Identification of Ongoing Human Immunodeficiency Virus Type 1 (HIV-1) Replication in Residual Viremia During Recombinant HIV-1 Poxvirus Immunizations in Patients With Clinically Undetectable Viral Loads on Durable Suppressive Highly Active Antiretroviral Therapy

J Virol. 2009 Oct;83(19):9731-42. doi: 10.1128/JVI.00570-09. Epub 2009 Jul 15.

Abstract

In most human immunodeficiency virus type 1 (HIV-1)-infected individuals who achieve viral loads of <50 copies/ml during highly active antiretroviral therapy (HAART), low levels of plasma virus remain detectable for years by ultrasensitive methods. The relative contributions of ongoing virus replication and virus production from HIV-1 reservoirs to persistent low-level viremia during HAART remain controversial. HIV-1 vaccination of HAART-treated individuals provides a model for examining low-level viremia, as immunizations may facilitate virus replication and sequence evolution. In a phase 1 trial of modified vaccinia virus Ankara/fowlpox virus-based HIV-1 vaccines in 20 HIV-infected young adults receiving HAART, we assessed the prevalence of low-level viremia and sequence evolution, using ultrasensitive viral load (<6.5 copies/ml) and genotyping (five-copy sensitivity) assays. Viral evolution, consisting of new drug resistance mutations and novel amino acid changes within a relevant HLA-restricted allele (e.g., methionine, isoleucine, glutamine, or arginine for leucine at position 205 of RT), was found in 1 and 3 of 20 subjects, respectively. Sequence evolution was significantly correlated with levels of viremia of between 6.5 and <50 copies/ml (P = 0.03) and was more likely to occur within epitopes presented by relevant HLA alleles (P < 0.001). These findings suggest that ongoing virus replication contributes to low-level viremia in patients on HAART and that this ongoing replication is subject to CD8(+) T-cell selective pressures.

Trial registration: ClinicalTrials.gov NCT00107549.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Anti-Retroviral Agents / pharmacology*
  • Antiretroviral Therapy, Highly Active
  • CD4-Positive T-Lymphocytes / virology
  • CD8-Positive T-Lymphocytes / virology
  • Cohort Studies
  • Female
  • Genotype
  • HIV Infections / drug therapy
  • HIV Infections / virology*
  • HIV-1 / metabolism*
  • Humans
  • Immunization
  • Male
  • Poxviridae / genetics*
  • Sequence Analysis, DNA

Substances

  • Anti-Retroviral Agents

Associated data

  • ClinicalTrials.gov/NCT00107549