Analysis of primary resistance mutations to HIV-1 entry inhibitors in therapy naive subtype C HIV-1 infected mother–infant pairs from Zambia

Abstract

Background Small molecular CCR5 inhibitors represent a new class of drugs for treating HIV-1 infection. The evaluation of the primary resistance mutations associated with entry inhibitors during HIV-1 perinatal transmission is required because they may have a profound impact on the clinical management in MTCT. Objectives To evaluate the primary resistance mutations to maraviroc and vicriviroc during perinatal transmission and analyze the sensitivity of Env derived from mother–infant pairs to maraviroc. Study design Nine MIPs infected by subtype C HIV-1 were recruited to analyze the prevalence and transmission of primary resistance mutations to maraviroc and vicriviroc. Moreover, Env derived from six MIPs were employed to construct provirus clones and to analyze the sensitivity to maraviroc. Results Mutations A316T, conferring partial resistance to maraviroc, T307I and R315Q, both conferring partial resistance to vicriviroc are prevalent in mother and infant cohorts, indicating the transmission of primary resistance mutations during HIV-1 perinatal transmission. However, the mutations of acutely infected mothers seem to directly transmit to their corresponding infants, while some mutations at low frequency of chronically infected mothers would be lost during transmission. Moreover, provirus clones derived from acutely infected MIPs are less susceptible to maraviroc than those from chronically infected MIPs. Conclusions Our study suggests that the transmission mode of primary resistance mutations and the sensitivity to maraviroc are dependent on infection status of MIPs either acutely or chronically infected. These results may indicate that higher dose of maraviroc could be needed for treatment of acutely infected MIPs compared to chronically infected MIPs.

Maraviroc: a review of its use in HIV infection and beyond

“… 119 The I323V mutation in the gp120 was rare but was only present with the A316T mutation. 119 A high prevalence of the A316T mutation, which results in partial resistance to MVC, was found in Zambian mother–infant pairs infected with HIV-1 subtype-C. 120 A study of 80 HIV-infected patients in Brazil who had failed treatment showed that 27.5% harbored the the A316T, I323V, and/or S405A mutations in the gp120. 121 However, in another study of 498 individuals infected with R5-tropic, subtype-B HIV-1, mutation patterns associated with MVC resistance were less than 5%.…”

Evolution of Multiple Domains of the HIV-1 Envelope Glycoprotein during Coreceptor Switch with CCR5 Antagonist Therapy

“…Although VCV has similar activity to MVC, the pharmaceutical producer chose not to continue its therapeutic development ( 29 ). The inhibitory spectrum of VCV appears very similar to that of MVC ( 30 , 31 ). Thus, we further analyzed the samples from a phase II clinical trial of vicriviroc, derived from the subset of individuals who developed virological failure (VF) and a shift from CCR5 to CXCR4 use while on treatment ( 28 ).…”