The number of CCR5 expressing CD4+ T lymphocytes is lower in HIV-infected long-term non-progressors with viral control compared to normal progressors: a cross-sectional study.

BACKGROUND: The HIV co-receptors CXCR4 and CCR5 play an important role in HIV infection and replication. Therefore we hypothesize that long-term non-progressors (LTNP) with viral control have lower expression of CCR5 and CXCR4 on CD4(+) cells, specifically on memory T-lymphocytes since they are the primary target cells of HIV. METHODS: In this cross-sectional study, we included five HIV-infected LTNP with viral control (CD4 > 750 cell/µl & HIV < 50 copies for ≥2 years), thirteen HIV-infected and seven HIV-uninfected individuals at Radboud UMC Nijmegen, the Netherlands. We determined the CCR5 and CXCR4 expression among CD4(+) and CD8(+) lymphocyte subsets; memory (CD45RO(+)), naïve (CD45RA(+)) cells and regulatory T-cells (CD4(+)CD25(high)FoxP3(+)). In addition, CCR5∆32 polymorphism is related with disease progression and was therefore determined using polymerase chain reaction. RESULTS: The percentage of CCR5-expressing CD4(+) cells of LTNP was comparable with healthy controls; whereas HIV-infected individuals showed more CCR5-expressing cells. This was observed in memory and naïve CD4(+) cells, but not in regulatory T-cells. The mean fluorescence intensity of CCR5-expressing CD4(+) cells was similar in all groups. All groups had comparable percentages of CXCR4-expressing cells. The mean fluorescence intensity of CXCR4-expressing cells was significantly higher in HIV-infected normally progressors in both memory and naïve CD4(+) cells, but not in CD8(+) cells. The CCR5∆32 polymorphism was not related to group. CONCLUSIONS: We show that HIV affects -directly or indirectly- the expression of CCR5 in CD4(+) T-lymphocytes; yet this effect is not seen in LTNP with viral control. Avoiding upregulation of CCR5 could be an important method via which LTNP counteracts the effects of HIV and suppresses viral replication. Exploring how LTNP suppress the upregulation of CCR5 could be an important step for discovering new therapeutics.

Mutation patterns of integrase gene affect antiretroviral resistance in various non-B subtypes of human immunodeficiency virus Type-1 and their implications for patients' therapy.

Although primary integrase strand transfer inhibitor resistance mutations are currently uncommon, the increasing use of integrase strand transfer inhibitor as a key component of the first, second and third-line antiretroviral regimens suggests that the prevalence of integrase drug resistance mutations will likely increase. The rise of several polymorphic mutations and natural polymorphisms also affects the level of susceptibility of human immunodeficiency virus (HIV) type-1 to integrase strand transfer inhibitor. The considerable variability among the various subtypes of human immunodeficiency virus type-1 may contribute to differences in integrase mutations associated with integrase strand transfer inhibitors. Notably, non-B subtypes of HIV type-1 (HIV-1) are the predominant cause of human immunodeficiency virus infection worldwide. The presence of diverse integrase drug resistance mutations can have significant implications on the administration of integrase strand transfer inhibitor-based antiretroviral therapy to patients with human immunodeficiency virus infection.

Anemia and iron homeostasis in a cohort of HIV-infected patients in Indonesia.

BACKGROUND: Anemia is a common clinical finding in HIV-infected patients and iron deficiency or redistribution may contribute to the development of low hemoglobin levels. Iron overload is associated with a poor prognosis in HIV and Hepatitis C virus infections. Iron redistribution may be caused by inflammation but possibly also by hepatitis C co-infection. We examined the prevalence of anemia and its relation to mortality in a cohort of HIV patients in a setting where injecting drug use (IDU) is a main mode of HIV transmission, and measured serum ferritin and sTfR, in relation to anemia, inflammation, stage of HIV disease, ART and HCV infection. METHODS: Patient characteristics, ART history and iron parameters were recorded from adult HIV patients presenting between September 2007 and August 2009 in the referral hospital for West Java, Indonesia. Kaplan-Meier estimates and Cox's regression were used to assess factors affecting survival. Logistic regression was used to identity parameters associated with high ferritin concentrations. RESULTS: Anemia was found in 49.6% of 611 ART-naïve patients, with mild (Hb 10.5 -12.99 g/dL for men; and 10.5-11.99 g/dL for women) anemia in 62.0%, and moderate to severe anemia (Hb < 10.5 g/dL) in 38.0%. Anemia remained an independent factor associated with death, also after adjustment for CD4 count and ART (p = 0.008). Seroprevalence of HCV did not differ in patients with (56.9%) or without anemia (59.6%). Serum ferritin concentrations were elevated, especially in patients with anemia (p = 0.07) and/or low CD4 counts (p < 0.001), and were not related to hsCRP or HCV infection. Soluble TfR concentrations were low and not related to Hb, CD4, hsCRP or ART. CONCLUSION: HIV-associated anemia is common among HIV-infected patients in Indonesia and strongly related to mortality. High ferritin with low sTfR levels suggest that iron redistribution and low erythropoietic activity, rather than iron deficiency, contribute to anemia. Serum ferritin and sTfR should be used cautiously to assess iron status in patients with advanced HIV infection.

Screening and diagnosis of HIV-infection in Indonesia: one, two or three tests?

AIM: to examine among high-risk populations or patients with signs or symptoms suggesting HIV-infection, two tests or even one single test might be sufficiently accurate for diagnosis of HIV in a hospital setting in Indonesia. METHODS: we retrospectively examined the rate of false-positive results of initial HIV-tests for all subjects tested in the referral hospital for HIV in West-Java, Indonesia, between 2006 and 2008. We also calculated the positive and negative predictive value of single test results and dual-testing, based on sensitivity and specificity of commonly used methods and prevalence data from Indonesia. RESULTS: among 3121 subjects, 803 were tested positive (25.7%). The initial rapid HIV-tests did not show a single false positive result, and no discrepancy was found between the second and third supplemental tests. Based on their high accuracy, most rapid tests carry a low risk of false-positive results among risk groups. Dual testing algorithms almost eliminate the risk of false-positive HIV-results, and are probably as accurate as three tests, even in low prevalence settings. CONCLUSION: based on expected prevalence rates and the accuracy of methods used in Indonesia, one or two tests are usually accurate for HIV-diagnosis, especially for high risk populations. The possible implications and optimal conditions for more simple testing algorithms warrant further investigation.

Women with HIV in Indonesia: are they bridging a concentrated epidemic to the wider community?

BACKGROUND: Male injecting drug users drove the onset of the HIV epidemic in Indonesia but over time more women have been diagnosed. We examined the relative proportion of female patients in an HIV cohort and characterized their probable transmission route and reproductive profile. DESIGNS: Prospective cohort study in a referral hospital in West Java. METHODS: Interviews with standardized questionnaires, physical and laboratory examinations were done for 2622 individuals enrolled in HIV care between 2007 and 2012. The proportion of women in this cohort was compared with national estimates. The general characteristics of HIV-infected women and men as well as the sexual and reproductive health of HIV-infected women were described. RESULTS: The proportion of female patients enrolled in HIV care increased from 22.2 % in 2007 to 38.3 % in 2012, in line with national estimates. Women were younger than men, fewer reported a history of IDU (16.1 vs. 73.8 %, p < 0.001) and more were tested for HIV because of a positive partner (25.5 vs. 4.0 %, p < 0.001). The majority of women were in their reproductive age, had children, and were not using contraceptives at the time of enrolment. CONCLUSION: HIV-infected women in Indonesia have specific characteristics that differ them from women in the general population. Further research to elucidate the characteristics of women exposed to HIV, their access to testing and care and sexual and reproductive needs can help reduce transmission to women and children in the context of concentrated HIV epidemic in Indonesia.

Heroin use in Indonesia is associated with higher expression of CCR5 on CD4+ cells and lower ex-vivo production of CCR5 ligands.

Opioid use may affect HIV infection through altered expression of HIV co-receptors. This was examined in Indonesia among antiretroviral therapy-naive HIV patients, many of whom use drugs. C-C chemokine receptor type 5 (CCR5) expression on CD4+ cells was higher in heroin (P = 0.007), methadone (P = 0.024) and former opioid users (P = 0.003) compared to nonusers, whereas production of RANTES and other CCR5 ligands was similar or lower. This suggests that opioids can affect HIV susceptibility through up-regulation of CCR5 or down-regulation of its ligands.

Inverse relationship of serum hepcidin levels with CD4 cell counts in HIV-infected patients selected from an Indonesian prospective cohort study.

BACKGROUND: Distortion of iron homeostasis may contribute to the pathogenesis of human immunodeficiency virus (HIV) infection and tuberculosis (TB). We studied the association of the central iron-regulatory hormone hepcidin with the severity of HIV and the association between hepcidin and other markers of iron homeostasis with development of TB. METHODS: Three groups of patients were selected from a prospective cohort of HIV-infected subjects in Bandung, Indonesia. The first group consisted of HIV-infected patients who started TB treatment more than 30 days after cohort enrollment (cases). The second group consisted of HIV-infected patients who were matched for age, gender and CD4 cell count to the cases group (matched controls). The third group consisted of HIV-infected patients with CD4 cell counts above 200 cells/mm(3) (unmatched controls). Iron parameters including hepcidin were compared using samples collected at cohort enrollment, and compared with recently published reference values for serum hepcidin. RESULTS: A total of 127 HIV-infected patients were included, 42 cases together with 42 matched controls and 43 unmatched controls. Patients with advanced HIV infection had elevated serum hepcidin and ferritin levels. Hepcidin levels correlated inversely with CD4 cells and hemoglobin. Cases had significantly higher hepcidin and ferritin concentrations at cohort enrollment compared to matched controls, but these differences were fully accounted for by the cases who started TB treatment between day 31 and 60 after enrollment. Hepcidin levels were not different in those with or without hepatitis C infection. CONCLUSION: Iron metabolism is distorted in advanced HIV infection with CD4 cell counts correlating inversely with serum hepcidin levels. High serum hepcidin levels and hyperferritinemia were found in patients starting TB treatment shortly after cohort enrollment, suggesting that these parameters have a predictive value for development of manifest TB in HIV-infected patients.