In vivo evolution of env in SHIV-AD8EO-infected rhesus macaques after AAV-vectored delivery of eCD4-Ig

被引：1

作者：

Hagan, Daniel O. ' ^{[1
]}

Shandilya, Siddhartha ^{[1
]}

Hopkins, Lincoln J. ^{[3
]}

Hahn, Patricia A. ^{[1
,2
]}

Fuchs, Sebastian P. ^{[4
]}

Martinez-Navio, Jose M. ^{[4
]}

Alpert, Michael D. ^{[5
]}

Gardner, Mathew R. ^{[6
]}

Desrosiers, Ronald C. ^{[4
]}

Gao, Guangping ^{[7
]}

Lifson, Jeffrey D. ^{[8
]}

Farzan, Michael ^{[9
]}

Ardeshir, Amir ^{[1
,10
]}

Martins, Mauricio A. ^{[1
]}

机构：

[1] Herbert Wertheim UF Scripps Inst Biomed Innovat &, Dept Immunol & Microbiol, Jupiter, FL 33458 USA

[2] Scripps Res Inst, Skaggs Grad Sch, Jupiter, FL 33458 USA

[3] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA

[4] Univ Miami, Miller Sch Med, Miami, FL 33136 USA

[5] Emmune Inc, Juno Beach, FL 33408 USA

[6] Emory Univ, Dept Med, Atlanta, GA 30322 USA

[7] Univ Massachusetts, Med Sch, Med Sch, Worcester, MA 01605 USA

[8] AIDS & Canc Virus Program, Frederick Natl Lab, Frederick, MD 21702 USA

[9] Harvard Med Sch, Boston Childrens Hosp, Dept Pediat, Boston, MA 02115 USA

[10] Tulane Univ, Tulane Natl Primate Res Ctr, Covington, LA 70433 USA

来源：

MOLECULAR THERAPY | 2025年 / 33卷 / 02期

关键词：

HUMAN-IMMUNODEFICIENCY-VIRUS; NEUTRALIZATION SENSITIVITY; CD4; INDEPENDENCE; HIV-1; BINDING; ANTIBODIES; INFECTION; EXPOSURE; CONFORMATION; MUTATIONS;

D O I：

10.1016/j.ymthe.2024.12.015

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

eCD4-immunoglobulin (Ig) is an HIV entry inhibitor that mimics the engagement of both CD4 and CCR5 with the HIV envelope (Env) protein, a property that imbues it with remarkable potency and breadth. However, env is exceptionally genetically malleable and can evolve to escape a wide variety of entry inhibitors. Here we document the evolution of partial eCD4-Ig resistance in SHIV-AD8EO-infected rhesus macaques (RMs) treated with adeno-associated virus vectors encoding eCD4-Ig. In one RM, setpoint viremia plateaued at 1,000 of eCD4-Ig in the 60-110 mg/mL range, implying that the virus had gained partial eCD4-Ig resistance. Env mutations occurring prominently in this animal were cloned and further characterized. Three of these mutations (R315G, A436T, and G471E) were sufficient to confer substantial resistance to eCD4-Ig-mediated neutralization onto the parental Env, accompanied by a marked loss of viral fitness. This resistance was not driven by decreased CD4 affinity, subverted sulfopeptide mimicry, changes to co-receptor tropism, or by a gain of CD4 independence. Rather, our data argue that the Env evolving in this animal attained eCD4-Ig resistance by decreasing triggerability, stabilizing the triggered state, and changing the nature of its relationship to the host CD4.

引用

页码：560 / 579

页数：20