Phenotypic Coreceptor Tropism in Perinatally HIV-infected Youth Failing Antiretroviral Therapy

Abstract

Background Perinatally HIV-infected (PHIV) children and youth are often heavily treatment-experienced, with resultant antiretroviral (ARV) resistance and limited treatment options. For those with virologic failure (VF), new agents such as CCR5 (R5) antagonists may be useful; however, reports of R5 antagonist susceptibility in children have mostly relied on genotypic testing, which may not accurately reflect the phenotypic tropism of the viral populations. We characterized phenotypic co-receptor usage among PHIV children and youth with VF on ARV treatment (ART) to identify predictors of CXCR4 (X4) tropism which preclude R5 antagonist use. Methods Plasma samples with >1,000 HIV RNA copies/mL were obtained from 73 PHIV-infected ART-treated children and youth (age 9–21 years) enrolled in the multi-center Pediatric HIV/AIDS Cohort Study. Samples were analyzed using the Trofile™ phenotypic assay. Multiple logistic regression was performed to identify factors associated with detectable X4-tropism. Results Tropism results were obtained for 59 (81%) of the 73 children and youth; 32 (54%) had X4-tropism. Persistent viremia (≥80% of HIV RNA measurements >400 copies/mL) was associated with detectable X4-tropism (adjusted odds ratio (aOR) 6.6, 95% CI 1.4, 31.4), while longer cumulative nucleoside reverse transcriptase inhibitor (NRTI) use was associated with lower risk of X4-tropism (aOR 0.6, 95% CI 0.5, 0.9). Conclusions Using a phenotypic assay, >50% of PHIV children and youth with VF had X4-tropism, similar to that in treatment-experienced adults, and higher than the 30% reported for children using genotypic assays. Persistent viremia and shorter NRTI exposure are associated with X4-tropism in children and youth and may help target phenotypic testing to those most likely to benefit from R5 antagonist.

HIV-1C env and gag Variation in the Cerebrospinal Fluid and Plasma of Patients with HIV-Associated Cryptococcal Meningitis in Botswana

“…All PNGSs at position 301 in the HIV-1 env V3 loop were conserved and were concordant in paired CSF/plasma samples. This is not surprising because as previously reported, glycosylation at this position is highly conserved rendering the virus resistant to broadly neutralizing antibodies by blocking epitopes that can be recognized by these antibodies [43,44]. All glycans at position 160 in the HIV-1 env V2 loop (N160) were conserved in all sequences except sequence 1452 from CSF.…”

Genotypic HIV-1 tropism determination might help to identify people with exhausted treatment options and advanced disease

“…Because of this, tropism testing is generally performed as it is a requirement when the use of a CCR5 antagonist is being considered. 4,5 Some studies [6][7][8][9][10][11][12] had previously attempted to determine the HIV-1 co-receptor usage among treatmentexperienced HIV-1-infected individuals. To date, the association of viral tropism with immunological parameters and perinatal HIV transmission among failing patients is well documented.…”

HIV-1 tropism prediction by the XGboost and HMM methods

“…Genotypic methods can predict R5 viruses (~90%) accurately, but are inaccurate in the prediction of X4-using viruses (~50–70%) 26 . Thus, more accurate tropism prediction methods are required.…”