Defensins inhibit HIV replication in vitro

Nakashima, Hideki; Yamamoto, Naoki; Masuda, Masao; Fujii, Nobutaka

doi:10.1097/00002030-199308000-00019

Cited by 119 publications

(74 citation statements)

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“…2 Neutrophils, the most abundant leukocytes in the circulation, are the first cells to infiltrate inflammatory sites and prominent components of inflammatory responses induced by viral infections. [16][17][18] The anti-HIV activity of ␣-defensins was first described in 1993, 19 but it received little attention until 2002 when Zhang et al claimed that ␣-defensins 1, 2, and 3 constitute major components of the soluble HIV-suppressive activity produced by CD8 ϩ T cells. 20 Subsequently, however, it was shown that CD8 ϩ T cells do not express ␣-defensin mRNA, 13,15 suggesting that the ␣-defensins detected in CD8 ϩ T-cell culture supernatants were derived from contaminating neutrophils.…”

Section: Introductionmentioning

confidence: 99%

α-defensins block the early steps of HIV-1 infection: interference with the binding of gp120 to CD4

Furci¹,

Sironi²,

Tolazzi³

et al. 2006

Blood

102

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␣-defensins are antibiotic peptides that act as natural inhibitors of HIV-1 infection. However, the mechanisms of such inhibition are still unclear. Here we demonstrate that ␣-defensins block the earliest steps in the viral infectious cycle, as documented using an HIV-1 envelopemediated cell-fusion assay. A broad-spectrum inhibitory activity was observed on primary and laboratory-adapted HIV-1 isolates irrespective of their coreceptor specificity and genetic subtype. A primary mechanism of such inhibition was identified as the ability of ␣-defensins to bind specifically both to the primary HIV-1 cellular receptor, CD4, and to the viral envelope glycoprotein, gp120. Moreover, treatment of CD4 ؉ T cells with ␣-defensins caused a dramatic downmodulation of CD4 expression. By monoclonal antibody competition, the regions of interaction with ␣-defensins were mapped to the D1 domain of CD4 and to a surface contiguous to the CD4-and coreceptorbinding sites of gp120. Consistent with these findings, ␣-defensins inhibited the binding of gp120 to CD4. These data demonstrate that ␣-defensins specifically block the initial phase of the HIV infectious cycle and modulate the expression of CD4, a critical receptor in the physiology of T-cell activation. IntroductionEvidence suggests that a concerted action of innate and adaptive immune responses is essential for the effective containment and, ultimately, the clearance of invading microorganisms. 1 The innate immune system is phylogenetically more archaic and constitutes the first line of antimicrobial defense, characterized by a rapid response time; however, it is limited in its target specificity. By contrast, the adaptive immune system has evolved refined molecular devices for the recognition of a wide variety of specific epitopes, but a lag time is required for its functional activation. Once activated, most of the cells involved in both innate and cognate immune responses secrete soluble factors, including cytokines, chemokines, antibiotic peptides, and others, which can directly antagonize infectious microorganisms and/or contribute to the recruitment and activation of other immune cells, thereby amplifying the cascade of defense mechanisms and bolstering their effectiveness. 2,3 In HIV infection, various host-derived soluble factors with antiviral activity have been described, which act by both specific and nonspecific mechanisms. These include chemokines such as RANTES, MIP-1␣, and MIP-1␤ 4 ; cytokines such as the interferons, IL-10, IL-13, IL-16, transforming growth factor-␤, and others 5 ; as well as, more recently, defensins. [6][7][8][9] Defensins are natural antibiotic peptides that play an important role in innate immune responses by acting as broad-spectrum antibacterial, antifungal, and antiviral effector molecules 10 as well as by enhancing certain adaptive immune responses. 11 ␣-defensins 1 to 3 are 3-to 4-kDa cationic peptides (29 to 30 amino acids [aa]) characterized by a conserved 6-cysteine motif, with 3 disulfide bonds that impose a characteristic ␤-sheet ...

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Section: Introductionmentioning

confidence: 99%

α-defensins block the early steps of HIV-1 infection: interference with the binding of gp120 to CD4

Furci¹,

Sironi²,

Tolazzi³

et al. 2006

Blood

102

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“…Overall, defensins have broad antimicrobial activity against fungi, bacteria, and viruses although the individual antimicrobial spectrum differs (22,23). ␣-Defensins inhibits multiple enveloped viruses including herpes simplex virus, influenza virus, cytomegalovirus, rhabdovirus, and HIV-1 (23)(24)(25)(26). ␤-Defensins exhibit antiviral activity against herpes simplex virus, respiratory syncytial virus, vaccinia virus, and HIV-1 (27)(28)(29)(30).…”

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confidence: 99%

Human α-Defensins Inhibit BK Virus Infection by Aggregating Virions and Blocking Binding to Host Cells

Dugan

Maginnis

Jordan

et al. 2008

Journal of Biological Chemistry

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BK virus (BKV) is a polyomavirus that establishes a lifelong persistence in most humans and is a major impediment to success of kidney grafts. The function of the innate immune system in BKV infection and pathology has not been investigated. Here we examine the role of antimicrobial defensins in BKV infection of Vero cells. Our data show that ␣-defensin human neutrophil protein 1 (HNP1) and human ␣-defensin 5 (HD5) inhibit BKV infection by targeting an early event in the viral lifecycle. HD5 treatment of BKV reduced viral attachment to cells, whereas cellular treatment with HD5 did not. Colocalization studies indicated that HD5 interacts directly with BKV. Ultrastructural analysis revealed HD5-induced aggregation of virions. HD5 also inhibited infection of cells by other related polyomaviruses. This is the first study to demonstrate polyomavirus sensitivity to defensins. We also show a novel mechanism whereby HD5 binds to BKV leading to aggregation of virion particles preventing normal virus binding to the cell surface and uptake into cells.BK virus is a member of the polyomaviridae family. Polyomaviruses are small (40 -50 nm in diameter), non-enveloped, double-stranded DNA viruses that cause tumors in some species outside of their natural host range (1). BKV infects ϳ80 -90% of the human population and establishes a lifelong persistence within epithelial cells of the urinary tract (2, 3). Although BKV infection remains asymptomatic throughout the lifetime of most humans, immunocompromised individuals are susceptible to BKV-induced disease. Reactivation of BKV has been linked to hemorrhagic cystitis in bone marrow transplant recipients and is the etiological agent of polyomavirus-induced nephropathy (PVN), 2 a complication found in 5% of kidney transplant recipients (4, 5). In PVN, BKV induces interstitial nephritis resulting in graft destruction and leads to transplant failure in ϳ50% of diagnosed cases (6, 7). BKV reactivation causes a serious viral infection after renal transplantation and is a significant obstacle to the success of kidney grafts.The factors that contribute to BKV-induced disease are largely unknown. As only a subset of kidney transplant recipients develop PVN, this raises the question of what unique factors are present in these situations for pathogenesis to ensue? The factors that contribute to PVN likely comprise multiple conditions that involve the virus, the host, and the graft. Some risk factors for the development of PVN include male gender, older age, and higher number of HLA mismatches (7, 8). Epidemiological studies suggest that the most significant cofactor leading to PVN is the degree of immunosuppression. The rise in PVN diagnoses is directly correlated to the increased use of the more potent anti-rejection drugs, tacromilus and mycophenolate mofetil (9, 10). Currently, a reduction of immunosuppressive therapy is effectively used to decrease viral replication in PVN patients suggesting that a functional immune system is critical in controlling BKV replication and pathology (11). ...

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“…Levels were in the range of what has been reported as peak concentrations for chemotactic activity (10 2 -10 5 pg/ml) 33 and lower than those demonstrated to inhibit HIV-1 in vitro (MIC 50 : 0.28-2 × 10 8 pg/ml). 23,24 We found that women with detectable α-defensins had ~0.5 log 10 higher HIV-1 concentrations in breast milk than women with undetectable α-defensins. These observations are consistent with a recent report by Kuhn et al 22 and may be secondary to the chemoattractant properties of α-defensins.…”

Section: Discussionmentioning

confidence: 80%

“…15,21,22 Increasing evidence supports a role for α-defensins in inhibiting HIV-1 infection, [23][24][25][26][27][28] and several different mechanisms have been proposed, including direct activity on HIV-1 virions, inhibition of viral replication following HIV-1 entry into cells, and upregulation of CC chemokines. [25][26][27] A recent study among 23 HIV-1-infected infants suggested that increased α-defensins in breast milk collected at 1 week postpartum were associated with reduced risk of infant HIV-1 acquisition after adjusting for breast milk HIV-1 RNA.…”

Section: Introductionmentioning

confidence: 99%

Breast Milk α-Defensins Are Associated with HIV Type 1 RNA And CC Chemokines in Breast Milk But Not Vertical HIV Type 1 Transmission

Bosire

John‐Stewart

Mabuka

et al. 2007

AIDS Research and Human Retroviruses

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Abstractα-Defensins are proteins exhibiting in vitro anti-HIV-1 activity that may protect against motherto-child transmission of HIV-1 via breast milk. Correlates of α-defensins in breast milk and transmission risk were determined in a cohort of HIV-1-infected pregnant women in Nairobi followed for 12 months postpartum with their infants. Maternal blood was collected antenatally and at delivery for HIV-1 viral load and infant HIV-1 infection status was determined <48 h after birth and at months 1, 3, 6, 9, and 12. Breast milk specimens collected at month 1 were assayed for α-defensins, HIV-1 RNA, subclinical mastitis, and CC and CXC chemokines. We detected α-defensins in breast milk specimens from 108 (42%) of 260 HIV-1-infected women. Women with detectable α-defensins (≥50 pg/ml) had a median concentration of 320 pg/ml and significantly higher mean breast milk HIV-1 RNA levels than women with undetectable α-defensins (2.9 log 10 copies/ml versus 2.5 log 10 copies/ml, p = 0.003). Increased α-defensins concentrations in breast milk were also associated with subclinical mastitis (Na + /K + ratio > 1) and increased breast milk chemokine levels. Overall, 40 (15%) infants were HIV-1 uninfected at birth and subsequently acquired HIV-1. There was no significant association between month 1 α-defensins and risk of HIV-1 transmission. In conclusion, α-defensins were associated with breast milk HIV-1 viral load, chemokine levels, and subclinical mastitis, all of which may alter risk of infant HIV-1 acquisition. Despite these associations there was no significant relationship between breast milk α-defensins and mother-to-child transmission, suggesting a complex interplay between breast milk HIV-1, inflammation, and antiinfective factors.

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Defensins inhibit HIV replication in vitro

Cited by 119 publications

References 0 publications

α-defensins block the early steps of HIV-1 infection: interference with the binding of gp120 to CD4

α-defensins block the early steps of HIV-1 infection: interference with the binding of gp120 to CD4

Human α-Defensins Inhibit BK Virus Infection by Aggregating Virions and Blocking Binding to Host Cells

Breast Milk α-Defensins Are Associated with HIV Type 1 RNA And CC Chemokines in Breast Milk But Not Vertical HIV Type 1 Transmission

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