HIV-1 viral variation and HIV-1 transmission. As a lentivirus, HIV-1 has a tremendous proven capacity for variation. However, despite this evident capacity, the effect of specific viral properties on risk of transmission is not well understood. Previous studies of HIV-1 heterosexual transmission have permitted characterization of important risk factors for HIV-1 transmission such as the transmitting partner's HIV-1 plasma RNA[2]^ GUD[3,4] and curable STI (e.g.,'syphilis, gonorrhea, chlamydia and trichomonas)[5] and lack of male circumcision[6,8]. If specific viral sequence characteristics can also be clearly documented to modify risk of HIV-1 transmission, HIV-1 vaccine development could focus on targeting host immune responses to these virus characteristics. Furthermore, if modifiable factors are associated with increased likelihood that an HIV-1 infected partner will generate more transmissible variants, prevention interventions can be focused to target those modifiable factors to reduce the risk of generating transmissible variants. 3.2 Synopsis of current knowledge about characteristics of transmitted HIV-1 variant(s). Early studies of HIV-1 variation in relation to mother-to-child[9] and sexual transmission [10,11] suggested that HIV-1 subtype B seroconverters have less diverse HIV-1 pools compared to their transmitting partners, and that transmitted variants are often closely related to virus variants present in low frequency in the transmitting partner's plasma. However, in a study of 32 heterosexual African women and 10 heterosexual African men evaluated a median of 59 and 65 days, respectively, after subtype A and D HIV-1 RNA detection, viral diversity assessed by heteroduplex mobility assay (HMA) revealed multiple HIV-1 variants present in 20/32 women while only a single variant was found in each of 10/10 men (p=0.001). These data suggest that the infected partner gender and/or virus subtype modify characteristics of the founder variant[12]. Further evidence that viral characteristics may influence transmissibility came subsequently from analysis of multiple plasma- and PBMC-derived HlV-1 subtype C env clones isolated within 3-4 months of HIV-1 seroconversion from both partners of 8 initially HIV-1 serodiscordant Zambian heterosexual couples. HIV-1 env sequence data suggested transmission or fulminate outgrowth of one founder virus in each of the 8 seroconverters (including male-to-female and female-to-male transmissions). Transmitted variants often had HIV-1 envelope glycoproteins more likely to be neutralization-sensitive, lower frequency of PNLGS and shorter variable regions compared to variants present in the original infected transmitting partne[13]. The importance of both the shorter variable regions and increased frequency of PNLGS in the envelope glycoprotein was corroborated in a study of plasma derived from 23 Kenyan women infected with HIV-1 subtype A[14]. A study of 13 HIV-1 subtype D transmitting serodiscordant couples also supports the association of transmissibility with shorter env variable lengths, but did not find an association with PNLGS[15]. The impact of these viral characteristics on transmission of subtype B variants has not been clearly defined, but to date the same distinctions have not beeen found[16,17]. Recently, two studies sequenced a large number of plasma-derived variants from individuals newly infected with HIV-1 subtype B (n= 102;only 20% admitted homosexual contacts)[18] and subtype C (n=69;all claimed to be heterosexuals)" viruses at various times after infection. Among the 171 individuals evaluated in these two studies, 109 (64%) were assessed during Fiebig stage l-IV (estimated to be <30 days post-infection). These studies reported that in 77% of newly infected individuals, virus populations were homogeneous in phylogenetic analysis, while in 23% multiple variants were detected. Similar results were obtained from a study of 37 MSM infected with HlV-1 subtype B who were assessed while in Fiebig stages I and ll [20]. While these frequencies of homogeneous and heterogeneous founder infection were interpreted as being independent of subtype, transmission route and gender of the infected person, these studies had limited behavioral and clinical data on which to characterize risk factors for homogenous and heterogeneous infection[18,19]. Furthermore, since only the seroconverting partners were assessed in these studies, they were unable to infer the characteristics of the infected partners'viral pool. As many transmissions are thought to occur when the TP is newly infected[21], these potentially acute-stage TP are unlikely to be capable of transmitting multiple founder variants.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI057005-08
Application #
8379839
Study Section
Special Emphasis Panel (ZCA1-GRB-T)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
8
Fiscal Year
2012
Total Cost
$605,162
Indirect Cost
$146,902
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Hu, Xintao; Valentin, Antonio; Dayton, Frances et al. (2016) DNA Prime-Boost Vaccine Regimen To Increase Breadth, Magnitude, and Cytotoxicity of the Cellular Immune Responses to Subdominant Gag Epitopes of Simian Immunodeficiency Virus and HIV. J Immunol 197:3999-4013
Johnston, Christine; Harrington, Robert; Jain, Rupali et al. (2016) Safety and Efficacy of Combination Antiretroviral Therapy in Human Immunodeficiency Virus-Infected Adults Undergoing Autologous or Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies. Biol Blood Marrow Transplant 22:149-56
Ma, Qing; Vaida, Florin; Wong, Jenna et al. (2016) Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients. J Neurovirol 22:170-8
Mothe, Beatriz; Hu, Xintao; Llano, Anuska et al. (2015) A human immune data-informed vaccine concept elicits strong and broad T-cell specificities associated with HIV-1 control in mice and macaques. J Transl Med 13:60
Iyer, Shyamala; Casey, Eleanor; Bouzek, Heather et al. (2015) Comparison of Major and Minor Viral SNPs Identified through Single Template Sequencing and Pyrosequencing in Acute HIV-1 Infection. PLoS One 10:e0135903
Manocheewa, Siriphan; Mittler, John E; Samudrala, Ram et al. (2015) Composite Sequence-Structure Stability Models as Screening Tools for Identifying Vulnerable Targets for HIV Drug and Vaccine Development. Viruses 7:5718-35
Manocheewa, Siriphan; Lanxon-Cookson, Erinn C; Liu, Yi et al. (2015) Pairwise growth competition assay for determining the replication fitness of human immunodeficiency viruses. J Vis Exp :e52610
Stekler, Joanne D; McKernan, Jennifer; Milne, Ross et al. (2015) Lack of resistance to integrase inhibitors among antiretroviral-naive subjects with primary HIV-1 infection, 2007-2013. Antivir Ther 20:77-80
Sunshine, Justine E; Larsen, Brendan B; Maust, Brandon et al. (2015) Fitness-Balanced Escape Determines Resolution of Dynamic Founder Virus Escape Processes in HIV-1 Infection. J Virol 89:10303-18
Maenza, Janine; Tapia, Kenneth; Holte, Sarah et al. (2015) How often does treatment of primary HIV lead to post-treatment control? Antivir Ther 20:855-63

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