New Insight into Host and Viral Factors that Influence HIV-1 Pathogenesis 公开

Claiborne, Daniel (2014)

Permanent URL: https://etd.library.emory.edu/concern/etds/nv935376j?locale=zh
Published

Abstract

Human immunodeficiency virus type-1 (HIV-1), the etiologic agent of acquired immunodeficiency syndrome (AIDS), was responsible for 1.6 million deaths in 2012, and there are over 35 million people worldwide currently living with HIV. HIV is a life-long, chronic viral infection characterized by a steady decline in CD4+ T cells resulting in a state of overt immunodeficiency. Despite the fact that a majority of HIV-1 infected individuals eventually progress to AIDS, they do so at varying rates, implying that host or viral factors may alter the trajectory of disease. Here, we study acute HIV-1 infection in a cohort of Zambian volunteers in order to define the complex interplay between transmitted viral characteristics and the host immune response and their influence on HIV-1 pathogenesis.

Here, we demonstrate that viral replicative capacity (vRC), as defined by the viral Gag protein, has a dramatic impact on HIV-1 disease progression, in that high vRC is associated with elevated plasma viral loads and accelerated loss of CD4+ T cells. Furthermore, we demonstrate that vRC drives multiple facets of HIV-1 immunopathology. High vRC initiates an exacerbated inflammatory state characterized by increased levels of inflammatory cytokines, aberrant T cell activation phenotypes, and increased infection of central memory CD4+ T cells.

Events dictated by vRC can be further modulated by the host's cellular immune response. In this same cohort we identify novel immunogenetic factors associated with significant protection from CD4+ T cell decline. Interestingly, these alleles exert a protective effect without significantly controlling plasma viral load, suggesting an alternate mechanism. Indeed, we find that in the earliest stages of infection, these protective immunogenetic factors are associated with reduced markers of gut damage and microbial translocation, which are known to contribute to chronic immune activation in HIV infection.

These data expand our current knowledge of the viral and host characteristics that influence the trajectory of HIV-1 pathogenesis and specifically highlight the importance of early events post transmission, which dramatically impact the course of disease. Furthermore, these results suggest that vaccine-induced immune responses or interventional therapeutics capable of attenuating early viral replication may have a significant, long-term benefit for the host.

Table of Contents

Table of Contents
Abstract
Dedication
Acknowledgements
Chapter I: Introduction ................................................................................................................. 1
The identification of HIV as the cause of AIDS and the state of the current pandemic ........... 1
Origins of HIV .................................................................................................................................... 3
Viral characteristics underlying HIV persistence ........................................................................... 5
Pathogenic mechanisms of HIV-1 infection ................................................................................. 14
Factors that influence the trajectory of HIV pathogenesis .......................................................... 19
Summary ........................................................................................................................................... 28
Chapter II: Role of transmitted Gag CTL polymorphisms in defining replicative capacity
and early HIV-1 pathogenesis ................................................................................................... 31
Table 1. Cohort statistics generated from the 149 transmission pairs selected from the
ZEHRP cohort .................................................................................................................................. 70
Figure 1. Insertion of the gag gene from newly infected individuals dramatically alters the
replicative capacity of MJ4 ............................................................................................................... 71
Figure 2. Replicative capacity is correlated to viral load in recipients and donors .................. 72
Figure 3. Identification of polymorphisms in Gag that significantly affect RC, several of
which can be linked to HLA-class I alleles ..................................................................................... 73
Figure 4. Rare polymorphisms have a significantly greater impact on RC ............................... 75
Figure 5. The balance of fitness increasing and decreasing HLA-associated polymorphisms
strongly correlates with RC .............................................................................................................. 76
Figure 6. The balance of HLA-associated fitness increasing and decreasing mutations
strongly correlates with set point viral load in newly infected individuals ............................... 77
Figure 7. RC affects the rate of CD4 decline in a manner that may be independent of viral
load ..................................................................................................................................................... 79
Table 2. Cox proportional hazard models demonstrate the independent effects of RC and VL
on CD4 decline ................................................................................................................................. 81
Figure S1. Donor and recipient population gag sequences cluster with one another ............. 82
Table S1. Amino acids in Gag associated with changes in replicative capacity ........................ 84
Figure S2. Gag sequences that are less like the Gag subtype C consensus sequence replicate
more efficiently in vitro .................................................................................................................... 86
Chapter III: Transmitted HIV-1 replicative capacity drives immune activation and CD4
proviral load ............................................................................................................................... 100
Figure 1. HIV-1 replicative capacity, when defined by the transmitted gag sequence, predicts
CD4 T cell decline in ART-naïve, HIV-1 infected individuals ................................................. 128
Figure 2. Low vRC is associated with a distinct cytokine profile early in infection,
characterized by muted inflammatory cytokine levels ............................................................... 129
Figure 3. High vRC is associated with increased CD8 T cell activation and lower cytotoxic
potential ........................................................................................................................................... 131
Figure 4. vRC is associated with increased cellular activation and proliferation in CD4 T cell
memory subsets ............................................................................................................................... 133
Figure 5. Inflammatory cytokine profiles associated with vRC correlate with T cell activation
........................................................................................................................................................... 135
Figure 6. Viral RC correlates with the burden of HIV-1 viral DNA in CD4+ TCM and TN ... 137
Figure S1. The gag gene chimera is representative of full-length HIV-1. ................................ 139
Figure S2. The effect of log10-increases in early set point VL on longitudinal CD4+ T cell
decline .............................................................................................................................................. 140
Figure S3. The first two principal components are significantly correlated with vRC and set
point VL, respectively ..................................................................................................................... 141
Figure S4. CD8+ T cell activation phenotypes early after infection are associated with CD4+
T cell decline ................................................................................................................................... 142
Figure S5. High vRC is associated with an increased level of activation and turnover in
CD4+ T cells that is highly deleterious ......................................................................................... 144
Table S1. Host and viral characteristics independently predict CD4+ T cell decline ............ 145
Table S2. High vRC significantly increases early inflammatory cytokine levels .................... 146
Chapter IV: Protective immunogenetic factors reduce microbial translocation in acute
HIV infection ............................................................................................................................. 156
Table 1. Immunogenetic factors significantly affecting CD4+ T cell decline or longitudinal
control of plasma viral load in HIV-1 subtype C infection ....................................................... 171
Figure 1. Protective HLA-I alleles are associated with reduced plasma lipopolysaccharide
(LPS) levels at seroconversion ....................................................................................................... 173
Figure 2. Protective HLA-I alleles are associated with reduced plasma LPS, sCD14, I-FABP,
and IL-10 at 6-months post seroconversion ................................................................................ 174
Figure 3. Circulating plasma LPS at seroconversion predicts CD4+ T cell decline and time to
initiation of ARV treatment ........................................................................................................... 176
Table 2. Prevention of early microbial translocation is a common mechanism among
protective host and viral characteristics. ...................................................................................... 178
Figure S1. Protective and deleterious HLA alleles are additive in nature represent distinct
pathogenesis profiles ....................................................................................................................... 179
Table S1. Protective HLA alleles predict CD4+ T cell decline in manner distinct from set
point VL ........................................................................................................................................... 180
Figure S2. Accounting for batch effects further improves the association between protective
HLA-I alleles and low levels of LPS at seroconversion .............................................................. 181
Table S2. Detectable LPS in the plasma at seroconversion drives CD4+ T decline via a
mechanism distinct from set point VL ......................................................................................... 182
Table S3. In a multivariable generalized linear model, total LPS levels are significantly
reduced by protective host and viral factors ................................................................................ 183
Chapter V: Discussion ............................................................................................................... 198
The impact and implications of heritable viral characteristics on HIV-1 pathogenesis ...... 198
Unique mechanisms of HLA-mediated protection ................................................................... 202
The complex nature of sex-based differences in the immune response to HIV infection .... 204
In Conclusion ................................................................................................................................. 207
Literature Cited in Chapters I (Introduction) and V (Discussion) .......................................... 210
Appendix .................................................................................................................................... 231
Figure 1. Females exhibit lower viral loads and higher CD4+ T cells counts in the first 2
years of HIV infection .................................................................................................................... 231
Figure 2. Females present with reduced cellular immune activation early in infection, even
when controlling for the effects of plasma viral load ................................................................. 232
Figure 3. Acute HIV infection in females is characterized by a distinct inflammatory
cytokine profile ............................................................................................................................... 233
Figure 4. Transmitted viruses in females exhibit differential reversion kinetics in comparison
to viruses transmitted to males ...................................................................................................... 234

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