Objective: To define risk factors for detection of HIV-1 RNA in semen in men attending the two largest HIV clinics in the West Midlands. Methods: 94 HIV-1 seropositive men at any stage of infection donated matched semen and blood samples. 36 subjects (38%) were on no antiretroviral treatment, 12 (13%) were on dual therapy, and 46 (49%) were on three or more drugs. Median CD4 count was 291 cells ×10 6 /l. 87 subjects underwent a urethritis screen (Gram stained urethral smear and culture for gonococcus, and LCR for Chlamydia trachomatis on first pass urine). Quantitative cell free HIV-1 RNA was determined by commercial nucleic acid sequence based assay with a lower detection limit of 800 copies/ml for semen and 400 copies/ml for blood. Independent risk factors for seminal HIV RNA detection were defined by logistic regression. Results: In univariate analysis, subjects not taking antiretrovirals were 11 times more likely to shed HIV RNA (21/36 (58%) v 6/58 (10%); p<0.0001). Seven subjects (8%) had urethritis (including one C trachomatis infection). Urethritis was significantly associated with detection of seminal HIV RNA (adjusted OR, 80.2; p=0.006), as was blood plasma viral load (adj OR, 19.3 per factor 10 increase; p<0.001) and age (adj OR, 1.16 per 1 year older; p=0.001). Antiviral treatment status, absolute CD4 and CD8 count, clinical stage, treatment centre, ethnicity, and risk factor were not independent predictors. No subject with undetectable blood viral load had detectable seminal HIV RNA. Conclusion: Asymptomatic urethritis is independently associated with seminal HIV RNA shedding. (Sex Transm Inf 1999;75:261-263)

Persistent immune activation in virologically suppressed HIV-1 patients, which may be the consequence of various factors including microbial translocation, is a major cause of comorbidities. We have previously shown that different profiles of immune activation may be distinguished in virological responders. Here, we tested the hypothesis that a particular profile might be the consequence of microbial translocation. To this aim, we measured 64 soluble and cell surface markers of inflammation and CD4+ and CD8+ T-cell, B cell, monocyte, NK cell, and endothelial activation in 140 adults under efficient antiretroviral therapy, and classified patients and markers using a double hierarchical clustering analysis. We also measured the plasma levels of the microbial translocation markers bacterial DNA, lipopolysaccharide binding protein (LBP), intestinal-fatty acid binding protein, and soluble CD14. We identified five different immune activation profiles. Patients with an immune activation profile characterized by a high percentage of CD38+CD8+ T-cells and a high level of the endothelial activation marker soluble Thrombomodulin, presented with higher LBP mean (± SEM) concentrations (33.3 ± 1.7 vs. 28.7 ± 0.9 μg/mL, p = 0.025) than patients with other profiles. Our data are consistent with the hypothesis that the immune activation profiles we described are the result of different etiological factors. We propose a model, where particular causes of immune activation, as microbial translocation, drive particular immune activation profiles responsible for particular comorbidities.

Chronic immune activation persists in persons living with HIV-1 even though they are aviremic under antiretroviral therapy, and fuels comorbidities. In previous studies, we have revealed that virologic responders present distinct profiles of immune activation, and that one of these profiles is related to microbial translocation. In the present work, we tested in 140 HIV-1-infected adults under efficient treatment for a mean duration of eight years whether low-level viremia might be another cause of immune activation. We observed that the frequency of viremia between 1 and 20 HIV-1 RNA copies/mL (39.5 ± 24.7% versus 21.1 ± 22.5%, p = 0.033) and transient viremia above 20 HIV-1 RNA copies/mL (15.1 ± 16.9% versus 3.3 ± 7.2%, p = 0.005) over the 2 last years was higher in patients with one profile of immune activation, Profile E, than in the other patients. Profile E, which is different from the profile related to microbial translocation with frequent CD38+ CD8+ T cells, is characterized by a high level of CD4+ T cell (cell surface expression of CD38), monocyte (plasma concentration of soluble CD14), and endothelium (plasma concentration of soluble Endothelial Protein C Receptor) activation, whereas the other profiles presented low CD4:CD8 ratio, elevated proportions of central memory CD8+ T cells or HLA-DR+ CD4+ T cells, respectively. Our data reinforce the hypothesis that various etiological factors shape the form of the immune activation in virologic responders, resulting in specific profiles. Given the type of immune activation of Profile E, a potential causal link between low-level viremia and atherosclerosis should be investigated.