Antisense-Derived HIV-1 Cryptic Epitopes Are Not Major Drivers of Viral Evolution during the Acute Phase of Infection.
Peng BJ., Carlson JM., Liu MKP., Gao F., Goonetilleke N., McMichael AJ., Borrow P., Gilmour J., Heath SL., Hunter E., Bansal A., Goepfert PA.
While prior studies have demonstrated that CD8 T cell responses to cryptic epitopes (CE) are readily detectable during HIV-1 infection, their ability to drive escape mutations following acute infection is unknown. We predicted 66 CE in a Zambian acute infection cohort based on escape mutations occurring within or near the putatively predicted HLA-I restricted epitope. The CE were evaluated for CD8 T cell responses in patients with chronic and acute HIV infection. Of the 66 predicted CE, 10 were recognized in 8/32 and 4/11 patients with chronic, and acute infection respectively. The immunogenic CE were all derived from a single antisense reading frame within pol However, when these CE were tested using longitudinal study samples, CE specific T cell responses were detected but did not consistently select for viral escapes. Thus, while we demonstrated that CE are immunogenic in acute infection, the immune responses to CE are not major drivers of viral escape in the initial stages of HIV infection. This latter finding may be due to either the subdominant nature of CE-specific responses, the low antigen sensitivity, and magnitude of CE responses during acute infections.IMPORTANCE Although prior studies demonstrated that cryptic epitopes of HIV-1 induce CD8 T cell responses, evidence supporting that targeting these epitopes to drive HIV escape mutations have been substantially limited and none have addressed this question following acute infection. In this comprehensive study, we utilized longitudinal viral sequencing data obtained from three separate acute infection cohorts to predict potential cryptic epitopes based on HLA-I associated viral escape. Our data shows that cryptic epitopes are immunogenic during acute infection and many of these responses are elicited towards translation products of HIV-1 antisense reading frames. However, despite cryptic epitope targeting, our study did not find any evidence of early CD8 mediated immune escape. Nevertheless, improving cryptic epitope specific CD8 T cell responses may still be beneficial in both preventative and therapeutic HIV-1 vaccines.