Background/Rationale: Human lymphocyte antigen (HLA)-restricted cytotoxic T lymphocytes (CTL) target HIVinfected cells expressing cognate HlV-1 epitopes. Numerous studies have examined the dynamics of CTL response and escape mutations following acute infection and disease progression. CTL escape mutations are typically associated with a fitness """"""""cost"""""""", inferred by the reversion of these mutations in absence of CTL selection pressure. It is important to note that multiple factors may contribute to in vivo fitness but fitness """"""""cost"""""""" is typically defined as a decrease in replicative capacity within target cells. Thus, this """"""""cost"""""""" is often ascribed to (DTL escape mutafions due to their absence in the CTL-suscepfible or """"""""wild type"""""""" sequence but few studies have actually empirically examined replicative fitness of HIV-1 escape variants. During the current grant period we accessed the costs of CTL escape mutations on replicative fitness of the infecting HIV-1 isolate. In general, we observed that in a subject's HIV-1 population, CTL escape mutations impart different fitness costs. CTL escape mutations in Gag emerged later in infection and were associated with higher fitness costs than the CTL escape mutations selected in Env (go to article)^. These pilot studies involved HlV-1 sequence and IFN-y ELISpot analyses to first identify 19 escape and compensatory mutafions that emerged in two epitopes encoded by gag and five in env during infection of SEAPIP subject 1362 (PIC1362)^?. Each of the 19 mutafions was then individually introduced into the autologous HlV-1 gag and env genes from the founder virus. Fitness analyses were performed using direct competitions between the chimeric viruses, which harbored the subject gag or env genes with or without the CTL escape mutafions. This is the most comprehensive analysis to date that examined the interplay between CTL response, selection of escape variants, and the associated fitness costs. The findings were quite striking in that 8/9 CTL escape mutations in env were either neutral or resulted in a fitness increase, rather than any loss in replicative capacity^. Based on our inifial findings, we have structured this renewal proposal to first compare the cost of CTL escape mutafions in more conserved versus more heterogeneous HIV-1 coding regions throughout the genome (AIM 1). We propose that low genefic diversity and limited functional plasficity within HlV-1 coding regions will slow the appearance of CTL escape mutafions due to higher fitness costs. Even in the same epitope under the same HLA-restriction, divergent HIV-1 isolates often take distinct evolutionary pathways towards different CTL escape mutations. Thus, In AIM 2, we will explore how specific CTL escape mutations in an HLA A3, A25, B27, and B57-restricted p24 epitopes affect replicative fitness of a virus derived from the autologous capsid (CA) p24 sequence, heterologous p24 sequence (but from a subject sharing the same restricfing HLA allele), and of a laboratory strain. Again, preliminary data would suggest a minimal fitness impact in the autologous versus heterologous background and emphasize the need to study these CTL escape mutations in the native context. Given the protective effects of B57 and B27 HLA alleles, we will also assessed whether CTL escape mutations confer higher fitness costs in unique B57- or B27-specific epitopes. Our preliminary studies on drug resistant and CTL escape mutafions suggest that the enfire HIV-1 genome evolves to compensate for any fitness loss. For this reason, fitness costs are often over-emphasized when analyzed in a heterologous HIV-1 background.
In AIM 3, we examine how a loss in replicative fitness conferred by CTL escape mutations will be compensated by mutations within the targeted gene and throughout the genome. Specifically, we have found that the HIV-1 env gene and the efficiency of host cell entry is dominant over all other HIV-1 genes and replicafion steps in determining fitness^. In fact, we found that many drug resistant HIV-1 isolates maintain high replicative fitness by increasing the efficiency of host cell entry to compensate for a loss in protease (PR) or reverse transcriptase (RT) activity. The same scenario may exist with CTL escape mutafions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI057005-06A2
Application #
7854611
Study Section
Special Emphasis Panel (ZCA1-GRB-T (01))
Project Start
2010-07-15
Project End
2015-06-30
Budget Start
2009-12-01
Budget End
2011-06-30
Support Year
6
Fiscal Year
2010
Total Cost
$387,847
Indirect Cost
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Patel, Rena C; Baeten, Jared M; Heffron, Renee et al. (2017) Brief Report: Hormonal Contraception Is Not Associated With Reduced ART Effectiveness Among Women Initiating ART: Evidence From Longitudinal Data. J Acquir Immune Defic Syndr 75:91-96
Obermeit, Lisa C; Beltran, Jessica; Casaletto, Kaitlin B et al. (2017) Evaluating the accuracy of self-report for the diagnosis of HIV-associated neurocognitive disorder (HAND): defining ""symptomatic"" versus ""asymptomatic"" HAND. J Neurovirol 23:67-78
Hu, Xintao; Valentin, Antonio; Rosati, Margherita et al. (2017) HIV Env conserved element DNA vaccine alters immunodominance in macaques. Hum Vaccin Immunother 13:2859-2871
Fife, Kenneth H; Mugwanya, Kenneth; Thomas, Katherine K et al. (2016) Transient Increase in Herpes Simplex Virus Type 2 (HSV-2)-Associated Genital Ulcers Following Initiation of Antiretroviral Therapy in HIV/HSV-2-Coinfected Individuals. J Infect Dis 213:1573-8
Smith, Kellie N; Mailliard, Robbie B; Piazza, Paolo A et al. (2016) Effective Cytotoxic T Lymphocyte Targeting of Persistent HIV-1 during Antiretroviral Therapy Requires Priming of Naive CD8+ T Cells. MBio 7:
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
Collier, Ann C; Chun, Tae-Wook; Maenza, Janine et al. (2016) A Pilot Study of Raltegravir Plus Combination Antiretroviral Therapy in Early Human Immunodeficiency Virus Infection: Challenges and Lessons Learned. Biores Open Access 5:15-21
Magaret, Amalia S; Mujugira, Andrew; Hughes, James P et al. (2016) Effect of Condom Use on Per-act HSV-2 Transmission Risk in HIV-1, HSV-2-discordant Couples. Clin Infect Dis 62:456-61
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

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