Humoral immunity to HIV-1: kinetics of antibody responses in chronic infection reflects capacity of immune system to improve viral set point

Trkola, Alexandra

doi:10.1182/blood-2004-01-0251

Cited by 43 publications

(48 citation statements)

References 52 publications

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“…Plasma IgG titers to recombinant gp120 from the JR-FL strain (Progenics) and recombinant p24 (Aalto BioReagents) were determined by enzyme-linked immunosorbent assay as described previously (10,93). Bound antibody was detected using alkaline phosphatase-conjugated anti-human immunoglobulin G (Sigma) and the luminescence generating CPD-Star system (Applied Biosystems).…”

Section: Patients Patient Demographics Are Listed Inmentioning

confidence: 99%

Virus Isolates during Acute and Chronic Human Immunodeficiency Virus Type 1 Infection Show Distinct Patterns of Sensitivity to Entry Inhibitors

Rusert

Küster

Joos

et al. 2005

J Virol

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We studied the effect of entry inhibitors on 58 virus isolates derived during acute and chronic infection to validate these inhibitors in vitro and to probe whether viruses at early and chronic disease stages exhibit general differences in the interaction with entry receptors. We included members of all types of inhibitors currently identified: (i) agents that block gp120 binding to CD4 (CD4-IgG 2 and monoclonal antibody [MAb] IgG 1 b12), (ii) compounds that block the interaction with CCR5 (the chemokine RANTES/CCL5, the smallmolecule inhibitor AD101, and the anti-CCR5 antibody PRO 140), (iii) the fusion inhibitor enfuvirtide (T-20), and (iv) neutralizing antibodies directed against gp120 (MAb 2G12) and gp41 (MAbs 2F5 and 4E10). No differences between viruses from acute and chronic infections in the susceptibility to inhibitors targeting the CD4 binding site, CCR5, or fusion or to MAb 2G12 were apparent, rendering treatment with entry inhibitors feasible across disease stages. The notable exceptions were antibodies 2F5 and 4E10, which were more potent in inhibiting viruses from acute infection (P ‫؍‬ 0.0088 and 0.0005, respectively), although epitopes of these MAbs were equally well preserved in both groups. Activities of these MAbs correlated significantly with each other, suggesting that common features of the viral envelope modulate their potencies.Therapy of human immunodeficiency virus type 1 (HIV-1) infection with a combination of antiretrovirals inhibiting the viral enzymes reverse transcriptase and protease can significantly decrease HIV-related morbidity and mortality (49, 62). However, due to the toxicity of these drugs and the emergence of resistant viral variants, alternative treatment strategies are urgently needed (31,33,36). Entry of HIV-1 into target cells requires expression of the receptor CD4 and a fusion coreceptor, most commonly the chemokine receptors CCR5 and CXCR4 (19,66). The entry process proceeds via a cascade of events that provide multiple opportunities for therapeutic intervention, and several agents targeting this process have been developed over recent years. Considerable effort has been put into investigating the interaction of the virus with its entry receptors and the identification of potential antiretrovirals (66). Neutralizing antibodies were among the first agents identified which block viral entry. Direct antiviral activity is attributed to antibodies directed against specific epitopes on the envelope glycoproteins gp120 and gp41, which inhibit viral entry by blocking virion attachment to its receptors or membrane fusion (65). During natural infection the effect of the autologous neutralization response appears to be limited, since the virus rapidly escapes the immune pressure in most individuals (14,15,54,55,67,76,101). Nevertheless, rare potent monoclonal antibodies (MAbs) with broad activity have been isolated from infected individuals. These antibodies define four neutralization-sensitive epitopes within gp120 and gp41; they are characterized by the MAbs IgG 1 b12 (5,...

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Section: Patients Patient Demographics Are Listed Inmentioning

confidence: 99%

Virus Isolates during Acute and Chronic Human Immunodeficiency Virus Type 1 Infection Show Distinct Patterns of Sensitivity to Entry Inhibitors

Rusert

Küster

Joos

et al. 2005

J Virol

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“…The contribution of the various alleles to HIV-1 susceptibility has been described elsewhere (12,81,87). Determination of HLA genotypes was performed as reported (63,89).…”

Section: Viral Replication Kinetics In Vitro (I) Autologous Patient mentioning

confidence: 99%

“…Autologous plasma neutralization activity was evaluated in a PBMC-based assay using replication-competent patient isolates as described (89). Virus inoculum was incubated with serial dilutions of heat inactivated patient or control plasma for 1 h at 37°C.…”

Section: Viral Replication Kinetics In Vitro (I) Autologous Patient mentioning

confidence: 99%

“…Plasma immunoglobulin G (IgG) titers to recombinant glycoprotein 120 (gp120) from the JR-FL strain (provided by W. Olson, Progenics Pharmaceuticals, Tarrytown, NY) were determined by enzymelinked immunosorbent assay (ELISA) as described (7). Bound antibody was detected using alkaline phospatase-conjugated anti-human IgG (Sigma, St. Louis, MO) and the luminescence-generating CPD-Star system (Applied Biosystems, Rotkreuz, Switzerland) as described (89).…”

Section: Viral Replication Kinetics In Vitro (I) Autologous Patient mentioning

confidence: 99%

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Low Human Immunodeficiency Virus Envelope Diversity Correlates with Low In Vitro Replication Capacity and Predicts Spontaneous Control of Plasma Viremia after Treatment Interruptions

Joos

Trkola

Fischer

et al. 2005

J Virol

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Genetic diversity of viral isolates in human immunodeficiency virus (HIV)-infected individuals variessubstantially. However, it remains unclear whether HIV-related disease progresses more rapidly in patients harboring virus swarms with low or high diversity and, in the same context, whether high or low diversity is required to induce potent humoral and cellular immune responses. To explore whether viral diversity predicts virologic control, we studied HIV-infected patients who received antiretroviral therapy (ART) for years before undergoing structured treatment interruptions (STI). Viral diversity before initiation of ART and the ability of the patients to contain viremia after STI and final cessation of treatment was evaluated. Seven out of 21 patients contained plasma viremia at low levels after the final treatment cessation. Clonal sequences encompassing the envelope C2V3C3 domain derived from plasma prior to treatment, exhibited significantly lower diversity in these patients compared to those derived from patients with poor control of viremia. Viral diversity pre-ART correlated with the viral replication capacity of rebounding virus isolates during STI. Neutralizing antibody activity against autologous virus was significantly higher in patients who controlled viremia and was associated with lower pretreatment diversity. No such association was found with binding antibodies directed to gp120. In summary, lower pretreatment viral diversity was associated with spontaneous control of viremia, reduced viral replication capacity and higher neutralizing antibody titers, suggesting a link between viral diversity, replication capacity, and neutralizing antibody activity.

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“…C (Rosenberg et al 2000;Harari et al 2004) and B cells (Emini et al 1992;Mascola 2003;Trkola et al 2004). It is assumed that virus is cleared at a rate of cZ mð1K ð1K…”

Section: (D) Viral Replication and Infection Hiv Infects Cd4mentioning

confidence: 99%

The role of mutation accumulation in HIV progression

Galvani

2005

Proc. R. Soc. B.

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The onset of AIDS is characterized by the collapse of the immune system after a prolonged asymptomatic period. The mechanistic basis of this disease progression has remained obscure, hindering the development of effective therapies. Here I present a mechanism that underlies the deterioration of the immune system during HIV infection. The elevated turnover of lymphocytes throughout the asymptomatic period is postulated to result in the accumulation of deleterious mutations, which impairs immunological function, replicative ability and viability of lymphocytes. This mutational meltdown is proposed to occur throughout the hierarchy of lymphocyte progenitors, resulting in the deterioration of lymphocyte regeneration and an ensuing rise in viral loads. A mathematical model is used to illustrate this mechanism of progressive immunological deterioration. Mutation accumulation may explain not only the decline in CD4 C T cells, but also the functional deterioration of CD4 C T cells, CD8C T cells and B cells, and the exhaustion of lymphocyte regeneration.

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Humoral immunity to HIV-1: kinetics of antibody responses in chronic infection reflects capacity of immune system to improve viral set point

Cited by 43 publications

References 52 publications

Virus Isolates during Acute and Chronic Human Immunodeficiency Virus Type 1 Infection Show Distinct Patterns of Sensitivity to Entry Inhibitors

Virus Isolates during Acute and Chronic Human Immunodeficiency Virus Type 1 Infection Show Distinct Patterns of Sensitivity to Entry Inhibitors

Low Human Immunodeficiency Virus Envelope Diversity Correlates with Low In Vitro Replication Capacity and Predicts Spontaneous Control of Plasma Viremia after Treatment Interruptions

The role of mutation accumulation in HIV progression

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