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

Claiborne, Daniel (2014)

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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

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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