The persistence of HIV-1 infection is the result of many factors, including rapid viral evolution to evade immunity, the establishment of reservoirs of both latent and cryptically replicating virus, and damage to the immune system caused directly or indirectly by virus replication. Our understanding of each of these factors remains inadequate to fully explain HIV-1 persistence and pathogenesis. The studies proposed will describe a previously unknown pathway of HIV-1 replication we have discovered that likely contributes to HIV-1 adaptation, to the establishment of viral reservoirs, and to pathogenesis. As a retrovirus, integration of HIV-1 DNA into the cellular chromosome is necessary for productive infection. Interestingly, 90-99% of HIV-1 DNA in vivo and in vitro remains unintegrated and by itself is unable to generate sufficient RNA and proteins to make new virions. However, our published studies reveal that in a productively infected cell, uDNA is complemented by the integrated provirus and completes its replication cycle. In other words, uDNA contributes to the replicating virus population and magnifies the amount of multiple infection. The result is an increased effective virus population size, abundant interactions among potentially divergent viruses, and enhanced virus evolution through recombination and mutation. This novel mechanism for HIV-1 replication is distinct from pre-integration latency and does not depend on subsequent integration by the uDNA. New preliminary data indicate the HIV-1 can superinfect cells and bypass integration, resulting in accelerated viral replication, an important parameter of viral fitness. We hypothesize that uDNA exerts a strong influence on viral evolution, persistence and pathogenesis. Owing to the high stability of circular forms of uDNA in non-proliferating cells, we hypothesize that uDNA constitutes a long-lived reservoir of virus whose replication is restored by productive reinfection of the host cell. Through a combination of experimental and analytical approaches, the following specific aims will test these hypotheses.
Aim 1. What is the contribution of uDNA to the replicating virus population? Aim 2. Test the hypothesis that uDNA can function as a reservoir of latent viruses in T cells and macrophages.
Aim 3. Examine the influence of uDNA on HIV-1 replication kinetics.
Aim 4. Develop descriptive and predictive mathematical models of uDNA's contribution to HIV-1 replication and diversification to explore our main hypothesis.
Understanding how HIV-1 evolves is critically important if we are to develop vaccines and improve upon the currently available antiviral drug treatments. Up to now it has been thought that 99% of the viruses in the body which fail to reach the host cell's chromosomes are lost, but we have found that through a novel pathway of replication, these viruses can reproduce and help HIV-1 evolve. This project will describe this new form of HIV-1 replication an its impact on HIV-1 evolution and pathogenesis.
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|Miles, Brodie; Miller, Shannon M; Folkvord, Joy M et al. (2016) Follicular Regulatory CD8 T Cells Impair the Germinal Center Response in SIV and Ex Vivo HIV Infection. PLoS Pathog 12:e1005924|
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|Thierry, Sylvain; Munir, Soundasse; Thierry, EloÃ¯se et al. (2015) Integrase inhibitor reversal dynamics indicate unintegrated HIV-1 dna initiate de novo integration. Retrovirology 12:24|
|Lau, John Wei; Levy, David N; Wodarz, Dominik (2015) Contribution of HIV-1 genomes that do not integrate to the basic reproductive ratio of the virus. J Theor Biol 367:222-9|
|Haas, Michelle K; Levy, David N; Folkvord, Joy M et al. (2015) Distinct patterns of Bcl-2 expression occur in R5- and X4-tropic HIV-1-producing lymphoid tissue cells infected ex vivo. AIDS Res Hum Retroviruses 31:298-304|
|Galloway, Nicole L K; Doitsh, Gilad; Monroe, Kathryn M et al. (2015) Cell-to-Cell Transmission of HIV-1 Is Required to Trigger Pyroptotic Death of Lymphoid-Tissue-Derived CD4 T Cells. Cell Rep 12:1555-63|
|DeMaster, Laura K; Liu, Xiaohe; VanBelzen, D Jake et al. (2015) A Subset of CD4/CD8 Double-Negative T Cells Expresses HIV Proteins in Patients on Antiretroviral Therapy. J Virol 90:2165-79|
|Miles, Brodie; Miller, Shannon M; Folkvord, Joy M et al. (2015) Follicular regulatory T cells impair follicular T helper cells in HIV and SIV infection. Nat Commun 6:8608|
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