CD4-independent use of the CCR5 receptor by sequential primary SIVsm isolates

Laurén, Anna; Vincic, Elzbieta; Hoshino, Hiroo; Thorstensson, Rigmor; Fenyõ, Éva Mária

doi:10.1186/1742-4690-4-50

Cited by 4 publications

(3 citation statements)

References 68 publications

(69 reference statements)

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“…Lauren et al [37] have suggested the two are interrelated properties for SIVsm, but this is not an absolute requirement. Which of the envelope mutations associated in our experiments with CD4 dependence determine CKR tropism is undefined.…”

Section: Discussionmentioning

confidence: 99%

“…The observed switch from mixed CCR5 and CXCR4 usage in hPBMCs to predominantly CXCR4 usage by both strains has been described for SIV cultured in hPBMCs [ 3 ] , and may be functionally related to acquisition of CD4-dependence [ 25 ] . Lauren et al [ 37 ] have suggested the two are interrelated properties for SIVsm, but this is not an absolute requirement. Which of the envelope mutations associated in our experiments with CD4 dependence determine CKR tropism is undefined.…”

Section: Discussionmentioning

confidence: 99%

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Acquisition of CD4-Dependence by CD4-Independent SIV Passaged in Human Peripheral Blood Mononuclear Cells

Iyengar

Schwartz

2012

Retrovirology

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Background Chemokine receptors (CKRs), the primordial receptors for primate lentiviruses, are sufficient to mediate virus-cell fusion. Several different fusogenic CKRs and related receptors provide a broad potential host cell range, presumably advantageous for viral spread within a given infected individual, and across species. By contrast, the additional constraint of obligatory CD4 binding, just prior to CKR engagement, radically restricts potential host cells within an individual (or lymph node microenvironment), and might also limit xenotransmission, as CD4 sequences vary among primates. In spite of these potential drawbacks, CD4 dependent entry for SIV and HIV is the rule rather than the exception, and is generally thought to have evolved by selection for 1) stabilization of virus–cell surface interactions, and 2) conformational shielding of readily neutralized CKR binding epitopes. CD4 binding residues of SIV and HIV envelope are recessed, (relatively hidden from immune detection) and may exhibit a strong degree of automimicry, thus benefitting from self tolerance. Documented evolution, within individual macaques, of neutralization-resistant CD4-dependent SIV, derived from CD4-independent inocula, supports these ideas, but does not explain CD4’s exclusive role as the penultimate receptor-even more striking, given the wide diversity of CKRs and other surface molecules that can serve as actual fusion receptors for SIV. We, therefore, explored the additional, non-exclusive, hypothesis that surface CD4 on leukocytes is a marker of a more favorable host cell environment, as compared to CD8, NK, or B cell surface markers. Results We demonstrate progressive in vitro evolution of two SIV strains to CD4-dependence (and CXCR4 tropism) in normal human PBMCs (hPBMCs). The two CD4-independent strains of SIV tested developed nearly complete CD4 dependence over several months of serial passage in hPBMCs, correlating with a limited number of non-synonymous env region mutations, some previously reported to be determinants of CD4-dependency. The initial ability of SIV stocks to grow to significant (albeit, relatively low) levels in CD4(−), CD14(−) cells was also lost with long term passage. Rapid emergence and subsequent prominence of G → A and A → G mutations within env regions associated with CD4 dependence was seen. Conclusions Progressive acquisition of strict CD4 tropism, independent of immunoselection, supports the idea that surface CD4 identifies optimal host cells having intracellular environments most favorable to viral replication. The prominence of mutations involving G to A, or A to G, suggests that APOBEC 3 mediated infidelity may facilitate rapid switching of cell surface receptor usage within SIV swarms encountering fluctuating availability of optimal CD4 + CKR + targets. These observations of non-immune selection a...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Acquisition of CD4-Dependence by CD4-Independent SIV Passaged in Human Peripheral Blood Mononuclear Cells

Iyengar

Schwartz

2012

Retrovirology

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“…We investigated the ability of CD4-CCR5-VLPs to suppress HIV-1 replication and prevent viral escape in vivo in HIV-1 YU2 –infected humanized mice (hu-mice). CD4-CCR5-VLPs were selected for in vivo experiments to prevent the potential emergence of CD4-independent HIV-1 escape variants ( 28 – 30 ). To determine an optimal administration regimen, initial half-life studies were performed in uninfected hu-mice.…”

Section: Resultsmentioning

confidence: 99%

Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells

Hoffmann

Bar-On

Yang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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CD4-based decoy approaches against HIV-1 are attractive options for long-term viral control, but initial designs, including soluble CD4 (sCD4) and CD4-Ig, were ineffective. To evaluate a therapeutic that more accurately mimics HIV-1 target cells compared with monomeric sCD4 and dimeric CD4-Ig, we generated virus-like nanoparticles that present clusters of membrane-associated CD4 (CD4-VLPs) to permit high-avidity binding of trimeric HIV-1 envelope spikes. In neutralization assays, CD4-VLPs were >12,000-fold more potent than sCD4 and CD4-Ig and >100-fold more potent than the broadly neutralizing antibody (bNAb) 3BNC117, with >12,000-fold improvements against strains poorly neutralized by 3BNC117. CD4-VLPs also neutralized patient-derived viral isolates that were resistant to 3BNC117 and other bNAbs. Intraperitoneal injections of CD4-CCR5-VLP produced only subneutralizing plasma concentrations in HIV-1–infected humanized mice but elicited CD4-binding site mutations that reduced viral fitness. All mutant viruses showed reduced sensitivity to sCD4 and CD4-Ig but remained sensitive to neutralization by CD4-VLPs in vitro. In vitro evolution studies demonstrated that CD4-VLPs effectively controlled HIV-1 replication at neutralizing concentrations, and viral escape was not observed. Moreover, CD4-VLPs potently neutralized viral swarms that were completely resistant to CD4-Ig, suggesting that escape pathways that confer resistance against conventional CD4-based inhibitors are ineffective against CD4-VLPs. These findings suggest that therapeutics that mimic HIV-1 target cells could prevent viral escape by exposing a universal vulnerability of HIV-1: the requirement to bind CD4 on a target cell. We propose that therapeutic and delivery strategies that ensure durable bioavailability need to be developed to translate this concept into a clinically feasible functional cure therapy.

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Implications from the SIV Model in Understanding HIV Neutralization

Laurén

Fenyõ

2007

Future HIV Ther.

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HIV has killed more than 25 million people since it was first recognized in 1981, making it one of the most destructive epidemics in recorded history. Despite recent, improved access to antiretroviral treatment and care in many regions of the world, the AIDS epidemic still claims millions of lives each year. To control the epidemic it is mandatory to develop a vaccine(s). Furthermore, vaccines may conceivably corroborate the effect of antiretroviral drugs, thereby providing alternative therapies. However, we still do not know the type of immune response needed for protection from infection or, importantly, protection from disease. Experimental SIV infection of macaques serves as a tool to analyze the neutralizing antibody response in acute infection as well as the control of virus in chronic infection. In this review we will discuss the accumulated knowledge on neutralization in the SIV model and compare HIV infection in humans and SIV infection in macaques.

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CD4-independent use of the CCR5 receptor by sequential primary SIVsm isolates

Cited by 4 publications

References 68 publications

Acquisition of CD4-Dependence by CD4-Independent SIV Passaged in Human Peripheral Blood Mononuclear Cells

Acquisition of CD4-Dependence by CD4-Independent SIV Passaged in Human Peripheral Blood Mononuclear Cells

Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells

Implications from the SIV Model in Understanding HIV Neutralization

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