The HIV-1 genome consists of only 9 genes and thus, depends highly on host cellular factors to replicate. Recent studies, through genome-wide siRNA screens, have identified many possible "HIV-1 dependency factors" HDFs. However, there lies a large inconsistency between these analyses and the majority of potential hits have not been verified in primary human target cells. Therefore, the goal of this proposal is to validat a recently identified possible HIV-1 Env-mediated host factor, Rab6A GTPase, in primary human monocyte-derived macrophages (MDMs) and define the mechanism by which this protein facilitates HIV-1 infection. Additionally, because Rab6A is ubiquitously expressed in two closely related isoforms, Rab6A and Rab6A', that have similar but distinct roles in the cell, both isoforms will be individually investigated. Similar to all GTPases, Rab6A(A/A') function is dependent on specific accessory proteins that allow cycling between active-GTP bound and inactive-GDP bound forms. We hypothesize that activated Rab6A(A/A') is required for efficient HIV-1 Env-mediated infection of MDMs and activation of Rab6A(A/A') is dependent on Ric1/Rgp1, a Rab6A(A/A')-specific guanine nucleotide-exchange factor, activity. We will utilize a pseudoviral single-round infection assay to define the mechanism by which Rab6A and Rab6A'facilitate HIV-1 replication in primary human macrophages. Our studies may reveal a novel therapeutic pathway to combat HIV-1/AIDS, as well as help dissect the fundamental biological role of Rab6A(A/A') in primary human macrophages.

Public Health Relevance

The success of this project will provide new information on the process of HIV-1 cellular entry, define the mechanism by which Rab6A(A/A'), a small Rab GTPase, regulates HIV-1 infection. Moreover, during these studies information on the fundamental roles of Rab6A(A/A') in primary human macrophages will also be generated. These investigations may reveal new drug targets that could lead to novel efficacious therapies to combat HIV-1 pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31AI110327-01A1
Application #
8732394
Study Section
Special Emphasis Panel (ZRG1-AARR-C (22))
Program Officer
Adger-Johnson, Diane S
Project Start
2014-01-27
Project End
2016-01-26
Budget Start
2014-01-27
Budget End
2015-01-26
Support Year
1
Fiscal Year
2014
Total Cost
$40,726
Indirect Cost
Name
Drexel University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104