20th February Kurioka et al., CD161-expressing NK cells

CD161 defines a functionally distinct subset of pro-inflammatory NK cells.    Frontiers

Natural killer (NK) cells are the most classical population of innate lymphoid cells, expressing a heterogeneous repertoire of germline-encoded receptors that allows them to distinguish infected or stressed cells from healthy cells. CD161 is a C-type lectin-like receptor expressed on the majority of natural killer (NK) cells; however, the significance of CD161 expression on NK cells has not been comprehensively investigated. Recently, the author-group has found that CD161 expression identifies a transcriptional and innate functional phenotype that is shared across various T cell populations.

In the current work, Kurioka et al. demonstrated using mass cytometry and microarray experiment that this functional phenotype extends to NK cells. CD161 marks NK cells that have retained the ability to respond to innate cytokines during their differentiation, and is lost upon cytomegalovirus-induced maturation in both healthy and human immunodeficiency virus (HIV)-infected patients. These pro-inflammatory NK cells are present in the inflamed lamina propria where they are enriched for integrin CD103 expression.

In summary, the study has shown that CD161 is a marker of NK cell function, particularly marking pro-inflammatory NK cells, which is expressed on all NK cells in cord blood, downregulated upon proliferation, and lost upon CMV-induced terminal differentiation. CD161 expression on CD56dim NK cells marks cells that have retained the capacity to respond to inflammatory cytokines alone. CD161, thus, identifies “innate” cells within both NK cells and CD161bright T cell family, previously described, with shared innate-type responses that are independent of receptorligation.

pdf publication

13th February Laut et al., Variation among HIV key populations

Variation in antiretroviral treatment (ART) coverage and virological suppression among three HIV key populations.   AIDS

Laut et al. on behalf of the EuroSIDA study group aimed to assess differences in antiretroviral treatment (ART) coverage and virological suppression across the three HIV transmission categories i) men who have sex with men, ii) injection drug users (IDU) and iii) heterosexuals.

Among 12’872 participants followed from 1 July 2014 to 30 June 2016, the percentages of ART-coverage and virological suppression varied between transmission categories, depending on geographical region (global P for interaction: P=0.0148 for ART-coverage, P=0.0006 for virological suppression).

• In Western [adjusted odds ratio (aOR) 1.41 (95% confidence interval 1.14–1.75)] and Northern Europe [aOR 1.68 (95% confidence interval 1.25–2.26)], heterosexuals were more likely to receive ART than MSM.

• In Eastern Europe, there was some evidence that infection through IDU [aOR 0.60 (95% confidence interval 0.31–1.14)] or heterosexual contact [aOR 0.58 (95% confidence interval 0.30–1.10)] was associated with lower odds of receiving ART.

• In terms of virological suppression, people infected through IDU or heterosexual contact in East Central and Eastern Europe were around half as likely as MSM to have a suppressed viral load on ART.

• There were no differences in virological suppression observed across transmission categories in Western and Northern Europe.

In conclusion, the study found that levels of ART-coverage and virological suppression varied depending on HIV transmission category, both across and within regions. Overall, people infected through IDU were the least likely to receive ART and to achieve virological suppression on ART, but the pattern varied significantly by region of residence. These results demonstrate that national estimates of ART coverage and virological suppression may represent an average that covers large differences across key populations. Hence, a differentiated HIV-response remains crucial to reaching control of the HIV epidemic and underline that high-quality disaggregated data are needed to inform and strengthen interventions.


6th February Rohner et al, Regional NHL risk in HIV-positive adults

Non-Hodgkin lymphoma risk in adults living with HIV across five continents.    AIDS

Rohner et al. for the AIDS-defining Cancer Project Working Group of IeDEA and COHERE in EuroCoord aimed to compare non-Hodgkin lymphoma (NHL) incidence rates in adults who started antiretroviral therapy (ART) after 1995 across the Asia-Pacific, South Africa, Europe, Latin, and North America.

The authors included 210’898 adults with 1.1 million person-years (pys) of follow-up and 1’552 incident NHL cases (raw overall incidence rate 142/100 000 pys). After adjusting for age at ART start, first-line ART regimen, calendar period of ART start, and especially current CD4+ cell count, NHL rates were similar across regions for most population groups. However, South African women remained at increased risk of developing NHL compared with their European counterparts [adjusted hazard ratio [aHR] 1.79, 95% CI 1.19–2.70]. In Europe, Latin, and North America, NHL risk was highest in MSM (aHR 1.30, 95% CI 1.14–1.48), followed by heterosexual men (referent), and women (aHR 0.66, 95% CI 0.57–0.78).

In conclusion, the risk of developing NHL is higher in women in South Africa than in Europe and higher in MSM compared with heterosexual men and women. Co-infection patterns might contribute to the increased NHL rates in MSM and South African women. A better understanding of lymphomagenesis and associated etiologic factors is needed to eventually be able to develop specific preventive measures against NHL in adults living with HIV. In the meantime, early access to ART and regular patient monitoring to avert low current CD4+ cell counts remain key for NHL prevention.


30th January Ronit et al., Serum albumin and non-AIDS events

Associations between serum albumin and serious non-AIDS events among people living with HIV.   AIDS

Ronit et al. for the D:A:D Study Group aimed to undertake a detailed evaluation of the association between serum albumin (sAlb) and serious non-AIDS events (SNAE) in a large and heterogeneous study population with long follow-up.

SNAE was defined as cardiovascular disease (CVD) (myocardial infarction, stroke, invasive cardiovascular procedure or death from CVD); end-stage renal disease (ESRD) or death from renal disease; end-stage liver disease (ESLD) or death from ESLD; non-AIDS-defining malignancies (NADMs, except for basal cell or squamous cell skin cancer) or death from cancer; and any other non-AIDS death.

Of 16’350 participants (71.8% male, median age 44 years), 1’463 developed an SNAE (371 CVD, 200 ESLD, 40 ESRD, 553 NADM, 299 deaths from other non-AIDS causes) over 80’264 person-years. Increased sAlb was associated with a decreased risk of an SNAE [adjusted rate ratio per 5 g/l: SNAE 0.79 (95% confidence interval: 0.76, 0.83); CVD 0.87 (0.80, 0.94); NADM 0.88 (0.82, 0.95)]. The association did not appear to wane with additional years of follow-up (P-interaction =0.79) but was stronger for current smokers than for never smokers (P-interaction <0.01).

In conclusion, in this study sAlb was found to be independently associated with SNAE, including CVD and NADM. This association did not appear to wane over time and was strongest in current smokers. The pathophysiology underlying the relationship between sAlb and SNAE, and its effect modifiers, are poorly understood, and warrants further mechanistic investigation. One potential explanation is that a low sAlb level might be a consequence of pathways of immune activation and that sAlb may exert a protective effect due to antioxidant activity.


29th January Shepherd et al., Cessation of cigarette smoking and cancer in HIV

Cessation of cigarette smoking and the impact on cancer incidence in HIV-positive persons: The D:A:D Study.     Clinical Infectious Diseases

Despite the well characterized harms of smoking in people living with HIV (PLWH), the clinical benefits of smoking cessation on cancer risk have not previously been reported in large epidemiological studies. The aim of this study was to estimate cancer rates after smoking cessation in PLWH from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study.

Participants were followed from 1 January 2004 until first cancer diagnosis, death, or 1 February 2016. Smoking status was defined as ex-smoker, current smoker, and never smoker. Of note, smoking information is reported in the D:A:D Study as current smoker (yes/no) and ever smoker (yes/no) at each visit, but more specific information, such as cigarette or pipe smoking, or intensity of smoking, is not available.

In total 35’442 persons from the D:A:D study contributed 309’803 person-years of follow-up. At baseline, 49% were current smokers, 21% were ex-smokers, and 30% had never smoked.

• Incidence of all cancers combined (n = 2’183) was highest <1 year after smoking cessation compared to never smokers (aIRR, 1.66 [95% confidence interval {CI}, 1.37–2.02]) and not significantly different from never smokers 1–1.9 years after cessation.

• Lung cancer incidence (n = 271) was elevated <1 year after cessation (aIRR, 19.08 [95% CI, 8.10–44.95]) and remained 8-fold higher 5 years after smoking cessation (aIRR, 8.69 [95% CI, 3.40–22.18]). 

• Incidence of other smoking-related cancers (n = 622) was elevated in the first year after cessation (aIRR, 2.06 [95% CI, 1.42–2.99]) and declined to a level similar to nonsmokers thereafter.

In conclusion, incidence of lung cancer incidence in PLWH was >8-fold higher than never smokers several years after cessation, at a similar level to current smokers, and with no evidence of a decline after the first year. This suggests that the oncogenic potential for smoking is not reduced for lung cancer in the time frame that was investigated. This is in contrast with similar studies in HIV-uninfected people, which show a consistent decline in lung cancer incidence with increasing time since cessation. Deterring uptake of smoking and smoking cessation efforts should be a priority to reduce the risk of cancer; however, monitoring and awareness of lung cancer should continue in those who stop smoking. Studies following PLWH throughout their lifetimes are needed to determine when the benefit of cessation will be seen.


23rd January Slogrove et al., The epidemiology of adolescents living with perinatally acquired HIV

The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis.   PLoS Medicine

Slogrove et al. for the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) Global Cohort Collaboration aimed to describe the global epidemiology of adolescents living with perinatally acquired HIV (APH) in terms of geographic and temporal trends of patient and treatment characteristics at entry into care, ART start, entry into adolescence (age 10 years), and last visit.

All children from 12 cohort networks infected with HIV who entered care before age 10 years and had acquired HIV around the time of birth or through breastfeeding, were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017.

Among 38’000 adolescents living with perinatally acquired HIV, 79% were living in sub-Saharan Africa. Analysis by country income group suggested that patients in high-income countries (North America and Europe) had younger age, higher CD4 percent, and less impaired height when starting antiretroviral therapy compared to middle- or low-income countries. Lost to follow-up rate was lowest in South America and the Caribbean and highest in sub-Saharan Africa. HIV-associated mortality during adolescence was substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe.

In summary, the analysis of a large cohort of APHs between 1982 and 2014 across several regions of the globe suggests that APHs generally entered HIV care at an earlier age in high-income countries compared to other country income groups. Despite probable under-ascertainment, mortality continued to be substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe and warrants further monitoring and understanding.

pdf publication

17th January Ramsuran et al., Inhibiting natural killer cells in AIDS

Elevated HLA-A expression impairs HIV control through inhibition of NKG2A-expressing cells.   Science

The highly polymorphic human leukocyte antigen (HLA) locus encodes cell surface proteins that are critical for immunity. HLA-A expression levels vary in an allele-dependent manner, diversifying allele-specific effects beyond peptide-binding preference.

Ramsuran et al. examined data from 9’763 HIV-infected individuals from 21 cohorts. They found that higher HLA-A levels confer poorer control of HIV.

Expression of the HLA-A and -B alleles was associated with:
    - higher viral load
    - reduced CD4+ T cell counts
    - accelerated progression to AIDS.

Higher levels of HLA-A expression increased expression of HLA-E, which blocks a specific receptor (NKG2A) on the immune cells that normally eliminate virus-infected cells.

In conclusion, the data suggest that antagonizing HLA-E/NKG2A interactions, perhaps in combination with other therapies, may provide benefit in HIV disease. This might be an attractive approach in HIV cure strategies. Genetic validation of NKG2A as a therapeutic target in additional diseases by testing for effects of HLA-A and HLA-B –21 genotypes may rationalize the use of anti-NKG2A therapy in other disorders.

pdf publication

16th January Pelchen-Matthews et al., Comorbidities in people living with HIV

Aging and the evolution of comorbidities among HIV-positive individuals in a European cohort.    AIDS

Pelchen-Matthews et al. for the EuroSIDA study aimed to characterize the evolution of the prevalence of chronic kidney disease (CKD) and cardio-vascular disease (CVD) and related risk factors in the aging people living with HIV (PLWHIV) population in Europe.

9’798 individuals were under active follow-up in EuroSIDA during 2006 and 12’882 during 2014.

Compared with study participants in 2006, those in 2014:
- were older [median age 48.6 years (IQR 40.3–55.1) vs. 43.1 years (37.2–50.0) in 2006]

- had higher prevalence of
   o hypertension (59.6 vs. 47% in 2006),
   o diabetes (6.3 vs. 5.4%),
   o CKD (6.9 vs. 4.1%)
   o CVD (5.0 vs. 3.7%).

Individuals in the 2014 cohort had higher odds for CKD (unadjusted OR 2.62, 95% CI2.30–2.99, P<0.0001) and CVD (OR 1.88, CI 1.68– 2.10, P<0.0001), but after multivariable adjustment for age group, comorbidities and other factors, year of cohort was no longer significantly associated with the odds of CKD [adjusted OR (aOR) 0.97, CI 0.52– 1.82, P=0.92) or of CVD (aOR 0.94, CI 0.54 –1.63, P=0.82).

In conclusion, this study of risk factors and comorbidities in a large cohort of HIV-positive individuals in Europe has shown an increase in the prevalence of non-AIDS comorbidities, including diabetes, CKD and CVD, along with increased prevalence of hypertension and a high prevalence dyslipidemia, which was largely explained by the aging of persons included. Higher prevalence of comorbidities was particularly evident for individuals at least 50 years old, highlighting the increase in non-AIDS-related conditions in the aging PLWHIV population. This shows a need for careful management not only to control HIV through optimal selection of ART, but also to address the effect of aging, including screening and regular monitoring of the major comorbidities and risk modification measures.