Frequent recombination contributes significantly to the diversity of the HIV-1 population. We have studied multiple aspects of HIV-1 recombination, including the mechanisms that generate intersubtype recombinants, which are playing an increasingly important role in the current AIDS epidemic. By comparing intra- and intersubtype HIV-1 recombination, we have found that the sequence diversity between different HIV-1 subtypes decreases the crossover events and reduces the replication fitness of the recombinants, thereby causing the loss of newly generated chimeric viruses. Additionally, the dimerization initiation signal (DIS), a 6-nt palindromic sequence in the 5'untranslated region of the viral genome, affects the HIV-1 recombination frequency by two separate mechanisms: first, the identity of the DIS affects the generation of recombinants between genotypes with different DIS by dictating the frequency of viral RNA copackaging;second, discordant DIS sequences in the copackaged RNAs can further decrease crossovers at the 5'end of the viral genome and generate a recombination gradient. As HIV-1 is thought to be a recombinant generated from two distinct primate lentiviruses, we also studied recombination between different AIDS viruses. We demonstrated that recombination can occur between distantly related HIV-1 and HIV-2, as well as group O and group M HIV-1 variants, albeit at low rates. These studies revealed insights into the recombination mechanisms that generate diversity in the HIV-1 genome and potentially novel chimeric viruses. Our efforts in this project are focused on critical steps of reverse transcription including minus-strand DNA transfer and how host restriction factors can affect HIV replication. We are also studying recombination between subtype A viruses and mechanisms that cause a loss of replication fitness in newly generated recombinants. These studies will reveal insights into the replication mechanisms of HIV-1. [Corresponds to Hu Project 1 in the October 2011 site visit report of the HIV Drug Resistance Program]

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010504-11
Application #
8763121
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2013
Total Cost
$262,808
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Delviks-Frankenberry, Krista A; Nikolaitchik, Olga A; Burdick, Ryan C et al. (2016) Minimal Contribution of APOBEC3-Induced G-to-A Hypermutation to HIV-1 Recombination and Genetic Variation. PLoS Pathog 12:e1005646
Shunaeva, Anastasia; Potashnikova, Daria; Pichugin, Alexey et al. (2015) Improvement of HIV-1 and Human T Cell Lymphotropic Virus Type 1 Replication-Dependent Vectors via Optimization of Reporter Gene Reconstitution and Modification with Intronic Short Hairpin RNA. J Virol 89:10591-601
Nikolaitchik, Olga; Keele, Brandon; Gorelick, Robert et al. (2015) High recombination potential of subtype A HIV-1. Virology 484:334-40
Sato, Kei; Takeuchi, Junko S; Misawa, Naoko et al. (2014) APOBEC3D and APOBEC3F potently promote HIV-1 diversification and evolution in humanized mouse model. PLoS Pathog 10:e1004453
Burdick, Ryan C; Hu, Wei-Shau; Pathak, Vinay K (2013) Nuclear import of APOBEC3F-labeled HIV-1 preintegration complexes. Proc Natl Acad Sci U S A 110:E4780-9
Chaipan, Chawaree; Smith, Jessica L; Hu, Wei-Shau et al. (2013) APOBEC3G restricts HIV-1 to a greater extent than APOBEC3F and APOBEC3DE in human primary CD4+ T cells and macrophages. J Virol 87:444-53
Izumi, Taisuke; Burdick, Ryan; Shigemi, Mayu et al. (2013) Mov10 and APOBEC3G localization to processing bodies is not required for virion incorporation and antiviral activity. J Virol 87:11047-62
Hu, Wei-Shau; Hughes, Stephen H (2012) HIV-1 reverse transcription. Cold Spring Harb Perspect Med 2:
Cingöz, Oya; Paprotka, Tobias; Delviks-Frankenberry, Krista A et al. (2012) Characterization, mapping, and distribution of the two XMRV parental proviruses. J Virol 86:328-38
Josefsson, Lina; King, Martin S; Makitalo, Barbro et al. (2011) Majority of CD4+ T cells from peripheral blood of HIV-1-infected individuals contain only one HIV DNA molecule. Proc Natl Acad Sci U S A 108:11199-204

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