Although crystallographic studies have provided a detailed description of the conserved core structure of the HIV-1 surface glycoprotein (gp120), much less is known about the structure and function of the first two hyper-variable regions (VIV2), which protrude from the core surface and often undergo extensive insertions and deletions over the course of disease. Elimination of glycosylation sites or deletion of amino acid residues from the VIV2 domain can influence a number of molecular interactions that are critical to virus entry. However, such studies may not fully describe the natural functions of V1V2, and few studies have comprehensively examined the consequences of natural variability within the V1V2 region during virus transmission or disease progression. Here we will define the structure-function relationships of naturally occurring V1V2 regions as they pertain to heterosexual transmission and virus evolution in Env molecules derived from a large heterosexual couple cohort in Zambia. Our preliminary studies demonstrated that a homogeneous virus population with compact length and restricted N-linked glycosylation in VIV2 were found in the recipient partners of eight heterosexual transmission pairs; however, the viral quasispecies of each donor partner contained up to nine different VIV2 variants, ranging as much as 3-fold in size and 9-fold in the number of glycosylation sites. These data suggest that the molecular determinants of heterosexual transmission are related to the structure of V1V2, and V1V2-chimeric Envs will be constructed from five !transmission pairs and utilized to define this relationship. To better understand the extensive variation that emerges in VIV2 following the acute infection period, the course of sequence evolution in VIV2 will be followed in longitudinal samples collected over a minimum of three years from ten newly identified seroconvertors in the same cohort. We will construct V1V2-chimeric Env molecules to investigate the ,biological consequences of temporal changes within the VIV2 region during infection. Through these studies, we will test the hypotheses that viruses with compact V1V2 regions establish infection and that progressive increases in length and glycosylation arise over the course of infection that contribute to immune evasion and replication fitness, but interfere with virus transmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI058706-02
Application #
6924406
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Young, Janet M
Project Start
2004-03-01
Project End
2008-02-29
Budget Start
2004-08-01
Budget End
2005-02-28
Support Year
2
Fiscal Year
2004
Total Cost
$197,166
Indirect Cost
Name
Emory University
Department
Pathology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Kasturi, Sudhir Pai; Kozlowski, Pamela A; Nakaya, Helder I et al. (2017) Adjuvanting a Simian Immunodeficiency Virus Vaccine with Toll-Like Receptor Ligands Encapsulated in Nanoparticles Induces Persistent Antibody Responses and Enhanced Protection in TRIM5? Restrictive Macaques. J Virol 91:
Smith, S Abigail; Kilgore, Katie M; Kasturi, Sudhir Pai et al. (2016) Signatures in Simian Immunodeficiency Virus SIVsmE660 Envelope gp120 Are Associated with Mucosal Transmission but Not Vaccination Breakthrough in Rhesus Macaques. J Virol 90:1880-7
Cartwright, Emily K; Spicer, Lori; Smith, S Abigail et al. (2016) CD8(+) Lymphocytes Are Required for Maintaining Viral Suppression in SIV-Infected Macaques Treated with Short-Term Antiretroviral Therapy. Immunity 45:656-668
Gu, Linlin; Krendelchtchikova, Valentina; Krendelchtchikov, Alexandre et al. (2016) Adenoviral vectors elicit humoral immunity against variable loop 2 of clade C HIV-1 gp120 via ""Antigen Capsid-Incorporation"" strategy. Virology 487:75-84
Smith, S Abigail; Derdeyn, Cynthia A (2015) A pathway to HIV-1 neutralization breadth. Nat Med 21:1246-7
Peters, Paul J; Gonzalez-Perez, Maria Paz; Musich, Thomas et al. (2015) Infection of ectocervical tissue and universal targeting of T-cells mediated by primary non-macrophage-tropic and highly macrophage-tropic HIV-1 R5 envelopes. Retrovirology 12:48
Burton, Samantha L; Kilgore, Katie M; Smith, S Abigail et al. (2015) Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses. Proc Natl Acad Sci U S A 112:10780-5
Kilgore, Katie M; Murphy, Megan K; Burton, Samantha L et al. (2015) Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope. J Virol 89:8130-51
Musich, Thomas; O'Connell, Olivia; Gonzalez-Perez, Maria Paz et al. (2015) HIV-1 non-macrophage-tropic R5 envelope glycoproteins are not more tropic for entry into primary CD4+ T-cells than envelopes highly adapted for macrophages. Retrovirology 12:25
Yue, Ling; Pfafferott, Katja J; Baalwa, Joshua et al. (2015) Transmitted virus fitness and host T cell responses collectively define divergent infection outcomes in two HIV-1 recipients. PLoS Pathog 11:e1004565

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