The clinical impact of IHIV-1 variant evolution and the special cases of dual- and super-infection have significant implications for understanding AIDS pathogenesis, virus transmission, and vaccine development. Dual infection can occur as a result of co-infection, wherein acquisition of two HIV-1 viral strains occurs during primary infection, or superinfection, wherein a second viral strain infects sometime after primary infection. Both forms of transmission are now well-documented, although the timing and frequency of each, and their impact on disease progression remain poorly understood. Our recent studies of a small cohort of seroconcordant sexual partners suggest that superinfection is extremely frequent. We propose in this continuing application to follow up our preliminary findings, expanding our studies of the virology of HIV-1 Infection and the impact of host genotype on disease outcome, Including exploration of the host genes we have recently implicated in contributing to the rate of disease progression. In addition, we are broadening our studies to examine the differential impact ofthe humoral and cellular immune responses on viral evolution, immunological escape, and dual infection. Specifically, we propose to address the following specific aims and linked hypotheses using genetic, virologic, immunological and bioinformatics methodologies:
Aim la-b) Determine the frequency of primary versus superinfection, and of X4 variant evolution during the progression to AIDS in the MACS.
Aim I c) Assess anti HIV-1 neutralizing Ab and CTL responses In individuals with mono and dual HIV-1 infection.
Aim 2) Determine the evolutionary and functional changes in Env that accompany transmission as a function of viral genetic subtype, route of transmission and gender of the recipient.
Aim 3) Biologically validate and investigate our set of novel AIDS restriction genes.

Public Health Relevance

The proposed studies are a continuation of our efforts to define the molecular events leading up to the development of AIDS. The expected benefits from our research include: 1) increasing our basic understanding of the infection and disease process, 2) developing new tools for optimizing the timing of antiretroviral therapy, and 3) understanding ofthe requirements for blocking reinfection, and 4) evaluation of the relative role of cellular and humoral immune responses in driving immunological escape in HIV during infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI047734-15
Application #
8639440
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Huebner, Robin E
Project Start
2000-04-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
15
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195
Nakamura, Kyle J; Heath, Laura; Sobrera, Edwin R et al. (2017) Breast milk and in utero transmission of HIV-1 select for envelope variants with unique molecular signatures. Retrovirology 14:6
Dapp, Michael J; Kober, Kord M; Chen, Lennie et al. (2017) Patterns and rates of viral evolution in HIV-1 subtype B infected females and males. PLoS One 12:e0182443
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
Liu, Yi; Rao, Ushnal; McClure, Jan et al. (2014) Impact of mutations in highly conserved amino acids of the HIV-1 Gag-p24 and Env-gp120 proteins on viral replication in different genetic backgrounds. PLoS One 9:e94240
Kahle, Erin; Campbell, Mary; Lingappa, Jairam et al. (2014) HIV-1 subtype C is not associated with higher risk of heterosexual HIV-1 transmission: a multinational study among HIV-1 serodiscordant couples. AIDS 28:235-43
Moroni, Marco; Ghezzi, Silvia; Baroli, Paolo et al. (2014) Spontaneous control of HIV-1 viremia in a subject with protective HLA-B plus HLA-C alleles and HLA-C associated single nucleotide polymorphisms. J Transl Med 12:335
Castro, Erika; Zhao, Hong; Cavassini, Matthias et al. (2014) HIV-1 superinfection with a triple-class drug-resistant strain in a patient successfully controlled with antiretroviral treatment. AIDS 28:1840-4
Herbeck, Joshua T; Mittler, John E; Gottlieb, Geoffrey S et al. (2014) An HIV epidemic model based on viral load dynamics: value in assessing empirical trends in HIV virulence and community viral load. PLoS Comput Biol 10:e1003673
Liu, Yi; Holte, Sarah; Rao, Ushnal et al. (2013) A sensitive real-time PCR based assay to estimate the impact of amino acid substitutions on the competitive replication fitness of human immunodeficiency virus type 1 in cell culture. J Virol Methods 189:157-66
McLaren, Paul J; Coulonges, Cédric; Ripke, Stephan et al. (2013) Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls. PLoS Pathog 9:e1003515

Showing the most recent 10 out of 51 publications