Entry inhibitors in the treatment of HIV-1 infection

Tilton, John C.; Doms, Robert W.

doi:10.1016/j.antiviral.2009.07.022

Cited by 185 publications

(148 citation statements)

References 154 publications

Supporting

Mentioning

139

Contrasting

Unclassified

Order By: Relevance

“…Upon binding to coreceptor, which is either CCR5 or CXCR4 for primary HIV isolates, Env undergoes further conformational changes resulting in insertion of the gp41 fusion peptide into the host cell membrane and gp41-mediated membrane fusion (8,15,26). Targeting stages of the HIV entry process with antiretroviral drugs is a productive method of inhibiting HIV replication, as demonstrated by the potent antiviral effects of small-molecule CCR5 antagonists and fusion inhibitors (23,35,49). As with other antiretroviral drugs, HIV can develop resistance to entry inhibitors, and a detailed understanding of viral and host determinants of resistance will be critical to the optimal clinical use of these agents.…”

mentioning

confidence: 99%

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells

Pfaff

Wilen

Harrison

et al. 2010

J Virol

Self Cite

View full text Add to dashboard Cite

We previously reported on a panel of HIV-1 clade B envelope (Env) proteins isolated from a patient treated with the CCR5 antagonist aplaviroc (APL) that were drug resistant. These Envs used the APL-bound conformation of CCR5, were cross resistant to other small-molecule CCR5 antagonists, and were isolated from the patient's pretreatment viral quasispecies as well as after therapy. We analyzed viral and host determinants of resistance and their effects on viral tropism on primary CD4 ؉ T cells. The V3 loop contained residues essential for viral resistance to APL, while additional mutations in gp120 and gp41 modulated the magnitude of drug resistance. However, these mutations were context dependent, being unable to confer resistance when introduced into a heterologous virus. The resistant virus displayed altered binding between gp120 and CCR5 such that the virus became critically dependent on the N terminus of CCR5 in the presence of APL. In addition, the drug-resistant Envs studied here utilized CCR5 very efficiently: robust virus infection occurred even when very low levels of CCR5 were expressed. However, recognition of drug-bound CCR5 was less efficient, resulting in a Entry of human immunodeficiency virus (HIV) into target cells is a complex, multistep process that is initiated by interactions between the viral envelope (Env) protein gp120 and the host cell receptor CD4, which trigger conformational changes in gp120 that form and orient the coreceptor binding site (9,24). Upon binding to coreceptor, which is either CCR5 or CXCR4 for primary HIV isolates, Env undergoes further conformational changes resulting in insertion of the gp41 fusion peptide into the host cell membrane and gp41-mediated membrane fusion (8,15,26). Targeting stages of the HIV entry process with antiretroviral drugs is a productive method of inhibiting HIV replication, as demonstrated by the potent antiviral effects of small-molecule CCR5 antagonists and fusion inhibitors (23,35,49). As with other antiretroviral drugs, HIV can develop resistance to entry inhibitors, and a detailed understanding of viral and host determinants of resistance will be critical to the optimal clinical use of these agents.The coreceptor binding site that is induced by CD4 engagement consists of noncontiguous regions in the bridging sheet and V3 loop of gp120 (4,18,42,43,50). Interactions between gp120 and CCR5 occur in at least two distinct areas: (i) the bridging sheet and the stem of the V3 loop interact with sul-

show abstract

mentioning

confidence: 99%

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells

Pfaff

Wilen

Harrison

et al. 2010

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…12 The first point of contact between HIV and the host is the interaction of CD4 with gp120, which has been extensively targeted using a variety of strategies, without yielding any compounds in the clinic. 11 The next point of intervention in HIV entry is the interaction of gp120 with its chemokine co-receptor (CCR5 or CXCR4). The importance of CCR5 for (R5-tropic) HIV entry is demonstrated by a well-established association between a 32 base pair deletion variant of CCR5 (CCR5-D32) in 5-14% of individuals of European Caucasians, and protection from HIV infection.…”

Section: Viral Entrymentioning

confidence: 99%

“…Although there are no current clinical trials of compounds that inhibit the interaction of gp120 with CXCR4, 11 there are several in development. 20 These compounds, when administered in combination with a CCR5 inhibitor, may provide an effective method for inhibiting HIV entry.…”

Section: This Journal Is C the Royal Society Of Chemistry 2010mentioning

confidence: 99%

“…22 There are several other fusion inhibitors currently in development. 11 These include several ''next generation'' peptides that have improved efficacy and are active against some fuzeon-resistant strains. 23 As these compounds target a different part of gp41 (to that targeted by fuzeon) there is potential for the development of synergistic therapies based on entry inhibitors.…”

Section: This Journal Is C the Royal Society Of Chemistry 2010mentioning

confidence: 99%

See 1 more Smart Citation

Targeting the protein–protein interactions of the HIV lifecycle

Tavassoli

2011

Chem. Soc. Rev.

View full text Add to dashboard Cite

“…HIV and simian immunodeficiency virus (SIV) Env glycoproteins possess an unusually long cytoplasmic tail (CT) sequence, and acquisition of CT truncations by premature stop codons, which remove almost the entire CT, is a potential mechanism used by HIV or SIV for adaptation to new cell types or escape from effects of entry inhibitors (Kodama et al, 1989;Mulligan et al, 1992;Tilton and Doms, 2010;Waheed et al, 2007). The size and sequence of the gp41 cytoplasmic domain can also modify the biological properties…”

Section: Introductionmentioning

confidence: 99%

An amphipathic sequence in the cytoplasmic tail of HIV-1 Env alters cell tropism and modulates viral receptor specificity

Vzorov¹,

Yang²,

Compans³

2015

View full text Add to dashboard Cite

Summary. -The human immunodeficiency virus type 1 (HIV-1) 92UG046 Env protein, obtained from a CD4-independent HIV-1 primary isolate (Zerhouni et al., 2004), has the ability to initiate an infection in HeLa cells expressing CD4 when carrying the full-length (FL) Env, but uses CD8 molecules for receptor-mediated entry when carrying a truncated Env (CT84). To determine whether a specific length or structure in the cytoplasmic tail (CT) is responsible for this alteration of tropism, we compared a series of Env constructs with different CT truncations and the presence or absence of an amphipathic alpha-helical sequence. We found that truncated constructs containing the alpha-helical LLP-2 structure in their CT domains conferred a switch from CD4 to CD8 tropism. The results support the conclusion that the structure of the CT domain can play an important role in determining receptor specificity.Keywords: HIV-1; Env glycoprotein; gp41; gp120; cytoplasmic tail truncation; alpha-helical LLP2 sequence; CD4, CD8; receptor specificity E-mail: avzorov@emory.edu; phone: +1-404-727-3228. Abbreviations: CT = cytoplasmic tail; FL = full-length; HIV-1 = human immunodeficiency virus type 1; LLP-1,-2,-3 = conserved alpha-helical "lentivirus lytic peptide" domains; SP = signal peptide sequence; SIV = simian immunodeficiency virus; SU(s) = surface subunit(s); TM = transmembrane protein; WT = wild type of the Env protein (Vzorov and

show abstract

Entry inhibitors in the treatment of HIV-1 infection

Cited by 185 publications

References 154 publications

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells

Targeting the protein–protein interactions of the HIV lifecycle

An amphipathic sequence in the cytoplasmic tail of HIV-1 Env alters cell tropism and modulates viral receptor specificity

Contact Info

Product

Resources

About

Entry inhibitors in the treatment of HIV-1 infection

Cited by 185 publications

References 154 publications

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 + T Cells

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 + T Cells

Targeting the protein–protein interactions of the HIV lifecycle

An amphipathic sequence in the cytoplasmic tail of HIV-1 Env alters cell tropism and modulates viral receptor specificity

Contact Info

Product

Resources

About

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells

HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4 ⁺ T Cells