Selection of human immunodeficiency virus type 1 R5 variants with augmented replicative capacity and reduced sensitivity to entry inhibitors during severe immunodeficiency

Abstract

Early in human immunodeficiency virus 1 (HIV-1) infection CCR5-using (R5) viruses predominate. With disease progression, approximately 50 % of infected individuals develop viruses able to use CXCR4. In the present work, the evolution of the biological properties of HIV-1 was studied in patients who retain viruses with an R5 phenotype despite AIDS onset. A panel of primary R5 HIV-1 isolates sequentially obtained at an asymptomatic stage and after AIDS diagnosis was examined. The viruses were selected based on our previous observation that R5 variants with reduced sensitivity to RANTES inhibition may appear during disease progression. Biological properties of the early and late R5 viruses, including infectivity, replicative capacity, impact of cationic polymer and sensitivity to inhibition by the entry inhibitors T-20 and TAK-779, were evaluated. R5 viruses isolated after AIDS onset displayed elevated replicative capacity and infectivity, and did not benefit from cationic polymer assistance during infection. Late R5 isolates also exhibited reduced sensitivity to inhibition by T-20 and TAK-779, even though the included patients were naïve to treatment with entry inhibitors and the isolates had not acquired mutations within the gp41 HR1 region. In addition, CD4 + T-cell counts at the time of R5 virus isolation correlated with infectivity, replicative capacity and sensitivity to inhibition by entry inhibitors. The results indicate that R5 HIV-1 variants with augmented replicative capacity and reduced sensitivity to entry inhibitors may be selected for during severe immunodeficiency. At a time when the clinical use of entry inhibitors is increasing, this observation could be of importance in the optimal design of such treatments. INTRODUCTIONMany factors, including virus variability, can contribute to the pathogenicity of human immunodeficiency virus type 1 (HIV-1) infection. The high mutation rate and rapid turnover of HIV-1 result in a population of distinct viral variants, in other words a quasispecies, within the infected individual. Antiretroviral drugs and pressure exerted by the immune system of the host are selective forces that can contribute to the emergence of new HIV-1 variants in the viral population (Albert et al., 1990;Mansky, 2002;Mansky et al., 2002;Richman et al., 2003). It has also been suggested that variable expression of viral receptors on target cells serves to select certain HIV-1 variants (van Rij et al., 2000). Upon infection of the target cells, the HIV-1 envelope glycoprotein gp120 interacts with two different cellular receptors. gp120 attaches both to CD4 and to a coreceptor, which ultimately leads to a gp41-mediated fusion of the viral and cell membranes.The coreceptors utilized by HIV-1 include CCR5 and/or CXCR4, which are seven transmembrane chemokine receptors (Feng et al., 1996;Deng et al., 1996;Dragic et al., 1996;Cheng-Mayer et al., 1997;Berger et al., 1999). Early in HIV-1 infection, viruses primarily use CCR5 as a coreceptorThe GenBank/EMBL/DDBJ accession numbers for the sequences...

Human Immunodeficiency Virus Type 1 V1-to-V5 Envelope Variants from the Chronic Phase of Infection Use CCR5 and Fuse More Efficiently than Those from Early after Infection

“…In that study, however, the virus isolates from the acute and chronic phases of infection were obtained from different subjects. In contrast to that publication and similar to our results, other studies which have examined longitudinally collected variants have suggested that viruses become more resistant to CCR5 and fusion inhibitors over time (27,33,68). In these studies, PBMC cocultures were used to demonstrate that viruses from the chronic phase of infection have differential susceptibility to receptor and fusion inhibitors compared to late-stage variants.…”

“…Furthermore, TAK779 IC 50 s correlate with sensitivity to the CCR5 competitive inhibitor RANTES (Fig. 5B) (40,68). Thus, we suggest that increased CCR5 usage is because of a greater affinity for the CCR5 receptor.…”

Baseline Susceptibility of Primary HIV-2 to Entry Inhibitors

“…R5 variants isolated from HIV-1 patients after AIDS diagnosis have reduced sensitivity to TAK-779 as compared to R5 variants isolated at the asymptomatic stage [8,9]. Strikingly, we also found a strong and significant negative correlation between HIV-2 sensitivity to MVC (as determined by the IC 50s ) and CD4 + T-cell counts at the time of virus isolation (Spearman's r=-0.831; P=0.008; Figure 1B).…”

“…A similar tendency was observed for TAK-779 (Additional file 3). In all, these results demonstrate that HIV-2 R5 variants have lower sensitivity to MVC than HIV-1 and suggest that resistance of these variants to MVC increases as disease progresses [8,9].…”

HIV Type 1 from a Patient with Baseline Resistance to CCR5 Antagonists Uses Drug-Bound Receptor for Entry

“…Patients with more advanced disease have a greater likelihood of harboring X4-utilizing viruses [52][53][54] and have R5-tropic viruses with reduced sensitivity to RANTES and the CCR5 antagonists TAK779 and AD101 compared with patients at earlier disease stages. [55][56][57][58] As a consequence, these patients may fail R5 antagonist therapy via either outgrowth of minor preexisting X4-utilizing populations or the continued use of CCR5 in the presence of drug. In patients treated earlier during the course of infection, who have lower levels of circulating X4-tropic viral isolates, continued use of R5 may be a more common resistance pathway.…”