HIV is a rapidly evolving pathogen, which results in nearly unique viral genetic sequence in every infected patient. This rapid evolution complicates vaccine design and antiretroviral therapy. However, changes in the genetic sequence can also be used to reconstruct the transmission history of the virus. Phylogenetic approaches have proven useful for understanding the origins, diversification, and worldwide migration of HIV. However, the potential for molecular evolutionary analysis to be utilized for public health goals remains underappreciated and underexplored. Previous work on the nature of HIV transmission networks suggests that individuals in the most highly connected parts of the network have the greatest potential to transmit virus in the future. Methods. In this application, HIV sequences that were acquired during drug- resistance surveillance by the New York City Department of Health and Mental Hygiene (NYC-DOHMH) will be used to construct the HIV transmission network in New York City. By identifying infected individuals whose viral sequences are highly similar, potential transmission partners can be identified and linked to construct a transmission network. Simulations of intervention (antiretroviral treatment, therapeutic vaccination, pre- exposure prophylaxis [PrEP], etc), targeted at the most highly connected individuals across this network will be performed and compared to simulations of random antiretroviral intervention. The goal of these simulations is to identify network-informed targeted intervention strategies that could reduce the incidence of HIV infection. Additionally, simulated clinical preventive trials wil also be performed across the NYC-DOHMH network to develop network-informed metrics, methods, and protocols to test for reduced transmission in a clinical preventative trial. Finally, this same network construction approach will be applied to all publicly available HIV sequences to develop a surveillance tool which will allow other researchers to rapidly determine how their generated HIV sequences fit into the global HIV transmission network. Conclusions. These findings will demonstrate how HIV transmission networks can be used to guide effective treatment strategies, improve clinical trial design, and monitor the progression of the pandemic.

Public Health Relevance

This research project will (i) use evolutionary principles to guide HIV treatment and clinical trial design and (ii) develop web-based computer software to assist researchers in monitoring the progression of the HIV pandemic. This work will improve the efficacy of treatment, the scope of clinical trials, and HIV surveillance efforts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AI110181-05
Application #
9487838
Study Section
Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
Program Officer
Mckaig, Rosemary G
Project Start
2014-06-04
Project End
2019-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Bhardwaj, N; Ragonnet-Cronin, M; Murrell, B et al. (2018) Intrapatient viral diversity and treatment outcome in patients with genotype 3a hepatitis C virus infection on sofosbuvir-containing regimens. J Viral Hepat 25:344-353
Chaillon, Antoine; Gianella, Sara; Lada, Steven M et al. (2018) Size, Composition, and Evolution of HIV DNA Populations during Early Antiretroviral Therapy and Intensification with Maraviroc. J Virol 92:
Oster, Alexandra M; France, Anne Marie; Panneer, Nivedha et al. (2018) Identifying Clusters of Recent and Rapid HIV Transmission Through Analysis of Molecular Surveillance Data. J Acquir Immune Defic Syndr 79:543-550
Singh, Rajendra; Stoneham, Charlotte; Lim, Christopher et al. (2018) Phosphoserine acidic cluster motifs bind distinct basic regions on the ? subunits of clathrin adaptor protein complexes. J Biol Chem 293:15678-15690
Kosakovsky Pond, Sergei L; Weaver, Steven; Leigh Brown, Andrew J et al. (2018) HIV-TRACE (TRAnsmission Cluster Engine): a Tool for Large Scale Molecular Epidemiology of HIV-1 and Other Rapidly Evolving Pathogens. Mol Biol Evol 35:1812-1819
Valverde, Eduardo E; Oster, Alexandra M; Xu, Songli et al. (2017) HIV Transmission Dynamics Among Foreign-Born Persons in the United States. J Acquir Immune Defic Syndr 76:445-452
Bartlett, Sofia R; Wertheim, Joel O; Bull, Rowena A et al. (2017) A molecular transmission network of recent hepatitis C infection in people with and without HIV: Implications for targeted treatment strategies. J Viral Hepat 24:404-411
Forrester, Naomi L; Wertheim, Joel O; Dugan, Vivian G et al. (2017) Evolution and spread of Venezuelan equine encephalitis complex alphavirus in the Americas. PLoS Negl Trop Dis 11:e0005693
Rose, Rebecca; Lamers, Susanna L; Dollar, James J et al. (2017) Identifying Transmission Clusters with Cluster Picker and HIV-TRACE. AIDS Res Hum Retroviruses 33:211-218
Temereanca, Aura; Oprea, Cristiana; Wertheim, Joel O et al. (2017) HIV transmission clusters among injecting drug users in Romania. Rom Biotechnol Lett 22:12307-12315

Showing the most recent 10 out of 37 publications