Publications (14) View all
-
Article: Cell-associated HIV RNA: a dynamic biomarker of viral persistence.
[show abstract] [hide abstract]
ABSTRACT: In most HIV-infected individuals adherent to modern antiretroviral therapy (ART), plasma viremia stays undetectable by clinical assays and therefore, additional virological markers for monitoring and predicting therapy responses and for measuring the degree of HIV persistence in patients on ART should be identified. For the above purposes, quantitation of cell-associated HIV biomarkers could provide a useful alternative to measurements of viral RNA in plasma. This review concentrates on cell-associated (CA) HIV RNA with the emphasis on its use as a virological biomarker. We discuss the significance of CA HIV RNA as a prognostic marker of disease progression in untreated patients and as an indicator of residual virus replication and the size of the dynamic viral reservoir in ART-treated patients. Potential value of this biomarker for monitoring the response to ART and to novel HIV eradication therapies is highlighted.Retrovirology 04/2013; 10(1):41. · 6.47 Impact Factor -
Article: Modest Nonadherence to Antiretroviral Therapy Promotes Residual HIV-1 Replication in the Absence of Virological Rebound in Plasma.
[show abstract] [hide abstract]
ABSTRACT: Background. Modern antiretroviral therapy (ART) regimens are widely assumed to forgive modest nonadherence, because virological suppression in plasma is common at adherence levels of >70%. Yet, it is unknown whether human immunodeficiency virus type 1 (HIV-1) replication is completely suppressed at these levels of adherence. Methods. We longitudinally quantified levels of cell-associated HIV-1 RNA and DNA in 40 patients (median duration of successful ART before study initiation, 46 months), whose 1-week adherence to therapy prior to the sampling moments was measured electronically. Results. Patients were constantly 100% adherent (the optimal-adherence group), demonstrated improving adherence over time (the improving-adherence group), or neither of the above (the poor-adherence group). Adherence never decreased to <70% in any patient, and no rebound in plasma virological levels was observed. Nevertheless, poor adherence but not optimal or improving adherence caused a significant longitudinal increase in cell-associated HIV RNA levels (P = .006). Time-weighted changes and regression slopes of viral RNA load for the poor-adherence group were significantly higher than those for the optimal-adherence group (P < .01). Conclusions. Because ART only blocks infection of new cells but not viral RNA transcription in cells infected before therapy initiation, the observed effects strongly suggest that modest nonadherence can cause new cycles of HIV-1 replication that are undetectable by commercial plasma viral load assays.The Journal of Infectious Diseases 08/2012; 206(9):1443-52. · 6.41 Impact Factor -
Article: HIV-1 dual infection is associated with faster CD4+ T-cell decline in a cohort of men with primary HIV infection.
[show abstract] [hide abstract]
ABSTRACT: In vitro, animal, and mathematical models suggest that human immunodeficiency virus (HIV) co- or superinfection would result in increased fitness of the pathogen and, possibly, increased virulence. However, in patients, the impact of dual HIV type 1 (HIV-1) infection on disease progression is unclear, because parameters relevant for disease progression have not been strictly analyzed. The objective of the present study is to analyze the effect of dual HIV-1 infections on disease progression in a well-defined cohort of men who have sex with men. Between 2000 and 2009, 37 men who had primary infection with HIV-1 subtype B, no indication for immediate need of combination antiretroviral therapy (cART), and sufficient follow-up were characterized with regard to dual infection or single infection and to coreceptor use. Patients were followed to estimate the effect of these parameters on clinical disease progression, as defined by the rate of CD4(+) T-cell decline and the time to initiation of cART. Four patients presented with HIV-1 coinfection; 6 patients acquired HIV-1 superinfection, on average 8.5 months from their primary infection; and 27 patients remained infected with a single strain. Slopes of longitudinal CD4(+) T-cell counts and time-weighted changes from baseline were significantly steeper for patients with dual infection compared with patients with single infection. Multivariate analysis showed that the most important parameter associated with CD4(+) T-cell decline over time was dual infection (P = .001). Additionally, patients with HIV-1 coinfection had a significantly earlier start of cART (P < .0001). Dual HIV-1 infection is the main factor associated with CD4(+) T-cell decline in men who have untreated primary infection with HIV-1 subtype B.Clinical Infectious Diseases 12/2011; 54(4):539-47. · 9.15 Impact Factor -
Article: Steady increase in cellular HIV-1 load during the asymptomatic phase of untreated infection despite stable plasma viremia.
[show abstract] [hide abstract]
ABSTRACT: To compare the dynamics of HIV-1 molecular markers in peripheral blood mononuclear cells (PBMCs) and in plasma during the asymptomatic phase of untreated HIV-1 infection. Using seminested real-time PCR assays, we measured the levels of HIV-1 proviral (pr) DNA, unspliced (us) RNA, and multiply spliced RNA in the PBMCs of 10 untreated HIV-1-infected men at multiple time points during the asymptomatic phase of infection and compared the longitudinal trends of these markers with those of viral RNA in plasma. Whereas plasma RNA levels did not significantly change in any of the individuals, levels of usRNA significantly increased with time in six out of 10 persons, and levels of prDNA in four. Slopes, changes, and time-weighted changes from baseline of usRNA, prDNA, and CD4 cell count, but not of plasma RNA, were significantly different from zero (P < 0.01). No significant longitudinal trend of plasma RNA was observed in the study group using linear mixed models, whereas the trends of usRNA, prDNA, and CD4 cell count were highly significant (P < 0.001). usRNA levels increased significantly faster than those of plasma RNA or prDNA, suggesting a temporal increase in viral replication rates in PBMCs. Finally, CD4 cell count inversely correlated with levels of usRNA and prDNA, but not with plasma RNA level. During the asymptomatic phase of untreated HIV-1 infection, when virion production and clearance are balanced, resulting in stable plasma viremia, viral load in PBMCs steadily increases and is a sensitive and direct longitudinal virological marker of infection progression.AIDS (London, England) 07/2010; 24(11):1641-9. · 4.91 Impact Factor -
Article: Cellular levels of HIV unspliced RNA from patients on combination antiretroviral therapy with undetectable plasma viremia predict the therapy outcome.
[show abstract] [hide abstract]
ABSTRACT: Combination antiretroviral therapy (cART), the standard of care for HIV-1 infection, is considered to be successful when plasma viremia remains below the detection limit of commercial assays. Yet, cART fails in a substantial proportion of patients after the apparent success. No laboratory markers are known that are predictive of cART outcome in initial responders during the period of undetectable plasma viremia. Here, we report the results of a retrospective longitudinal study of twenty-six HIV-infected individuals who initially responded to cART by having plasma viremia suppressed to <50 copies/ml. Eleven of these patients remained virologically suppressed, whereas fifteen experienced subsequent cART failure. Using sensitive methods based on seminested real-time PCR, we measured the levels of HIV-1 proviral (pr) DNA, unspliced (us) RNA, and multiply spliced RNA in the peripheral blood mononuclear cells (PBMC) of these patients at multiple time points during the period of undetectable plasma viremia on cART. Median under-therapy level of usRNA was significantly higher (0.43 log(10) difference, P = 0.0015) in patients who experienced subsequent cART failure than in successfully treated patients. In multivariate analysis, adjusted for baseline CD4(+) counts, prior ART experience, and particular cART regimens, the maximal usRNA level under therapy was the best independent predictor of subsequent therapy failure (adjusted odds ratio [95% CI], 24.4 [1.5-389.5], P = 0.024). The only other factor significantly associated with cART failure was prior ART experience (adjusted odds ratio [95% CI], 12.3 [1.1-138.4], P = 0.042). Levels of usRNA under cART inversely correlated with baseline CD4(+) counts (P = 0.0003), but did not correlate with either baseline usRNA levels or levels of prDNA under therapy. Our data demonstrate that the level of HIV-1 usRNA in PBMC, measured in cART-treated patients with undetectable plasma viremia, is a strong predictive marker for the outcome of therapy.PLoS ONE 01/2009; 4(12):e8490. · 4.09 Impact Factor
