Antibody-Mediated Neutralization of Primary Human Immunodeficiency Virus Type 1 Isolates: Investigation of the Mechanism of Inhibition

Spenlehauer, Catherine; Kirn, A.; Aubertin, Anne-Marie; Moog, Christiane

doi:10.1128/jvi.75.5.2235-2245.2001

Cited by 28 publications

(33 citation statements)

References 55 publications

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“…The neutralization capacity of sera was lower for the HIV-1 R5 isolate and reached its plateau for most sera samples at dilution 1:80, whereas neutralizing titers for the HIV-1 X4 isolate were at 1:320 dilution with these sera. These data are in agreement with earlier observations that an HIV-1 isolate of X4 phenotype adapted for growth in T cell lines is more sensitive to neutralizing antibodies (41,42). Comparing neutralizing capacity of paired sera samples obtained from patients before and during HAART, the same pattern of decline was found as in the case of anti-HIV-1gp160 antibody detection by ELISA.…”

Section: Antibody Responses To Hiv-1 Structural Proteins and Glycoprosupporting

confidence: 81%

Persistence of HIV-1 structural proteins and glycoproteins in lymph nodes of patients under highly active antiretroviral therapy

Popovič

Tenner-Rácz

Pelser

et al. 2005

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

151

125

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Here we report a long-term persistence of HIV-1 structural proteins and glycoproteins in germinal centers (GCs) of lymph nodes (LNs) in the absence of detectable virus replication in patients under highly active antiretroviral therapy (HAART). The persistence of viral structural proteins and glycoproteins in GCs was accompanied by specific antibody responses to HIV-1. Seven patients during the chronic phase of HIV-1 infection were analyzed for the presence of the capsid protein (HIV-1p24), matrix protein (HIV-1p17), and envelope glycoproteins (HIV-1gp120͞gp41), as well as for viral RNA (vRNA) in biopsy specimens from LNs obtained before initiation of therapy and during HAART that lasted from 5 to 13 months. In parallel, these patients were also monitored for viremia and specific anti-HIV-1 antibody responses to structural proteins and glycoproteins both before and during treatment. Before-therapy viral levels, as determined by RT-PCR, ranged from 3 ؋ 10 3 to 6.3 ؋ 10 5 copies of vRNA per ml, whereas during treatment, vRNA was under detectable levels (<25 copies per ml). The pattern of vRNA detection in peripheral blood was concordant with in situ hybridization results of LN specimens. Before treatment, vRNA associated with follicular dendritic cells (FDCs) was readily detected in GCs of LNs of the patients, whereas during therapy, vRNA was consistently absent in the GCs of LN biopsies of treated patients. In contrast to vRNA hybridization results, viral structural proteins and glycoproteins, evaluated by immunohistochemical staining, were present and persisted in the GC light zone of LNs in abundant amounts not only before initiation of therapy but also during HAART, when no vRNA was detected in GCs. Consistent with immunohistochemical findings, specific antibody responses to HIV1p17, -p24, and -gp120͞gp41, as evaluated by ELISA and virus neutralization, persisted in patients under therapy for up to 13 months of follow-up. The implications of these findings are discussed in relation to HIV-1 persistence in infected individuals and the potential role of chronic antigenic stimulation by the deposited structural proteins in GCs for AIDS-associated B cell malignancies.

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Section: Antibody Responses To Hiv-1 Structural Proteins and Glycoprosupporting

confidence: 81%

Persistence of HIV-1 structural proteins and glycoproteins in lymph nodes of patients under highly active antiretroviral therapy

Popovič

Tenner-Rácz

Pelser

et al. 2005

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

151

125

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“…The selective nature of the phenomenon may indeed derive from the differential permissiveness of cells for adsorption of virus-Ab complexes. Inasmuch, even contradictory findings reported for the same virus-Ab-cell system may be explained by the specific experimental conditions applied, and hence, by the experimental definition of stable attachment (5,40). Nevertheless, since the large majority of virions in HIV preparations are noninfectious (ratios of infectious to physical particles range between 10 Ϫ3 and 10 Ϫ7 ), viral particle adsorption assays are limited in their capacities to reflect the behavior of the insignificant infection-relevant fraction (24,45).…”

Section: Discussionmentioning

confidence: 88%

“…While several studies have shown that addition of Ab to virus preparations reduces binding of viral particles to target cells, the effect is limited to specific cell and Ab types (5,7,28,33,40,43). The selective nature of the phenomenon may indeed derive from the differential permissiveness of cells for adsorption of virus-Ab complexes.…”

Section: Discussionmentioning

confidence: 99%

“…While several studies have shown that specific Abs may prevent virus attachment to certain cell types (5, 43), others have demonstrated that neutralization may be effected by interference with a postattachment step of infection (28,33,40). Indeed, several Abs have shown the capacity to neutralize virus that has already attached to the cell surface but has not yet entered the cytoplasm (2, 23).…”

mentioning

confidence: 99%

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Time Frames for Neutralization during the Human Immunodeficiency Virus Type 1 Entry Phase, as Monitored in Synchronously Infected Cell Cultures

Haim¹,

Steiner²,

Panet³

2007

J Virol

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Characterization of the neutralizing interaction between antibody and virus is hindered by the nonsynchronized progression of infection in cell cultures. Discrete steps of the viral entry sequence cannot be discerned, and thus, the mode of antibody-mediated interference with virus infectivity remains undefined. Here, we magnetically synchronize the motion and cell attachment of human immunodeficiency virus type 1 (HIV-1) to monitor the progression of neutralization, both in solution and following virus attachment to the cell. By simultaneous transfer of all viral particles from reaction solution with antibody to the cell-bound state, the precise rate of neutralization of cell-free virus could be determined for each antibody. HIV-1 neutralization by both monoclonal and polyclonal antibody preparations followed distinct pseudo-first-order kinetics. For all antibodies, cell types, and HIV-1 strains examined, postattachment interference served a major role in the neutralizing effect. To monitor the progression of postattachment interference, we synchronized the entry process at initiation and measured the escape of cell-bound virus from antibody. We found that different antibodies neutralized the virus over different time frames during the entry phase. Virus was observed to progress through a sequence of shifting sensitivities to different antibodies during entry, suggested here to correlate with the exposure time of the target epitope on receptor-activated viral envelope proteins. Thus, by monitoring the progression of HIV-1 entry under synchronized conditions, we identify a new and significant determinant of antibody neutralization capacity, namely, the time frames for neutralization during the course of the viral entry phase.It is commonly accepted that antibodies (Abs) neutralize viruses by binding to the virion surface (22, 34). Indeed, good correlation exists between neutralizing capacity and binding affinity of the Ab to the target epitope (35, 39). However, the mode of Ab-mediated interference with virus infectivity remains undefined, largely due to the limited ability to monitor the neutralizing interaction between virus and Ab, in solution or following virus attachment to the cell surface. The diffusionlimited nature of the virus-cell interaction is central to this shortcoming of current in vitro systems.Viruses in solution behave as charged colloidal masses. Their motion is controlled by diffusion (1, 32), and their attachment to cells is primarily determined by electrostatic interactions with the charged cell surface (12). It is these coupled stochastic processes of cell encounter and attachment that constitute the rate-limiting steps to infection of cells in culture (1,20). Cell attachment progresses continuously, and thus, infection is initiated asynchronously, precluding step-by-step monitoring of viral events that precede or follow the attachment step.The lack of synchrony has challenged attempts both to characterize the dynamics of the viral entry sequence and to determine the mechanism and precise ...

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“…Neutralization of HIV T-cell-line-adapted (TCLA) strains was shown to be mediated primarily by inhibition of virus-cell attachment when T-lymphocytic cell lines were used as targets (42,44). The mechanism of neutralization might be different for HIV type 1 (HIV-1) primary isolates (PIs), as contradictory results were reported concerning the exact stage of the viral cycle that is impaired by nAbs.…”

mentioning

confidence: 94%

Polyclonal Immunoglobulin G from Patients Neutralizes Human Immunodeficiency Virus Type 1 Primary Isolates by Binding Free Virions, but without Interfering with an Initial CD4-Independent Attachment of the Virus to Primary Blood Mononuclear Cells

Burrer

Haessig-Einius

Aubertin

et al. 2003

J Virol

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We investigated the relationship between human immunodeficiency virus type 1 (HIV-1) primary isolate (PI) antibody-mediated neutralization and attachment to primary blood mononuclear cells (PBMC). Incubation of PIs with immunoglobulin G (IgG) purified from infected patients did not inhibit attachment of the viruses with PBMC, but partial to complete neutralization was achieved. Neutralization of PIs already fixed on the cells was achieved by some IgG samples only and was of limited intensity compared to the former neutralization protocol. On the contrary, the binding of IgG to free virions was shown to be sufficient to reach potent neutralization, as the infectivity of IgG-PI complexes purified from the bulk of antibodies before addition to PBMC was strongly diminished compared to mock-treated controls. Monoclonal antibodies to the CDR2 domain of CD4 completely inhibited the infection of PBMC without interfering with the attachment of PIs to the cells, suggesting that, under these experimental conditions, the initial attachment of viruses to PBMC involves alternative cellular receptors. This initial interaction may also involve other components of the viral envelope than gp120, as partial depletion of the surface glycoproteins of primary viral particles that resulted in an almost complete loss of infectivity did not impair attachment to PBMC. A limited inhibition of attachment was observed when interfering with putative interactions with cellular heparan sulfate, whereas no effect was observed for cellular CD147 or nucleolin or for virion-incorporated cyclophilin A. Altogether, our results favor a mechanism of neutralization of HIV-1 PIs by polyclonal IgG where antibodies predominantly bind free virions and neutralize without interfering with the attachment to PBMC, which, in this model, is mainly CD4 independent.

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Antibody-Mediated Neutralization of Primary Human Immunodeficiency Virus Type 1 Isolates: Investigation of the Mechanism of Inhibition

Cited by 28 publications

References 55 publications

Persistence of HIV-1 structural proteins and glycoproteins in lymph nodes of patients under highly active antiretroviral therapy

Persistence of HIV-1 structural proteins and glycoproteins in lymph nodes of patients under highly active antiretroviral therapy

Time Frames for Neutralization during the Human Immunodeficiency Virus Type 1 Entry Phase, as Monitored in Synchronously Infected Cell Cultures

Polyclonal Immunoglobulin G from Patients Neutralizes Human Immunodeficiency Virus Type 1 Primary Isolates by Binding Free Virions, but without Interfering with an Initial CD4-Independent Attachment of the Virus to Primary Blood Mononuclear Cells

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