Incompatible Natures of the HIV-1 Envelope in Resistance to the CCR5 Antagonist Cenicriviroc and to Neutralizing Antibodies

Abstract

bCenicriviroc is a CCR5 antagonist which prevents human immunodeficiency virus type 1 (HIV-1) from cellular entry. The CCR5-binding regions of the HIV-1 envelope glycoprotein are important targets for neutralizing antibodies (NAbs), and mutations conferring cenicriviroc resistance may therefore affect sensitivity to NAbs. Here, we used the in vitro induction of HIV-1 variants resistant to cenicriviroc or NAbs to examine the relationship between resistance to cenicriviroc and resistance to NAbs. The cenicriviroc-resistant variant KK 652-67 (strain KK passaged 67 times in the presence of increasing concentrations of cenicriviroc) was sensitive to neutralization by NAbs against the V3 loop, the CD4-induced (CD4i) region, and the CD4-binding site (CD4bs), whereas the wild-type (WT) parental HIV-1 strain KK WT from which cenicriviroc-resistant strain KK 652-67 was obtained was resistant to these NAbs. The V3 region of KK 652-67 was important for cenicriviroc resistance and critical to the high sensitivity of the V3, CD4i, and CD4bs epitopes to NAbs. Moreover, induction of variants resistant to anti-V3 NAb 0.5␥ and anti-CD4i NAb 4E9C from cenicriviroc-resistant strain KK 652-67 resulted in reversion to the cenicriviroc-sensitive phenotype comparable to that of the parental strain, KK WT . Resistance to 0.5␥ and 4E9C was caused by the novel substitutions R315K, G324R, and E381K in the V3 and C3 regions near the substitutions conferring cenicriviroc resistance. Importantly, these amino acid changes in the CCR5-binding region were also responsible for reversion to the cenicriviroc-sensitive phenotype. These results suggest the presence of key amino acid residues where resistance to cenicriviroc is incompatible with resistance to NAbs. This implies that cenicriviroc and neutralizing antibodies may restrict the emergence of variants resistant to each other.

Prediction of HIV-associated neurocognitive disorder (HAND) from three genetic features of envelope gp120 glycoprotein

“…Holman and Gabuzda also reported the involvement of Pos315 in HAND-predicting signature [ 21 ]. Pos315 resides in the tip of the V3-loop, and various variants such as R315K, R315T, and R315Q have been associated with reduced efficacy of neutralizing antibodies (NAbs) [ 35 – 38 ]. In our analysis, R315K and R315Q were enriched in the HAND and NonHAND cases, respectively (Fig.…”

Global Variability of V3 Loop Tetrapeptide Motif: a Concern for HIV-1 Neutralizing Antibodies-based Vaccine Design and Antiretroviral Therapy

“…9 No. 3 fusion inhibitors drug [20,36] (Table 1), but appear to escape from neutralizing antibodies [20,[36][37][38][39]. Although additional mutations can promote drug resistance or escape from the immune system, the potential fitness cost of the variants may affect the pathogenesis of HIV-1.…”

“…These sequences encompass the ten most frequent V3 motifs around the world, together with GPGR and GPGQ. The binding capacity of anti-V3 neutralizing antibodies can be reduced in the presence of GPGK, GAGR, GLGR, and GPGA [20,36,40,[45][46][47], impairing the course of HIV-1 infection and affecting a vaccine design (Table 1). Contrarily, GWGR increases the neutralizing capacity of antibodies [48].…”

“…On the other hand, although the GPGR motif has been considered a conserved region of the V3 loop, this motif presents significant variability [3,15]. Diverses studies associated the specific variants of GPGR with fusion inhibitor drug resistance, escape from neutralizing antibodies, or even with pathogenicity [16][17][18][19][20]. Altogether, the diversity of the motifs at the crown of the V3 loop spread worldwide has been proven to be an epidemiologic problem.…”

Driving HIV-1 into a Vulnerable Corner by Taking Advantage of Viral Adaptation and Evolution

“…These results indicated that the MVC-resistance mutations might improve the accessibility of epitopes for the NAbs and, therefore, be incompatible with resistance to the NAbs ( Yoshimura et al, 2014 ). More recently, Kuwata et al (2015) showed that resistant variants against a CCR5 inhibitor, cenicriviroc, also became sensitive to three NAbs: VRC01 (CD4bs), 4E9C, and 0.5γ (V3).…”