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Joel N Blankson

Publications and source records attributed to Joel N Blankson.

10 recordsLinked to original sources
PubMed2006

Isolation and characterization of replication-competent human immunodeficiency virus type 1 from a subset of elite suppressors.

Elite suppressors (ES) are untreated human immunodeficiency virus type 1 (HIV-1)-infected individuals who control viremia to levels below the limit of detection of current assays. The mechanisms involved in this control have not been fully elucidated. Several studies have demonstrated that some ES are infected with defective viruses, but it remains unclear whether others are infected with replication-competent HIV-1. To answer this question, we used a sensitive coculture assay in an attempt to isolate replication-competent virus from a cohort of 10 ES. We successfully cultured six replication-competent isolates from 4 of the 10 ES. The frequency of latently infected cells in these patients was more than a log lower than that seen in patients on highly active antiretroviral therapy with undetectable viral loads. Full-length sequencing of all six isolates revealed no large deletions in any of the genes. A few mutations and small insertions and deletions were found in some isolates, but phenotypic analysis of the affected genes suggested that their function remained intact. Furthermore, all six isolates replicated as well as standard laboratory strains in vitro. The results suggest that some ES are infected with HIV-1 isolates that are fully replication competent and that long-term immunologic control of replication-competent HIV-1 is possible.

Base Sequence↗
PubMed2006

Maintenance of viral suppression in HIV-1-infected HLA-B*57+ elite suppressors despite CTL escape mutations.

Rare human immunodeficiency virus 1-infected individuals, termed elite suppressors (ES), maintain plasma virus levels of <50 copies/ml and normal CD4 counts without therapy. The major histocompatibility complex class I allele group human histocompatibility leukocyte antigen (HLA)-B*57 is overrepresented in this population. Mutations in HLA-B*57-restricted epitopes have been observed in ES, but their significance has remained unclear. Here we investigate the extent and impact of cytotoxic T lymphocyte (CTL) escape mutations in HLA-B*57+ ES. We provide the first direct evidence that most ES experience chronic low level viremia. Sequencing revealed a striking discordance between the genotypes of plasma virus and archived provirus in resting CD4+ T cells. Mutations in HLA-B*57-restricted Gag epitopes were present in all viruses from plasma but were rare in proviruses, suggesting powerful selective pressure acting at these epitopes. Surprisingly, strong CD8+ T cell interferon-gamma responses were detected against some mutant epitopes found in plasma virus, suggesting the development of de novo responses to viral variants. In some individuals, relative CD8+ T cell interleukin-2 responses showed better correlation with the selection observed in vivo. Thus, analysis of low level viremia reveals an unexpectedly high level of CTL escape mutations reflecting selective pressure acting at HLA-B*57-restricted epitopes in ES. Continued viral suppression probably reflects CTL responses against unmutated epitopes and residual or de novo responses against epitopes with escape mutations.

CD4 Lymphocyte Count↗
PubMed2006

Neutralizing antibodies do not mediate suppression of human immunodeficiency virus type 1 in elite suppressors or selection of plasma virus variants in patients on highly active antiretroviral therapy.

Neutralizing antibodies (NAb) against autologous virus can reach high titers in human immunodeficiency virus type 1 (HIV-1)-infected patients with progressive disease. Less is known about the role of NAb in HIV-1-infected patients with viral loads of <50 copies/ml of plasma, including patients on effective highly active antiretroviral therapy (HAART) and elite suppressors, who control HIV-1 replication without antiretroviral therapy. In this study, we analyzed full-length env sequences from plasma viruses and proviruses in resting CD4(+) T cells of HAART-treated patients, elite suppressors, and untreated HIV-1-infected patients with progressive disease. For each patient group, we assessed plasma virus neutralization by autologous, contemporaneous plasma. The degree of env diversity, the number of N-linked glycosylation sites, and the lengths of variable loops were all lower in elite suppressors than in HAART-treated and untreated viremic patients. Both elite suppressors and HAART-treated patients had lower titers of NAb against HIV-1 lab strains than those of untreated viremic patients. Surprisingly, titers of NAb against autologous, contemporaneous plasma viruses were similarly low in chronic progressors, elite suppressors, and HAART-treated patients. In elite suppressors and HAART-treated patients, titers of NAb against autologous plasma viruses also did not differ significantly from titers against autologous proviruses from resting CD4(+) T cells. These results suggest that high-titer NAb are not required for maintenance of viral suppression in elite suppressors and that NAb do not select plasma virus variants in most HAART-treated patients. Both drug-mediated and natural suppression of HIV-1 replication to levels below 50 copies/ml may limit the stimulation and maintenance of effective NAb responses.

Antiretroviral Therapy, Highly Active↗
PubMed2005

Primary HIV-1 infection: to treat or not to treat?

Treatment of primary HIV-1 infection with HAART may represent a unique opportunity to alter the course of this chronic disease. In spite of this, enthusiasm for the "ht early, hit hard" approach has waned over time, given the lack of data showing long-term clinical benefit. This article will examine the risks and benefits of starting HAART during acute HIV-1 disease.

Acute Disease↗
PubMed2004

Mechanisms of HIV-1 escape from immune responses and antiretroviral drugs.

Despite the fact that HIV-1 induces vigorous antiviral immune responses, viral replication is never completely controlled in infected individuals. Recent studies have provided insight into the mechanisms by which focused immune pressure directed at particular B or T cell epitopes leads to the rapid appearance of escape mutations. Even if anti-HIV-1 immune responses could be enhanced to the point where they inhibit viral replication to the same extent as certain combinations of antiretroviral drugs, eradication would be unlikely because of the persistence of the virus in an extremely stable latent reservoir in resting memory CD4(+) T cells.

Acquired Immunodeficiency Syndrome↗
PubMed2002

The challenge of viral reservoirs in HIV-1 infection.

A viral reservoir is a cell type or anatomical site in association with which a replication-competent form of the virus accumulates and persists with more stable kinetic properties than the main pool of actively replicating virus. This article reviews several cell types and anatomical sites proposed as potential reservoirs for HIV-1. It is now clear that HIV-1 persists in a small reservoir of latently infected resting memory CD4(+) T cells, which shows minimal decay even in patients on highly active antiretroviral therapy (HAART). The persistence of virus in this reservoir is consistent with the biology of these cells and the long-term persistence of immunologic memory. The viral replication that continues in patients on suppressive HAART may also contribute to the stability of this reservoir. There may be other reservoirs, but the latent reservoir in resting CD4(+) T cells appears to be sufficient to guarantee lifetime persistence of HIV-1 in the majority of patients on current HAART regimens, and unless new approaches are developed, eradication will not be possible. The clinical implications of this and other HIV-1 reservoirs are discussed.

Animals↗