Influence of the Timing of Antiretroviral Therapy on the Potential for Normalization of Immune Status in Human Immunodeficiency Virus 1–Infected Individuals

Okulicz, Jason F.; Le, Tuan; Agan, Brian K.; Camargo, José F.; Landrum, Michael L.; Wright, Edwina; Dolan, Matthew J.; Ganesan, Anuradha; Ferguson, Tomas; Smith, Davey M.; Richman, Douglas D.; Little, Susan J.; Clark, Robert A.; He, Weijing; Ahuja, Sunil K.

doi:10.1001/jamainternmed.2014.4010

Cited by 79 publications

(92 citation statements)

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“…8B). Previously, we showed that in patients receiving ART, normalization of CD4+ counts (>800 cells per μL) was associated with beneficial clinical and immune outcomes (33). In the present study, among HIV+ patients who received ART during primary infection, CD4+ ≥800 vs. <800 cells per μL was associated with higher intron 2 methylation status (Fig.…”

Section: Ccr5 Cis-regionssupporting

confidence: 61%

Epigenetic mechanisms, T-cell activation, andCCR5genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor

Gornalusse

Mummidi

Gaitán

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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T-cell expression levels of CC chemokine receptor 5 (CCR5) are a critical determinant of HIV/AIDS susceptibility, and manifest wide variations (i) between T-cell subsets and among individuals and (ii) in T-cell activation-induced increases in expression levels. We demonstrate that a unifying mechanism for this variation is differences in constitutive and T-cell activation-induced DNA methylation status of CCR5 cis-regulatory regions (cis-regions). Commencing at an evolutionarily conserved CpG (CpG −41), CCR5 cis-regions manifest lower vs. higher methylation in T cells with higher vs. lower CCR5 levels (memory vs. naïve T cells) and in memory T cells with higher vs. lower CCR5 levels. HIV-related and in vitro induced T-cell activation is associated with demethylation of these cis-regions. CCR5 haplotypes associated with increased vs. decreased gene/surface expression levels and HIV/AIDS susceptibility magnify vs. dampen T-cell activation-associated demethylation. Methylation status of CCR5 intron 2 explains a larger proportion of the variation in CCR5 levels than genotype or T-cell activation. The ancestral, protective CCR5-HHA haplotype bears a polymorphism at CpG −41 that is (i) specific to southern Africa, (ii ) abrogates binding of the transcription factor CREB1 to this cis-region, and (iii) exhibits a trend for overrepresentation in persons with reduced susceptibility to HIV and disease progression. Genotypes lacking the CCR5-Δ32 mutation but with hypermethylated cis-regions have CCR5 levels similar to genotypes heterozygous for CCR5-Δ32. In HIV-infected individuals, CCR5 cis-regions remain demethylated, despite restoration of CD4+ counts (≥800 cells per mm 3 ) with antiretroviral therapy. Thus, methylation content of CCR5 cis-regions is a central epigenetic determinant of T-cell CCR5 levels, and possibly HIV-related outcomes.HIV | CCR5 | methylation | T-cell activation | polymorphism C C chemokine receptor 5 (CCR5) is the major coreceptor for T-cell entry of HIV-1 (1). CCR5 levels on T cells influence HIV acquisition, disease progression rates, viral load, and immune recovery during antiretroviral therapy (ART), among other traits (1-4) (discussed in ref. 5). In these instances, lower CCR5 levels correlate with beneficial outcomes. Polymorphisms in the ORF and cis-regulatory regions (cis-regions) of CCR5 that correlate with higher vs. lower surface and/or gene expression levels are associated with increased vs. decreased HIV/AIDS risk and immune recovery (4-12). Classic examples are homozygosity Significance Levels of CC chemokine receptor 5 (CCR5) on T cells are a critical factor influencing HIV/AIDS susceptibility. DNA methylation is an epigenetic feature associated with lower gene expression. Here we show that the DNA methylation status of CCR5 cisregulatory regions (cis-regions) correlates inversely with CCR5 levels on T cells. T-cell activation induces demethylation of CCR5 cis-regions, upregulating CCR5 expression. Higher vs. lower sensitivity of CCR5 cis-regions to undergoing T-cell activationinduced...

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Section: Ccr5 Cis-regionssupporting

confidence: 61%

Epigenetic mechanisms, T-cell activation, andCCR5genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor

Gornalusse

Mummidi

Gaitán

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…This recommendation reversed earlier guidelines that limited treatment to patients with lower CD4 counts or severe illness 1. Although expanding eligibility is expected to reduce morbidity, mortality and transmission among patients with high CD4 2, 3, 4, 5, 6, 7, 8, it is possible that a large influx of newly eligible patients in a resource‐limited health system could crowd out sicker patients and reduce quality of care for all patients. As of September 2016, South Africa has joined three other countries in sub‐Saharan Africa in adopting the WHO ‘test‐and‐treat’ policy 9, 10, and additional resource‐limited countries are also considering expanding eligibility 11, 12.…”

Section: Introductionmentioning

confidence: 99%

Do HIV treatment eligibility expansions crowd out the sickest? Evidence from rural South Africa

Kluberg

Fox

LaValley

et al. 2018

Tropical Med Int Health

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ObjectiveThe 2015 WHO recommendation to initiate all HIV patients on antiretroviral therapy (ART) at diagnosis could potentially overextend health systems and crowd out sicker patients, mitigating the policy's impact. We evaluate whether South Africa's prior eligibility expansion from CD4 ≤ 200 to CD4 ≤ 350 cells/μl reduced ART uptake in the sickest patients.MethodsUsing data on all patients presenting to the Hlabisa HIV Treatment and Care Programme in KwaZulu‐Natal from April 2010 to June 2012 (n = 13 809), we assessed the impact of the August 2011 eligibility expansion on the number of patients seeking care, number initiating ART and time from HIV diagnosis to ART initiation among patients always eligible (CD4 0–200), newly eligible (CD4 201–350) and not yet eligible by CD4 count (>350). We used interrupted time series methods to control for long‐run trends and isolate the effect of the policy.ResultsExpanding ART eligibility led to an increased number of patients initiating ART per month [+95.5; 95% CI (−1.3; 192.3)]. Newly eligible patients (CD4 201–350) initiated treatment 47% faster than before (95% CI 19%; 82%), while the sickest patients (CD4 ≤ 200) saw no decline in the monthly number of patients initiating treatment or the rate of treatment uptake.ConclusionThe Hlabisa programme successfully extended ART to patients with CD4 ≤ 350 cells/μl, while ensuring that the sickest patients did not experience delays in ART initiation. Treatment programmes must be vigilant to maintain quality of care for the sickest as countries move to treat all patients irrespective of CD4 count.

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“…A recent study found that the median CD4 count in HIV-uninfected subjects was 900 cells/mm 3 , and that HIV-infected subjects who started antiretroviral therapy earlier were both more likely to achieve CD4 counts >900 cells/mm 3 , and more likely to respond to HBV vaccination. 34 Further studies are needed to explore whether this is also true for other vaccines.…”

Section: Discussionmentioning

confidence: 99%

Association of CMV, HBV, or HCV co-infection with vaccine response in adults with well-controlled HIV infection

Troy

Rossheim

Siik

et al. 2016

Human Vaccines & Immunotherapeutics

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Even after CD4 count recovery on antiretroviral therapy, HIV infection is associated with decreased response to most vaccines compared to the general population. Chronic infections with viruses such as cytomegalovirus (CMV), hepatitis B virus (HBV), and hepatitis C virus (HCV), which are more prevalent in HIV-infected populations, have been linked to immune dysfunction and decreased vaccine response in the general population. However, whether co-infection with these other viruses contributes to the decreased vaccine response seen in adults with well-controlled HIV infection is unknown. We conducted a secondary analysis of data and serum from adults with well-controlled HIV infection from an inactivated polio vaccine trial (224 subjects) and a pneumococcal conjugate vaccine study (128 subjects). We evaluated the association of CMV, HBV, or HCV co-infection with post-vaccination antibody levels using both univariate and multivariate analyses, controlling for factors such as age, race, CD4 count, comorbidities, smoking status, and baseline antibody levels. Ninety-three percent, 7%, and 14% of subjects were co-infected with CMV, HBV, and HCV respectively. On both univariate and multivariate analysis, neither CMV nor HCV co-infection were significantly associated with post-vaccination antibody levels to either vaccine. HBV co-infection was significantly associated with post-vaccination antibody concentrations for pneumococcal serotype 7F on univariate analysis and 6A on multivariate analysis, but the association was with higher antibody concentrations. In conclusion, co-infection with CMV, HBV, or HCV does not appear to contribute to the decreased vaccine response seen in adults with well-controlled HIV infection.

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Influence of the Timing of Antiretroviral Therapy on the Potential for Normalization of Immune Status in Human Immunodeficiency Virus 1–Infected Individuals

Abstract: Influence of the timing of antiretroviral therapy on the potential for normalization of immune status in human immunodeficiency virus 1-infected individuals.

Cited by 79 publications

References 33 publications

Epigenetic mechanisms, T-cell activation, andCCR5genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor

Epigenetic mechanisms, T-cell activation, andCCR5genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor

Do HIV treatment eligibility expansions crowd out the sickest? Evidence from rural South Africa

Association of CMV, HBV, or HCV co-infection with vaccine response in adults with well-controlled HIV infection

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