Susceptibility of HIV-1 Subtypes B′, CRF07_BC and CRF01_AE that Are Predominantly Circulating in China to HIV-1 Entry Inhibitors

Abstract

BackgroundThe B′, CRF07_BC and CRF01_AE are the predominant HIV-1 subtypes in China. It is essential to determine their baseline susceptibility to HIV entry inhibitors before these drugs are used in China.Methodology/Principal FindingsThe baseline susceptibility of 14 representative HIV-1 isolates (5 CRF07_BC, 4 CRF01_AE, and 5 B′), most of which were R5 viruses, obtained from drug-naïve patients to HIV entry inhibitors, including two fusion inhibitors (enfuvirtide and C34), two CCR5 antagonists (maraviroc and TAK779) and one CXCR4 antagonist (AMD3100), were determined by virus inhibition assay. The sequences of their env genes were amplified and analyzed. These isolates possessed similar susceptibility to C34, but they exhibited different sensitivity to enfuvirtide, maraviroc or TAK779. CRF07_BC isolates, which carried polymorphisms of A578T and V583I in the N-terminal heptad repeat and E630Q, E662A, K665S, A667K and S668N in the C-terminal heptad repeat of gp41, were about 5-fold less sensitive than B′ and CRF01_AE isolates to enfuvirtide. Subtype B′ isolates with a unique polymorphism site of F317W in V3 loop, were about 4- to 5-fold more sensitive than CRF07_BC and CRF01_AE isolates to maraviroc and TAK779. AMD3100 at the concentration as high as 5 µM exhibited no significant inhibitory activity against any of the isolates tested.ConclusionOur results suggest that there are significant differences in baseline susceptibility to HIV entry inhibitors among the predominant HIV-1 subtypes in China and the differences may partly result from the naturally occurring polymorphisms in these subtypes. This study provides useful information for rational design of optimal therapeutic regimens for HIV-1-infected patients in China.

Epidemiological and molecular characteristics of HIV infection among money boys and general men who have sex with men in Shanghai, China

“…The B, CRF-01AE and CRF-BC are the predominant HIV subtypes in China (Yu et al, 2011), but there are some variations in different transmission routes. For IDUs or heterosexually transmitted infections, subtype C (Chen et al, 2012a) or CRF-08BC/07BC (Chen et al, 2013) was found to be the predominant strain in Yunnan province.…”

“…In China, the predominant HIV-1 subtypes are CRF01_AE, CRF07_BC, CRF08_BC, B’ and B (Liao et al, 2010; Tao et al, 2014; Yu et al, 2011), with considerable variations by geographic region and HIV transmission mode (Chen et al, 2013; Han et al, 2013; Li et al, 2012; Tao et al, 2014). Non-B subtypes including CRF01_AE and CRF07_BC have rapidly increased among MSM in China (Shao et al, 2013; Wang et al, 2008; 2011; Zhang et al, 2007).…”

Determination of the High Prevalence of Dual/Mixed- or X4-Tropism Among HIV Type 1 CRF01_AE in Hong Kong by Genotyping and Phenotyping Methods

“…Some R5-tropic CRF01_AE isolates in other studies were shown to have a lower baseline susceptibility than subtype B viruses toward CCR5 antagonists. 40 Thus, an investigation of CRF01_AE viral pathogenesis will be necessary in the future due to the high prevalence of X4 observed.…”

Mutations in variable domains of the HIV-1 envelope gene can have a significant impact on maraviroc and vicriviroc resistance

“…In their study, R5 isolates harboring 2 dominant polymorphisms, R315Q and F317W in V3, were less susceptible than B isolates to MVC and TAK779. They postulated that baseline resistance to entry inhibitors may be associated with naturally-occurring polymorphisms [21]. Yuan et al [22] studied a combination of polymorphisms in the gp120 V3 loop of HIV-1JR-FL virus that can confer non-competitive resistance to MVC with a V3 loop library containing a set of random combinations of 0-10 polymorphic mutations in vitro .…”