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Evidence for a cytopathogenicity determinant in HIV-1 Vpr
Mohan Somasundaran1, Mark Sharkey, Beda Brichacek
1Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605, USA.
Insights
This study identifies a novel HIV-1 Vpr gene determinant linked to reduced T-lymphocyte damage. This finding suggests viral replication can occur without causing cell death, offering new insights into HIV pathogenesis.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Human Immunodeficiency Virus type 1 (HIV-1) typically causes CD4(+) T lymphocyte depletion, contributing to disease progression.
- Lymphocyte depletion generally correlates with viral load, with non-progressors maintaining stable counts despite viral replication.
Purpose of the Study:
- To investigate a non-progressor HIV-1 case where CD4(+) T lymphocyte homeostasis was maintained despite high viremia.
- To identify viral factors responsible for the lack of cytopathicity in this unique patient.
Main Methods:
- Analysis of biological HIV-1 isolates from the non-progressor patient.
- Examination of the viral protein R (Vpr) gene for mutations and functional effects.
- Introduction of patient-derived Vpr alleles into a cytopathic HIV-1 clone.
Main Results:
- HIV-1 isolates from the patient replicated without inducing T-lymphocyte cytopathicity.
- Patient-derived Vpr alleles, featuring premature stop codons and a Q3R polymorphism, significantly impaired viral cytopathicity.
- The Vpr-mediated reduction in cytopathicity correlated with its ability to induce host cell apoptosis, independent of other known Vpr functions.
Conclusions:
- HIV-1 Vpr contains a determinant of in vivo cytopathogenicity.
- Viral replication can be dissociated from cytopathicity, challenging previous assumptions in HIV pathogenesis.
- This discovery offers potential new avenues for therapeutic strategies targeting HIV-induced immune damage.
Abstract:
HIV-1 is cytopathic for CD4(+) T lymphocytes in vitro and this property of HIV-1 is generally considered to account for some of its in vivo cytopathogenicity. Thus, the extent of lymphocyte depletion correlates with the level of viremia whereas low levels of viral replication are typically associated with stable lymphocyte levels and asymptomatic infection such as is observed in non-progressors. Here, we describe a non-progressor who did not fit this general pattern in that CD4(+) T lymphocyte homeostasis was maintained in the face of high-level viral replication. Biological viral isolates from this patient replicated in primary lymphocytes without inducing cytopathicity. Because this phenotype is reminiscent of Vpr-deleted viruses, we examined the contribution of the Vpr gene to the viral phenotype. Vpr alleles derived from this patient contained both premature stop codons and an unusual Q3R polymorphism. Insertion of patient-derived Vpr alleles or a Q3R substitution into a cytopathic HIV-1 clone resulted in a marked impairment of cytopathicity without affecting viral replication efficiency. The effect of Vpr on cytopathicity was unrelated to reported activities of Vpr including virion association, interaction with uracil DNA glycosylase, G(2) arrest, or enhancement of macrophage infection but correlated with the ability of Vpr to induce host cell apoptosis. This study suggests the presence of a determinant of in vivo cytopathogenicity within HIV-1 Vpr and further indicates that viral replication can be uncoupled from cytopathicity in vitro and in vivo.