIV-1, HIV-2, and HIV-1/2 dually infected patients. There were no differences in sCD163 levels at baseline or during follow-up without antiretroviral therapy (ART). At follow-up on ART, median sCD163 levels were decreased for HIV-1-infected patients (P < 0.001), but not among HIV-2 (P = 0.093) or HIV-1/2 dually infected patients (P = 0.145). The larger decrease in sCD163 levels among HIV-1-infected patients during ART may indicate an HIV type-dependent differential effect of ART on macrophage activation during HIV infection.

Short-term gentamicin therapy and risk of renal toxicity in patients with bacteraemia.

The renal safety of gentamicin has been questioned even when dosed once daily. This retrospective cohort study comprised adult patients with community-acquired bacteraemia and no record of chronic renal disease or malignancy. We included patients treated with gentamicin once daily for ≤ 5 days (165 exposed patients) and a balanced sample of patients not receiving aminoglycosides (150 non-exposed patients). The primary endpoint, which was an elevation in plasma creatinine of > 40 µmol/l from baseline, was equally common among exposed (7.9%) and non-exposed patients (8.7%) (p = 0.80). Among 26 patients with the primary endpoint, follow-up creatinine levels were evaluable in 21 patients and reached the normal range in 8/12 (67%) exposed patients and in 7/9 (78%) non-exposed patients (p = 0.66). Thirty-day mortality was 7.9% in exposed patients versus 7.3% in non-exposed patients (p = 0.86). We conclude that renal impairment in bacteraemic patients is independent of short-term (≤ 5 days) gentamicin administration.