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Pathogenesis of primary R5 human immunodeficiency virus type 1 clones in SCID-hu mice
R M Scoggins1, J R Taylor, J Patrie
1Department of Microbiology and Myles H. Thaler Center for AIDS and Human Retrovirus Research, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, Virginia 22908, USA.
Abstract:
We studied the replication and cytopathicity in SCID-hu mice of R5 human immunodeficiency virus type 1 (HIV-1) biological clones from early and late stages of infection of three patients who never developed MT-2 cell syncytium-inducing (SI; R5X4 or X4) viruses. Several of the late-stage non-MT-2 cell syncytium-inducing (NSI; R5) viruses from these patients depleted human CD4(+) thymocytes from SCID-hu mice. Earlier clones from the same patients did not deplete CD4(+) thymocytes from SCID-hu mice as well as later clones. We studied three R5 HIV-1 clones from patient ACH142 in greater detail. Two of these clones were obtained prior to the onset of AIDS; the third was obtained following the AIDS diagnosis. In GHOST cell infection assays, all three ACH142 R5 HIV-1 clones could infect GHOST cells expressing CCR5 but not GHOST cells expressing any of nine other HIV coreceptors tested. Furthermore, these patient clones efficiently infected stimulated peripheral blood mononuclear cells from a normal donor but not those from a homozygous CCR5Delta32 individual. Statistical analyses of data obtained from infection of SCID-hu mice with patient ACH142 R5 clones revealed that only the AIDS-associated clone significantly depleted CD4(+) thymocytes from SCID-hu mice. This clone also replicated to higher levels in SCID-hu mice than the two earlier clones, and a significant correlation between viral replication and CD4(+) thymocyte depletion was observed. Our results indicate that an intrinsic property of AIDS-associated R5 patient clones causes their increased replication and cytopathic effects in SCID-hu mice and likely contributes to the development of AIDS in patients who harbor only R5 quasispecies of HIV-1.
Insights
Late-stage R5 human immunodeficiency virus type 1 (HIV-1) clones from AIDS patients show increased replication and CD4(+) thymocyte depletion in mice. This suggests intrinsic properties of these viruses contribute to AIDS progression in patients with R5-only HIV-1 infections.
Area of Science:
- Virology
- Immunology
- Pathogenesis
Background:
- Human immunodeficiency virus type 1 (HIV-1) infection progresses through stages, with viral properties potentially influencing disease severity.
- Syncytium-inducing (SI) and non-syncytium-inducing (NSI) viral phenotypes have been associated with different disease courses.
- The role of specific viral clones in the pathogenesis of acquired immunodeficiency syndrome (AIDS) in patients with R5-tropic HIV-1 requires further elucidation.
Purpose of the Study:
- To investigate the replication and cytopathic effects of R5 HIV-1 biological clones from different stages of infection in SCID-hu mice.
- To determine if late-stage, AIDS-associated R5 HIV-1 clones exhibit enhanced replication and CD4(+) thymocyte depletion compared to earlier clones.
- To explore the correlation between viral replication, cytopathicity, and disease progression in the context of R5-tropic HIV-1.
Main Methods:
- Isolation and characterization of R5 HIV-1 biological clones from early and late stages of infection in three patients.
- Infection of severe combined immunodeficient (SCID)-hu mice with HIV-1 clones to assess replication and CD4(+) thymocyte depletion.
- GHOST cell infection assays to evaluate coreceptor usage (CCR5) and infectivity of peripheral blood mononuclear cells (PBMCs).
Main Results:
- Late-stage, non-MT-2 cell syncytium-inducing (NSI; R5) HIV-1 clones from patients depleted CD4(+) thymocytes in SCID-hu mice more effectively than earlier clones.
- An AIDS-associated R5 HIV-1 clone from patient ACH142 significantly depleted CD4(+) thymocytes and replicated to higher levels in SCID-hu mice compared to pre-AIDS clones.
- A strong correlation was observed between viral replication levels and CD4(+) thymocyte depletion in SCID-hu mice infected with ACH142 R5 clones.
Conclusions:
- An intrinsic property of AIDS-associated R5 HIV-1 clones contributes to their increased replication and cytopathic effects in SCID-hu mice.
- These findings suggest that specific R5 HIV-1 clones can play a significant role in the pathogenesis of AIDS in patients harboring R5-tropic quasi-species.
- The study highlights the importance of viral characteristics in driving disease progression in HIV-1 infection.