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APOBEC3G/3A Expression in Human Immunodeficiency Virus Type 1-Infected Individuals Following Initiation of Antiretroviral Therapy Containing Cenicriviroc or Efavirenz.

ABSTRACT: Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3) family members are cytidine deaminases that play crucial roles in innate responses to retrovirus infection. The mechanisms by which some of these enzymes restrict human immunodeficiency virus type 1 (HIV-1) replication have been extensively investigated in vitro. However, little is known regarding how APOBEC3 proteins affect the pathogenesis of HIV-1 infection in vivo and how antiretroviral therapy influences their expression. In this work, a longitudinal analysis was performed to evaluate APOBEC3G/3A expression in peripheral blood mononuclear cells of antiretroviral-naive HIV-1-infected individuals treated with cenicriviroc (CVC) or efavirenz (EFV) at baseline and 4, 12, 24, and 48?weeks post-treatment follow-up. While APOBEC3G expression was unaffected by therapy, APOBEC3A levels increased in CVC but not EFV arm at week 48 of treatment. APOBEC3G expression correlated directly with CD4+ cell count and CD4+/CD8+ cell ratio, whereas APOBEC3A levels inversely correlated with plasma soluble CD14. These findings suggest that higher APOBEC3G/3A levels may be associated with protective effects against HIV-1 disease progression and chronic inflammation and warrant further studies.

SUBMITTER: Covino DA

PROVIDER: S-EPMC6092507 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Project description:Abstract Background Single-nucleotide polymorphisms (SNPs) in CYP2B6 have previously been associated with a 10-fold range in trough plasma efavirenz concentrations, but associations between these SNPs and efavirenz (EFV)-mediated viral suppression and tolerability remain unclear. Methods We evaluated three SNPs in CYP2B6 (rs3745274, rs28399499, and rs4803419, Illumina OmniExpress) among HIV-infected Ugandans observed in a cohort study every 3–4 months from 2005–2015. Genotypes from these SNPs were used to group participants into previously described pharmacokinetic strata: extensive (EXT), intermediate (INT), and slow metabolizers (Figure 1). The primary outcomes were viral suppression, defined by an undetectable viral load in the first measurement a minimum of three months after ART initiation, and incident depression in the first two years, defined by a mean score >1.75 on the Hopkins Symptom Checklist. We fitted standard and generalized estimating equations (GEE) logistic regression models for viral suppression and depression, respectively. Models were adjusted for clinical and demographic covariates that reached a significance of P < 0.25 in unadjusted models. Results Among 103 participants with genotyping, there were no differences in pre-ART viral load or depression by metabolism strata (P > 0.5). Minor allele frequencies for rs3745274, rs28399499, and rs4803419 were 33%, 7%, and 4%, respectively. Approximately 79%, 78%, and 94% of participants were suppressed at their first viral load measurement in the extensive, intermediate, and slow metabolizer strata, respectively (Figure 2; P = 0.35). In adjusted models, metabolism strata were not associated with viral suppression (AORINT 0.81, 95% CI 0.26–2.56; AORSLOW 3.92, 95% CI 0.39–39.40) or with depression (AORINT 1.95, 95% CI 0.75–5.09; AORSLOW 0.72, 95% CI 0.17–3.02; Table). Conclusion We did not identify an association between efavirenz-metabolizing polymorphisms and viral suppression or depression in a cohort of HIV-infected individuals initiating ART in southwestern Uganda. Future work should reassess these relationships with larger samples and longer-term outcomes and explore additional polymorphisms that may be associated with efavirenz metabolism in this population. Disclosures P. Hunt, Merck: Consultant, Consulting fee; Gilead: Consultant, Consulting fee; Viiv: Consultant, Consulting fee

Project description:Background:Combination antiretroviral therapy (cART) use in pregnancy has been associated with hormonal dysregulation. We performed a secondary retrospective analysis of longitudinal progesterone and estradiol levels in pregnancy using specimens from the Protease Inhibitors to Reduce Malaria Morbidity in HIV-infected Pregnant Women study, which randomized Ugandan human immunodeficiency virus (HIV)-infected ART-naive women to initiate either lopinavir/ritonavir (LPV/r)-based or efavirenz (EFV)-based cART. Methods:Three hundred twenty-six women (160 randomized to the EFV arm and 166 women to the LPV/r arm) with at least 1 plasma sample collected during pregnancy were included. Enrollment samples collected prior to cART initiation were used as a cART-naive comparator group. Hormone levels were quantified by enzyme-linked immunosorbent assay. Results:Estradiol levels were differentially affected by the 2 cART regimens. Exposure to LPV/r was associated with an increase in estradiol (P < .0001), whereas exposure to EFV was associated with a decrease in estradiol (P < .0001), relative to the cART-naive gestationally matched comparator group. Lower estradiol levels correlated with small for gestational age (SGA) (P = .0019) and low birth weight (P = .019) in the EFV arm, while higher estradiol levels correlated with SGA in the LPV/r arm (P = .027). Although progesterone levels were similar between treatment arms, we observed an association between SGA and lower progesterone in the LPV/r arm (P = .04). No association was observed between hormone levels and preterm birth in either arm. Levels of progesterone and estradiol were lower in cases of stillbirth, and levels of both hormones declined immediately prior to stillbirth in 5 of 8 cases. Conclusions:Combination ART regimens differentially affect estradiol levels in pregnancy, a hormone critical to the maintenance of a healthy pregnancy. Identifying cART regimens that minimize perinatal HIV transmission without contributing to hormonal dysregulation represents an urgent public health priority. Clinical Trials Registration:NCT00993031.

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APOBEC3G/3A Expression in Human Immunodeficiency Virus Type 1-Infected Individuals Following Initiation of Antiretroviral Therapy Containing Cenicriviroc or Efavirenz.

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