Sex Differences in HIV-1 Pathogenesis: Role of Steroid Hormones and Type I Interferon in CD4+ T Cell Activation and Viral Control 公开
El-Badry, Elina (Summer 2020)
Abstract
Sex differences play a role in the pathogenesis of a number of viral diseases. To date, the preponderance of data on the influence of sex in HIV-1 infection has been limited to the chronic phase of disease, and little is known about how sex differences influence acute HIV-1 infection. We have observed profound differences in viral load (VL) and CD4+ T cell activation from the earliest time-points in men and women in a Zambian heterosexual acute infection cohort. Women exhibited a more than two-fold higher rate of CD4+ T cell loss despite significantly lower VL than men. The importance of studying acute infection was highlighted by the observation that very early in infection, women exhibited significantly higher levels of CD4+ T cell activation, a difference that was lost over the first 3 years of infection as activation in men increased. In women, activation of CD4+ T cells in the acute phase was significantly correlated to plasma levels of 17β-estradiol (E2). E2 level in early infection was also associated with lower early and set-point VL in women, and was able to significantly restrict HIV-1 replication in vitro. In order to better understand the mechanism behind these observations, we compared gene expression between CD4+ T cells from acutely HIV-1 infected men and women. We have identified a set of genes that are both more highly expressed in women and negatively correlated with VL, indicating that they may play a role in the comparative control of VL observed in women. This gene set is significantly enriched for type I interferon (IFN) signaling genes including IRF7, DDX58, SAMHD1, OAS2, and TRIM14.
Table of Contents
Abstract
Acknowledgements
Chapter I: Introduction…………………………………………………………………………….1
Current Status of the HIV/AIDS Epidemic…………………………………………………1
Pathogenic Mechanisms of HIV-1 Infection………………………………………………3
HIV/AIDS in Women………………………………………………...……………….……6
Sex and the Immune System…………………………………...………………………….12
Sex Differences in the Immune Response to HIV-1 Infection…………………………….18
References………………………………………………………...……………………...24
Chapter II: Better viral control despite higher CD4+ T cell activation during acute HIV-1 infection in Zambian women is linked to the sex hormone estradiol...…………………… ………………48
Abstract………………………………………………...………………………………...49
Introduction………………………………………………...…………………………….50
Results………………………………………………...………………………………….52
Discussion………………………………………………...……………………………...57
Materials and Methods……………………………………………...…………………....61
Figures and Tables…………………………………...…………………………………..66
References…………………………………...……………………………………...……73
Chapter III: Heightened expression of type I interferon signaling genes in CD4+ T cells from acutely HIV-1 infected women contributes to lower viral loads…………………...……………..81
Abstract………………………………………………...………………………………...82
Introduction………………………………………………...…………………………….83
Results……………………………………………………………………………………85
Discussion………………………………………………...……………………………...89
Materials and Methods…………………………………………………………………..93
Figures and Tables……………………………………...……………………………….96
References…………………………………...………………………………………….103
Chapter IV: Discussion…………………………………………...…………………………….110
Significance…………………………………………...………………………………...110
Future Directions…………………………………………...…………………………..116
References………………………………………………...…………………………….119
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