Dynamics of spontaneous HIV-1 specific and non-specific B-cell responses in patients receiving antiretroviral therapy

Fournier, Anne-Marie; Baillat, Vincent; Alix‐Panabières, Catherine; Fondere, Jean-Michel; Merle, Corinne; Segondy, Michel; Huguet, Marie-France; Reynes, Jacques; Vendrell, Jean-Pierre

doi:10.1097/00002030-200209060-00007

Cited by 29 publications

(32 citation statements)

References 22 publications

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“…Despite effective elimination of viremia, the immune system in a number of patients is not fully recovered to normal, and there is a discrepancy between the rapid decline of circulating Ig-secreting cells and a slow decline of IgG in the sera of patients during therapy. Patients successfully treated with anti-HIV-1 drugs generate specific antibodies to HIV-1 in the absence of detectable vRNA, suggesting persistent immune system activation by retention of HIV-1 antigens over long periods (19,21). Based on these observations, Morris et al (50) postulated that production of polyclonal IgG molecules in some compartment that is not in equilibrium with other components of the immune system is sustained for some time.…”

Section: Discussionmentioning

confidence: 99%

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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.

152

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: Discussionmentioning

confidence: 99%

“…As a result, CD4ϩT cell counts increase, T cell activation decreases, and antigen-specific and nonspecific T cell function improves (13)(14)(15)(16)(17)(18). Similarly, B cell responses are normalized, although this reversal of profound alteration of immune system is a slow and incomplete process in a number of long-term treated patients (19)(20)(21)(22).…”

mentioning

confidence: 99%

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.

152

125

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“…The B cells of HIV-infected patients spontaneously secrete Ig but are unable to mount a T cell-dependent B cell response (1,9,10). Antiretroviral therapy decreases HIV-1-driven B cell hyperactivity, polyclonal B cell activation, and Ig production in patients (11). These findings strongly suggest that the sustained replication of HIV-1 affects differentiation in lymphoid tissue.…”

Section: H Uman Immunodeficiency Virus-1 Infection Is Associatedmentioning

confidence: 97%

HIV Type 1 Glycoprotein 120 Inhibits Human B Cell Chemotaxis to CXC Chemokine Ligand (CXCL) 12, CC Chemokine Ligand (CCL)20, and CCL21

Badr

Borhis

Treton

et al. 2005

The Journal of Immunology

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We analyzed the modulation of human B cell chemotaxis by the gp120 proteins of various HIV-1 strains. X4 and X4/R5 gp120 inhibited B cell chemotaxis toward CXCL12, CCL20, and CCL21 by 40–50%, whereas R5 gp120 decreased inhibition by 20%. This gp120-induced inhibition was strictly dependent on CXCR4 or CCR5 and lipid rafts but not on CD4 or VH3-expressing BCR. Inhibition did not impair the expression or ligand-induced internalization of CCR6 and CCR7. Our data suggest that gp120/CXCR4 and gp120/CCR5 interactions lead to the cross-desensitization of CCR6 and CCR7 because gp120 does not bind CCR6 and CCR7. Unlike CXCL12, gp120 did not induce the activation of phospholipase Cβ3 and PI3K downstream from CXCR4, whereas p38 MAPK activation was observed. Similar results were obtained if gp120-treated cells were triggered by CCL21 and CCL20. Our results are consistent with a blockade restricted to signaling pathways using phosphatidylinositol-4,5-bisphosphate as a substrate. X4 and X4/R5 gp120 induced the cleavage of CD62 ligand by a mechanism dependent on matrix metalloproteinase 1 and 3, CD4, CXCR4, Gαi, and p38 MAPK, whereas R5 gp120 did not. X4 and X4/R5 gp120 also induced the relocalization of cytoplasmic CD95 to the membrane and a 23% increase in CD95-mediated apoptosis. No such effects were observed with R5 gp120. The gp120-induced decrease in B cell chemotaxis and CD62 ligand expression, and increase in CD95-mediated B cell apoptosis probably have major deleterious effects on B cell responsiveness during HIV infection and in vaccination trials.

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“…After HAART has reduced viremia to undetectable levels, have so far been less than successful. During successful HAART, a decline in antibody response is generally observed (Fournier et al 2002, Devito et al 2006, with cases of seroreversion being described (Amor et al 2006) and the extent of immune reconstitution in HAART treated individuals is controversial, apparently depending on the immune status of the individuals at the start of therapy (Cheonis et al 2005). However, the benefits of HAART are evident even when treatment apparently fails, leading neither to a complete control of viremia nor to a complete reconstitution in CD4 T lymphocytes (Brígido et al 2004, Kovacs et al 2005).…”

Section: Highly Active Antiretroviral Treatment (Haart) Of Human Immumentioning

confidence: 99%

Anti-human immunodeficiency virus type 1 humoral immune response and highly active antiretroviral treatment

Bongertz

Ouverney

Fernandez

et al. 2007

Mem. Inst. Oswaldo Cruz

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Highly active antiretroviral treatment (HAART) of human immunodeficiency type 1 (HIV-1) infection is very effective in controlling infection, but elimination of viral infection has not been achieved as yet, and upon treatment interruption an immediate rebound of viremia is observed. A combination of HAART with an immune stimulation might allow treatment interruption without this rebounding viremia, as the very low viremias observed with successful HAART may be insufficient to permit maintenance of a specific anti-HIV-1 immune response. The objective of this study was to compare the humoral immune response of individuals undergoing successful HAART (NF=no failure) with that of individuals with evidence of failure of therapy (FT) and to verify if the viremia peaks observed in individuals with therapy failure would act as a specific stimulus for the humoral anti-HIV-1 immune response. Antibodies binding to gp120 V3 genotype consensus peptides were more frequently observed for FT, mainly against peptides corresponding to sequences of genotypes prevalent in the Rio de Janeiro city area, B and F. HIV-1 neutralization of HIV-1 IIIB and of four primary isolates from Rio de Janeiro was less frequently observed for plasma from the NF than the FT group, but this difference was more expressive when plasma from individuals with detectable viremia were compared to that of individuals with undetectable viral loads in the year before sample collection. Although statistically significant differences were observed only in some specific comparisons, the study indicates that presence of detectable viremia may contribute to the maintenance of a specific anti-HIV-1 humoral immune response.Key words: antibodies -seroreactivity -neutralization -antiretroviral treatment -treatment failure Anti-HIV highly active antiretroviral treatment (HAART) reduces HIV in peripheral blood and reverts the characteristic immunodeficiency, and has benefited patients increasing individual survival at least 13-14 years (Vermund et al. 2006). However, no elimination of viral infection has been achieved, and the antiretroviral drugs will probably have to be taken throughout the life of the patient. Attempts to stimulate a potent specific anti-HIV-1 immune response to permit control of viral replication. After HAART has reduced viremia to undetectable levels, have so far been less than successful. During successful HAART, a decline in antibody response is generally observed (Fournier et al. 2002, Devito et al. 2006, with cases of seroreversion being described (Amor et al. 2006) and the extent of immune reconstitution in HAART treated individuals is controversial, apparently depending on the immune status of the individuals at the start of therapy (Cheonis et al. 2005). However, the benefits of HAART are evident even when treatment apparently fails, leading neither to a complete control of viremia nor to a complete reconstitution in CD4 T lymphocytes (Brígido et al. 2004, Kovacs et al. 2005).During successful anti-HIV therapy, a reduction in virus specific ce...

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Dynamics of spontaneous HIV-1 specific and non-specific B-cell responses in patients receiving antiretroviral therapy

Cited by 29 publications

References 22 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

HIV Type 1 Glycoprotein 120 Inhibits Human B Cell Chemotaxis to CXC Chemokine Ligand (CXCL) 12, CC Chemokine Ligand (CCL)20, and CCL21

Anti-human immunodeficiency virus type 1 humoral immune response and highly active antiretroviral treatment

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