1. Adaptation to HLA-associated immune pressure over the course of HIV infection and in circulating HIV-1 strains.
- Author
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Alves, Eric, Al-Kaabi, Marwah, Keane, Niamh M., Leary, Shay, Almeida, Coral-Ann M., Deshpande, Pooja, Currenti, Jennifer, Chopra, Abha, Smith, Rita, Castley, Alison, Mallal, Simon, Kalams, Spyros A., Gaudieri, Silvana, and John, Mina
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HIV infections ,CYTOTOXIC T cells ,T cells ,HLA histocompatibility antigens ,DIAGNOSIS of HIV infections ,HIV ,CELLULAR immunity - Abstract
Adaptation to human leukocyte antigen (HLA)-associated immune pressure represents a major driver of human immunodeficiency virus (HIV) evolution at both the individual and population level. To date, there has been limited exploration of the impact of the initial cellular immune response in driving viral adaptation, the dynamics of these changes during infection and their effect on circulating transmitting viruses at the population level. Capturing detailed virological and immunological data from acute and early HIV infection is challenging as this commonly precedes the diagnosis of HIV infection, potentially by many years. In addition, rapid initiation of antiretroviral treatment following a diagnosis is the standard of care, and central to global efforts towards HIV elimination. Yet, acute untreated infection is the critical period in which the diversity of proviral reservoirs is first established within individuals, and associated with greater risk of onward transmissions in a population. Characterizing the viral adaptations evident in the earliest phases of infection, coinciding with the initial cellular immune responses is therefore relevant to understanding which changes are of greatest impact to HIV evolution at the population level. In this study, we utilized three separate cohorts to examine the initial CD8
+ T cell immune response to HIV (cross-sectional acute infection cohort), track HIV evolution in response to CD8+ T cell-mediated immunity over time (longitudinal chronic infection cohort) and translate the impact of HLA-driven HIV evolution to the population level (cross-sectional HIV sequence data spanning 30 years). Using next generation viral sequencing and enzyme-linked immunospot interferon-gamma recall responses to peptides representing HLA class I-specific HIV T cell targets, we observed that CD8+ T cell responses can select viral adaptations prior to full antibody seroconversion. Using the longitudinal cohort, we uncover that viral adaptations have the propensity to be retained over time in a non-selective immune environment, which reflects the increasing proportion of pre-adapted HIV strains within the Western Australian population over an approximate 30-year period. Author summary: Human immunodeficiency virus (HIV) utilizes numerous mechanisms to evade the host's immune response, including the selection of specific polymorphisms, termed viral adaptations, which can alter recognition and elimination by cytotoxic T-lymphocytes (CTLs). This study utilized three unique treatment-naïve cohorts to characterize the initial CTL response to HIV, track the dynamics of viral adaptation during early infection, and examine how viral adaptations shape the circulating stains within one population over decades of time. Using an acute HIV-infected cohort, we applied genetic and cellular assays to identify evidence of anti-HIV CTL immune responses prior to antibody seroconversion providing an early selection environment. In the longitudinally-sampled chronic cohort, we identify viral adaptations already evident by the first year of infection that do not revert, and are stably retained over time. Finally, we present evidence for viral adaptations accumulating in the circulating strains of the Western Australian population over a thirty year period. [ABSTRACT FROM AUTHOR]- Published
- 2022
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