Investigation of the role of VIF in the HIV-1 life cycle / Nathan Clay Gaddis.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Gaddis, Nathan Clay.

Contributor:

Malim, Michael H., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Cell and Molecular Biology.

Academic Dissertations as Topic.

Medical Subjects:

Cell and Molecular Biology.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Physical Description:

x, 163 pages : illustrations ; 29 cm

Production:

2002.

Summary:

The Vif protein of human immunodeficiency virus type 1 (HIV-1) is required for replication in primary T lymphocytes, some T-cell lines, and most likely in vivo. Evidence suggests that Vif acts late in the viral life cycle to enhance the infectivity of progeny virions. Virions produced in the absence of Vif are blocked at a post-entry, pre-integration step during infection of new target cells. The primary aim of this dissertation is to clarify the mechanism by which Vif promotes HIV-1 infectivity. In the first set of experiments, we sought to determine why Vif is required for in vitro replication in certain cells (non-permissive cells), but not others (permissive cells). Measurement of the infectivity of vif-deficient virions produced by heterokaryons between permissive and non-permissive cells demonstrated that the non-permissive phenotype is dominant, suggesting that non-permissive cells harbor an activity that inhibits HIV-1 in the absence of Vif. Therefore, Vif appears to enhance HIV-1 infectivity by suppressing this host antiviral activity. In the next section, we investigated whether the transmission of some primate lentiviruses to humans might be inhibited by an inability of their Vif proteins to counteract the human antiviral factor(s). Consistent with this possibility, a number of Vif proteins derived from primate lentiviruses lacking known human counterparts failed to complement vif-deficient HIV-1 in non-permissive cells. However, not only did some of these Vif proteins enhance the infectivity of their cognate viruses in non-permissive human cells, but also some of their parent viruses replicated in the absence of Vif, indicating that Vif is probably not a barrier to transmission in many instances. The apparent virus-specific activity of Vif also indicates that interactions with viral components may be important for Vif function. In the final section, we attempted to characterize the molecular defect in virions produced in the absence of Vif expression. However, aside from lacking the Vif protein itself, vif-deficient virions were compositionally and functionally indistinguishable from wild type virions in the assays we employed. Overall, these findings suggest that Vif enhances infectivity by interacting with both host and viral factors to prevent a subtle host-mediated alteration of virions.

Notes:

Supervisor: Michael H. Malim.

Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 2002.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 3072999.

OCLC:

244972846