Differential levels of soluble inflammatory markers by human immunodeficiency virus controller status and demographics.

Background. Human immunodeficiency virus (HIV)-1 elite controllers (ECs) represent an ideal population to study the effects of HIV persistence on chronic inflammation in the absence of antiretroviral therapy (ART). Methods. Twenty inflammatory markers measured in cohorts of ECs, HIV suppressed noncontrollers, and HIV-uninfected controls were compared using rank-based tests and partial least squares discriminant analysis (PLSDA). Spearman correlations were determined among the inflammatory markers, residual viremia by the single-copy assay, and CD4(+) T cell slope. Results. Significant differences were seen between cohorts in 15 of the soluble inflammatory markers. Human immunodeficiency virus-1 ECs were found to have the highest levels for all of the markers with the exception of RANTES. In particular, median levels of 7 inflammatory markers (soluble CD14 [sCD14], interferon [IFN]-γ, IFN-γ-inducible protein [IP]-10, interleukin [IL]-4, IL-10, sCD40L, and granulocyte-macrophage colony-stimulating factor) were twice as high in the HIV-1 ECs compared with either of the HIV-suppressed or uninfected groups. Multivariate PLSDA analysis of inflammatory markers improved differentiation between the patient cohorts, discerning gender differences in inflammatory profile amongst individuals on suppressive ART. Soluble markers of inflammation in ECs were not associated with either levels of residual HIV-1 viremia or CD4(+) T cell decline. Conclusions. Despite maintaining relatively low levels of viremia, HIV-1 ECs had elevated levels of a set of key inflammatory markers. Additional studies are needed to determine whether ECs may benefit from ART and to further evaluate the observed gender differences.

Relationship of HIV reservoir characteristics with immune status and viral rebound kinetics in an HIV therapeutic vaccine study.

OBJECTIVES: The objective of this study is to evaluate the impact of therapeutic HIV vaccination on the HIV reservoir and assess the relationship of the viral reservoir with HIV-specific immune status and viral rebound kinetics. DESIGN: A retrospective analysis of ACTG A5197, a randomized, placebo-controlled trial of a therapeutic rAd5 HIV-1 gag vaccine. METHODS: Participants received vaccine/placebo at weeks 0, 4 and 26 prior to a 16-week analytic treatment interruption (ATI) at week 38. Cell-associated HIV-1 RNA and DNA (CA-RNA and CA-DNA) and HIV-1 residual viremia were quantified at weeks 0, 8 and 38. HIV-specific CD4(+)/CD8(+) activity was assessed by an intracellular cytokine staining assay. RESULTS: At study entry, CA-RNA and CA-DNA levels were correlated inversely with the numbers of HIV-specific CD4(+) interferon-γ producing cells (CA-RNA: r = -0.23, P = 0.03 and CA-DNA: r = -0.28, P < 0.01, N = 93). Therapeutic HIV vaccination induced HIV-specific CD4(+) activity, but did not significantly affect levels of CA-RNA or CA-DNA. Vaccine recipients with undetectable residual viremia at week 8 had higher frequencies of HIV-specific CD4(+) and CD8(+) interferon-γ producing cells (undetectable versus detectable residual viremia: 277 versus 161 CD4(+) cells/10(6) lymphocytes, P = 0.03 and 1326 versus 669 CD8(+) cells/10 lymphocytes, P = 0.04). Pre-ATI CA-RNA and CA-DNA were associated with post-ATI plasma HIV set point (CA-RNA: r = 0.51, P < 0.01 and CA-DNA: r = 0.47, P < 0.01). CONCLUSION: Vaccine-induced T-cell responses were associated with a modest transient effect on residual viremia, but more potent immune responses and/or combination treatment with latency-reversing agents are needed to reduce the HIV reservoir. HIV reservoir measures may act as biomarkers of post-ATI viral rebound kinetics. CLINICAL TRIALS REGISTRATION: NCT00080106.

Antiretroviral-free HIV-1 remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases.

BACKGROUND: It is unknown whether the reduction in HIV-1 reservoirs seen after allogeneic hematopoietic stem cell transplantation (HSCT) with susceptible donor cells is sufficient to achieve sustained HIV-1 remission. OBJECTIVE: To characterize HIV-1 reservoirs in blood and tissues and perform analytic antiretroviral treatment interruptions to determine the potential for allogeneic HSCT to lead to sustained, antiretroviral-free HIV-1 remission. DESIGN: Case report with characterization of HIV-1 reservoirs and immunity before and after antiretroviral interruption. SETTING: Tertiary care center. PATIENTS: Two men with HIV with undetectable HIV-1 after allogeneic HSCT for hematologic tumors. MEASUREMENTS: Quantification of HIV-1 in various tissues after HSCT and the duration of antiretroviral-free HIV-1 remission after treatment interruption. RESULTS: No HIV-1 was detected from peripheral blood or rectal mucosa before analytic treatment interruption. Plasma HIV-1 RNA and cell-associated HIV-1 DNA remained undetectable until 12 and 32 weeks after antiretroviral cessation. Both patients experienced rebound viremia within 2 weeks of the most recent negative viral load measurement and developed symptoms consistent with the acute retroviral syndrome. One patient developed new efavirenz resistance after reinitiation of antiretroviral therapy. Reinitiation of active therapy led to viral decay and resolution of symptoms in both patients. LIMITATION: The study involved only 2 patients. CONCLUSION: Allogeneic HSCT may lead to loss of detectable HIV-1 from blood and gut tissue and variable periods of antiretroviral-free HIV-1 remission, but viral rebound can occur despite a minimum 3-log10 reduction in reservoir size. Long-lived tissue reservoirs may have contributed to viral persistence. The definition of the nature and half-life of such reservoirs is essential to achieve durable antiretroviral-free HIV-1 remission. PRIMARY FUNDING SOURCE: Foundation for AIDS Research and National Institute of Allergy and Infectious Diseases.

Incomplete adherence to antiretroviral therapy is associated with higher levels of residual HIV-1 viremia.

OBJECTIVES: To evaluate the relationship between incomplete antiretroviral therapy (ART) adherence and levels of residual HIV-1 viremia. DESIGN: Medication adherence and residual viremia less than 50 copies/ml were quantified in participants of a cohort of homeless and marginally housed individuals with HIV/AIDS. METHODS: Participants had at least 6 months of virologic suppression of less than 50 copies/ml and were in the adherence monitoring cohort with monthly unannounced pill counts. Residual viremia was measured by the single-copy assay. RESULTS: The median average ART adherence over the prior 1 and 2 months were 94% [interquartile range (IQR) 79-100%] and 93% (IQR 82-98%), respectively. Average ART adherence over the past 2 months was significantly associated with levels of residual HIV viremia (Spearman r = -0.25, P = 0.04). One-third of participants with 100% ART adherence over the past 2 months had detectable residual viremia. On multivariate regression analysis, ART adherence over the past 2 months, but not duration of virologic suppression, CD4 T-cell count or ART regimen, was significantly associated with levels of residual HIV viremia. Detectable residual viremia was associated with virologic failure (>50 copies/ml) on univariate Cox proportional hazard analysis (hazard ratio 2.08, P = 0.02). However, on multivariate analysis, only ART adherence was associated with risk of virologic failure. CONCLUSION: Incomplete ART adherence is associated with higher levels of residual HIV-1 viremia, but detectable residual viremia can be present despite 100% measured ART adherence.