The overall goal of this proposal is to examine the relative fitness of SIV variants cloned from early and late stages of infection and to characterize the factors regulating infection and replication. Studies using the SIV macaque model have shown that viral burden and pathogenicity are influenced by the phenotype of the infecting virus and variants that evolve from it, and that increased pathogenicity correlates with greater viral replication capacity in T-cells. However, it is unclear whether increased pathogenicity necessarily equals greater overall fitness or if changes in pathogenicity may result in a fitness cost in terms of sexual transmission. We propose to test the hypothesis that the phenotoypic properties of SIV will influence its fitness, and therefore, infection and persistence in the host. We predict that upon infection, the capacity of a virus to infect T-cells and modulate and utilize cellular activation signals will influence replicative fitness, facilitating dissemination. However, increased replication in T-cells may not confer a fitness advantage during the establishment of infection after mucosal transmission. To test the hypothesis, we will further characterize the cellular and viral factors involved in regulating infection and replication of cloned SIVmne variants of known pathogenicity, and we will examine the relative fitness of the variants in the macaque host.
Three specific aims are proposed for these studies.
AIM1 : To examine the competitive replication fitness of SIVmne variants with distinct phenotypes. To examine the impact of macrophages and dendritic cells on competitive replication fitness.
AIM2 : To characterize the viral determinants that promote SIVmne replication in T-cells. Specifically, we plan to define the mechanism by which RT mutations increase viral infectivity, and to determine whether the RT infectivity determinant enhances nef expression in resting T-cells.
AIMS : To define the relative in vivo fitness of SIVmne variants. To examine the amplification and dissemination of SIVmne variants during dual-infection of pig-tailed macaques. The results of these studies may provide greater insight into the types of viruses that infect and predominate at early and late stages of infection, and the mechanisms that they use to infect and persist in the host. Furthermore, they may have important implications for the design of vaccine and therapeutic strategies against HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047725-11
Application #
7797662
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Sharma, Opendra K
Project Start
2000-04-15
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2012-03-31
Support Year
11
Fiscal Year
2010
Total Cost
$331,620
Indirect Cost
Name
Baylor College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Belshan, Michael; Kimata, Jason T; Brown, Charles et al. (2012) Vpx is critical for SIVmne infection of pigtail macaques. Retrovirology 9:32
Liu, Lihong; Wen, Michael; Wang, Weiming et al. (2011) Potent and broad anti-HIV-1 activity exhibited by a glycosyl-phosphatidylinositol-anchored peptide derived from the CDR H3 of broadly neutralizing antibody PG16. J Virol 85:8467-76
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Wen, Michael; Arora, Reetakshi; Wang, Huiqiang et al. (2010) GPI-anchored single chain Fv--an effective way to capture transiently-exposed neutralization epitopes on HIV-1 envelope spike. Retrovirology 7:79
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Biesinger, Tasha; Yu Kimata, Monica T; Kimata, Jason T (2008) Changes in simian immunodeficiency virus reverse transcriptase alleles that appear during infection of macaques enhance infectivity and replication in CD4+ T cells. Virology 370:184-93
Biggins, Julia E; Biesinger, Tasha; Yu Kimata, Monica T et al. (2007) ICAM-3 influences human immunodeficiency virus type 1 replication in CD4(+) T cells independent of DC-SIGN-mediated transmission. Virology 364:383-94

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