Evaluation of Distinct Blood Lymphocyte Populations in Human Immunodeficiency Virus Type 1–Infected Subjects in the Absence or Presence of Effective Therapy

Abstract

Virus reservoirs can persist in human immunodeficiency virus type 1 (HIV-1)-infected subjects despite effective plasma virus suppression. To compare viral dynamics in the absence and presence of antiretroviral therapy, blood mononuclear cells from 19 subjects with high plasma RNA levels and 18 subjects following prolonged virus suppression were examined, by use of in situ hybridization, to detect virus RNA expression before and after in vitro T cell activation. This approach reveals circulating lymphocytes expressing HIV-1 RNA before activation and an increase in cells with detectable HIV-1 RNA transcription after in vitro activation. The frequencies of these 2 cell populations are strongly correlated with plasma virus load and appear to be stable once a new steady state is established during therapy. The frequency of viral RNA-positive cells is equivalent to the frequency of cells that produce infectious virus. Thus, in HIV-1-infected subjects there are distinct virus reservoirs comprising both latent and replication-active cells.

Sensitivity of Human Immunodeficiency Virus Type 1 to the Fusion Inhibitor T-20 Is Modulated by Coreceptor Specificity Defined by the V3 Loop of gp120

“…Heavily pretreated patients with advanced disease that harbor X4 viruses may experience additional benefits from treatment regimens containing T-20. Second, administration of T-20 as part of an antiretroviral regimen in patients with early disease might delay the emergence of more pathogenic strains of HIV-1 that are associated with CXCR4 specificity if viral replication is not completely suppressed (9,12,16,58). Our data also suggest that R5 viruses may be able to generate resistance more rapidly than X4 viruses in vivo in the presence of suboptimal doses of T-20, since R5 viruses remain infectious at higher concentrations of T-20 in vitro.…”

Human Immunodeficiency Virus Type 1 (HIV-1) Antigen Secretion by Latently Infected Resting CD4 + T Lymphocytes from HIV-1-Infected Individuals

“…Moreover, it is important to quantify the rare HIV-1 DNA-infected cells which are able to sustain a viral cycle leading to the production of HIV-1 viral proteins and virions. To this end, the enumeration of these cells was recently estimated by the detection of spliced and multispliced HIV-1 mRNAs (13,20) and by an HIV-1-Ag ELISPOT assay, which is based on the detection of HIV-1-AgSCs induced by strong in vitro CD4…”

“…On the other hand, integrated forms of HIV-1 DNA can be detected in highly purified resting CD4 ϩ T cells by the inverse PCR method, and typically less than 0.01% of resting CD4 ϩ T cells carry integrated HIV-1 DNA (5,7,18,33). Since it is necessary to quantify resting CD4 ϩ T cells able to produce HIV-1 antigens (HIV-1-Ag), different approaches have been developed to detect HIV-1 mRNAs, such as in situ hybridization (13,21) and a recently described reverse transcriptase PCR method, which affords possibilities of detecting unspliced and spliced HIV-1 mRNAs (20). These observations suggest that HIV-1 DNA-positive resting CD4…”

Zidovudine, Lamivudine, and Abacavir Have Different Effects on Resting Cells Infected with Human Immunodeficiency Virus In Vitro

“…The success of highly active antiretroviral therapy in reducing circulating HIV in plasma to levels below the limit of detection in many infected individuals has encouraged investigators to initiate studies aimed at eradicating HIV. However, replication-competent HIV has been isolated from infected individuals after prolonged treatment with highly active antiretroviral therapy (7-11, 16, 17, 23, 30, 37, 43, 45), and several studies have demonstrated that resting CD4 ϩ T cells are a long-lived latent reservoir of the virus (4,6,9,10,14,16,23,38,46). The virus may remain viable in nonproducing resting cells in a latent form either as integrated (8,9,11,14,16,18,30,38) or preintegrated DNA with the ability to integrate into host DNA after cell activation (4,6,8,9,18,38,39,44).…”